Abstract
Natural products have made significant contribution to cancer chemotherapy over the past decades and remain an indispensable source of molecular and mechanistic diversity for anticancer drug discovery. More often than not, natural products may serve as leads for further drug development rather than as effective anticancer drugs by themselves. Generally, optimization of natural leads into anticancer drugs or drug candidates should not only address drug efficacy, but also improve ADMET profiles and chemical accessibility associated with the natural leads. Optimization strategies involve direct chemical manipulation of functional groups, structure-activity relationship-directed optimization and pharmacophore-oriented molecular design based on the natural templates. Both fundamental medicinal chemistry principles (e.g., bio-isosterism) and state-of-the-art computer-aided drug design techniques (e.g., structure-based design) can be applied to facilitate optimization efforts. In this review, the strategies to optimize natural leads to anticancer drugs or drug candidates are illustrated with examples and described according to their purposes. Furthermore, successful case studies on lead optimization of bioactive compounds performed in the Natural Products Research Laboratories at UNC are highlighted.
Keywords: Natural products, Lead optimization, Anticancer Drugs
1 Introduction
Historically, natural products have played a crucial role in human’s combat against diseases and have been a predominant source of early medicines.1,2 With the advance of alternative drug discovery technologies, such as rational drug design, combinatorial chemistry, and high-throughput screening, natural products remain an essential element in modern drug discovery. As an indispensable source for lead generation and drug discovery, natural products have provided molecular diversity and structural novelty inaccessible by other means. The differences between the molecular properties of natural products and synthetic compounds were first investigated by Henkel et al, 3 and natural products were found to be significantly different from synthetic compounds. As compared to synthetic compounds, natural products generally have higher molecular weights, fewer nitrogen, halogen, or sulfur atoms, more oxygen atoms, and more sp3-hybridized or bridgehead atoms. In addition, natural products typically have more rings and more chiral centers in their structures. Since this initial report, chemoinformatic methods have been regularly applied to analyze the molecular properties of natural products, synthetic compounds (especially those from combinatorial chemistry), and drug molecules. 4–7 The unique distribution of natural products in the chemical space was evident from these studies, and it has been gradually realized that natural products generally exhibit higher structural diversity and greater biological relevance than synthetic compounds. 4
In recent years, many excellent review articles have highlighted the significant contributions of natural products to drug discovery. 8–13 A series of reports 14–17 emphasized the great impact of natural products on the discovery of new chemical entities (NCSs) by full analysis of the sources of all approved therapeutic agents. During the time frame from 1981 to 2010, 17 when all the approved small-molecule drugs categorized as NCEs are considered, only 36% are synthetic molecules, while the others are all originated from natural products (Table 1). 17 Although natural products play a critical role in the drug discovery of virtually all therapeutic areas, 18–20 they are particularly important for lead identification and drug discovery in oncology. As indicated in Table 1, the percentage of natural product-based molecules in anticancer drugs are significantly higher than in average drugs (79.8% for anticancer drugs approved in 1981–2010 and 74.9% for all the anticancer drugs approved worldwide). 17 The impressive role of natural products in the therapeutic area of oncology was extensively reviewed both in general 21–24 and for specific subcategories in the recent years. 25–30 In addition, two monographs have carefully elaborated the discovery and development of representative anticancer agents from natural products. 31, 32
Table 1.
Source of approved small-molecule drugs categorized as NCEs
| All drugs, 1981–2010 | Anticancer drugs, 1981–2010 | All anticancer drugs | |
|---|---|---|---|
| N | 5.5% (59)# | 11.1% (11) | 15.4% (27) |
| ND | 27.9% (299) | 32.3% (32) | 32.6% (57) |
| NB | 0.5% (5) | 1.0% (1) | 0.6% (1) |
| S* | 5.1% (55) | 11.1% (11) | 11.4% (20) |
| S*/NM | 11.4% (122) | 8.1% (8) | 4.6% (8) |
| S | 36.0% (387) | 20.2% (20) | 25.1% (44) |
| S/NM | 13.6% (146) | 16.2% (16) | 10.3% (18) |
| Total | 100.0% (1073) | 100.0% (99) | 100.0% (175) |
percentage (number)
“N”: Natural product; “ND”: Derived from a natural product; “NB” Natural product “botanical” ;“S*”: Synthetic drug with a pharmacophore from a natural product; “NM”: Natural product mimic; “S”: Totally synthetic drug. For detailed definition of the categories, please refer to reference 17.
Furthermore, the importance of natural products in anticancer drug discovery could go beyond molecular diversity and structural novelty. The discovery of novel natural structures with significant biological relevance and the recognition of new mechanism of action thereby could pioneer innovative research fields. The potent anticancer agent paclitaxel (1) is an excellent example. The discovery of paclitaxel and, in particular, its novel mechanisms of action featured by tubulin-assembly promotion was a milestone and initialized a new era in anticancer drug discovery. 33, 34
It is worth to note that natural products are a major source of mechanistic diversity for both cytotoxic chemotherapy and molecular targeted cancer therapy. Phenotypic screening has identified numerous natural products as anticancer agents and significantly expanded the molecular diversity of anticancer drugs in the early days. With the recent advances of molecular pharmacology in cancer research, a vast diversity of molecular targets have emerged as potential intervention points to achieve specific therapeutic consequences. 35 Strikingly, target-focused approaches have revealed that natural products have great influences on many of these molecular processes and targets. As illustrated in the review by Cragg et al., 23 natural products are reported to interfere various molecular targets involved in the cell cycle and natural product-based anticancer drugs have been discovered as therapeutic agents with diverse mechanisms. The underlying molecular targets of these anticancer drugs include but not limit to tubulin, topoisomerases I and II, histone deacetylases, protein kinases, heat shock protein 90 and proteasome. These observations indicate that natural products are still a vital reservoir of molecular and mechanistic diversity for anticancer drug discovery.
2 Strategies for natural lead optimization
Although natural products have historically been a critical source for therapeutic drugs, sometimes natural molecules may suffer from insufficient efficacy, unacceptable pharmacokinetic properties, undesirable toxicity, or poor availability, which impede their direct therapeutic application. As demonstrated by data in Table 1, for all the natural product-based drugs, only a small portion are natural products per se, and the majority of these drugs are either natural product derivatives or synthetic molecules inspired by the structure or pharmacophore of natural products. Therefore, natural products often serve as lead templates and are subjected to structural optimization to generate clinically useful structures.
In general, the optimization of natural lead structures may involve efforts on three different purposes: to enhance drug efficacy, to optimize absorption, distribution, metabolism, excretion and toxicity (ADMET) profiles and to improve chemical accessibility. Traditionally, most structural optimization efforts are devoted to increasing efficacy. These efforts can often be assisted by the application of either classic medicinal chemistry principles or modern rational drug design techniques. In recent years, it has been gradually acknowledged that poor pharmacokinetic profiles and unacceptable toxicity might be the major reasons for attritions in drug development. Therefore, optimization of ADME properties and reduction of toxicity should also be carefully considered in the lead optimization stage. For natural products, it is even more important to optimize their ADME profiles, since their structural complexity might confer unfavorable effects on their pharmacokinetic properties, such as solubility, cellular permeability, and chemical or metabolic stability. The last aspect, but probably the most practical aspect, is to improve the chemical accessibility of natural leads during structural optimization. The development of natural products into therapeutic drugs is often hampered by limited availability and synthetic intractability. Efforts to improve the chemical accessibility of natural products via rational drug design may overcome this bottleneck and eventually lead to the therapeutic application of natural product-based drugs.
Chemically, strategies for natural lead optimization can be subdivided into three progressive levels. The most straightforward approach is direct chemical manipulation of functional groups. In this approach, the natural structure can be modified by derivation or substitution of the functional groups, alteration of the ring systems, and isosteric replacement. These efforts are mainly empirical and intuition-guided, especially in the phenotypic approach. Structure-based design could assist the optimization efforts in the target-focused approach, if the structure of the biomacromolecule is available. The second approach for natural lead optimization involves the initial establishment of structure-activity relationships (SAR) and subsequent SAR-directed optimization. This approach is usually applied to natural leads with significant biological relevance, which attract extensive modification efforts. With the accumulation of chemical and biological information obtained from the first approach, meaningful SAR can be established to ensure more rational optimization of the natural leads. As indicated in Table 1, derivatives of natural products (categorized as “ND”) resulted from the afore-mentioned two approaches account for about one third of the small-molecule anticancer drugs. It is worth to note that since the basic structural cores of the natural products are generally not altered in these two approaches, therefore they mainly address efficacy and ADMET issues, while seldomly impose amelioration on the chemical accessibility of natural molecules. The last resort for natural lead optimization is pharmacophore-oriented molecular design based on the natural templates. The core structures of the natural products might be changed significantly and modern rational drug design techniques (e.g., structure-based design and scaffold hopping) can be applied to expedite the optimization efforts. SAR clues acquired in the SAR-directed approach can also facilitate the recognition of pharmacophores. This approach often intends to solve the problems associated with the chemical accessibility of the natural leads as well as to generate novel leads with intellectual properties.
In this review, we will discuss the strategies for the optimization of natural leads to anticancer drugs or drug candidates with case studies. The discussion are arranged according to the optimization purpose for natural leads. Namely, the optimization efforts to enhance drug efficacy, optimize ADMET profiles and improve chemical accessibility will be described successively. Obviously, the purposes for the structural optimization may not be exclusive, and multi-facet improvement could be achieved simultaneously by a single structural alteration. Under such circumstances, we will categorize it according to the “main” purpose. Furthermore, the major concerns in optimization strategies vary with the different purpose involved. For example, if the drug efficacy is considered, strategies to enhance molecular interactions between the small-molecule and a specific molecular target are emphasized. When the ADME profile is aimed, strategies to modulate the physicochemical properties of the small-molecules are prioritized. While if chemical accessibility is targeted, strategies to simplify the complex natural templates are underscored. However, no matter what the purpose is, the chemical operations exploited in the optimization strategies are the same, which basically march from the empirical modification of the functional groups to the more rational SAR-directed optimization and eventually to the pharmacophore-oriented molecular design. To avoid redundancy, we will only elaborate the operations of these three progressive chemical strategies in the section on the optimization of drug efficacy. While, for the other two sections, we will only highlight the effects of structural alterations on ADMET profiles and chemical accessibility respectively. Our discussion will by no means be exhaustive; however, the main optimization strategies will be exemplified with case studies resulted in NCEs for either clinical uses or clinical trials. For the readers’ reference, brief information on the clinical and investigational drugs mentioned in this review is provided in Tables 2 and 3. Furthermore, successfully examples developed in the Natural Products Research Laboratories at UNC, which have led to the development of clinical candidates, are also highlighted herein.
Table 2.
Clinical anticancer drugs optimized from natural leads
| Clinical drug | Lead compound | Year first introduced * | Section cited |
|---|---|---|---|
| fluorouracil (2) | uracil | 1962 | 3.1.1 |
| mercaptopurine (3) | hypoxanthine | 1955 | 3.1.1 |
| thioguanine (4) | guanine | 1966 | 3.1.1 |
| cytarabine (5) | deoxycytidine | 1969 | 3.1.1 |
| decitabine (6) | deoxycytidine | 2006 | 3.1.1 |
| cladribine (7) | adenosine | 1993 | 3.1.1 |
| clofarabine (8) | adenosine | 2005 | 3.1.1 |
| methotrexate (9) | folic acid (78) | 1954 | 3.1.1 |
| calusterone (10) | testosterone | 1973 # | 3.1.1 |
| fluoxymesterone (11) | testosterone | pre-1970 # | 3.1.1 |
| ixabepilone (13) | epothilone B (12) | 2007 | 3.1.1 |
| temsirolimus (17) | rapamycin (16) | 2004 | 3.1.1 |
| everolimus (18) | rapamycin (16) | 2009 | 3.1.1 |
| ridaforolimus (19) | rapamycin (16) | 2005 | 3.1.1 |
| midostaurin (21) | staurosporine (20) | 2004 | 3.1.1 |
| flavopiridol (24) | rohitukine (25) | 2007 | 3.1.1 |
| lestaurtinib (27) | K-252a (26) | 2006 | 3.1.1 |
| triphendiol (30) | daidzein (28) | 2008 | 3.1.1 |
| irofulven (32) | illudin S (31) | 1999 | 3.1.1 |
| obatoclax (40) | streptorubin B (38) | 2004 | 3.1.1 |
| vindesine (48) | vinblastine (47) | 1979 | 3.1.1 |
| vinorelbine (49) | vinblastine (47) | 1989 | 3.1.1 |
| vinflunine (50) | vinblastine (47) | 2010 | 3.1.1 |
| epirubicin (53) | doxorubicin (51) | 1984 | 3.1.1 |
| pirarubicin (54) | doxorubicin (51) | 1988 | 3.1.1 |
| valrubicin (55) | doxorubicin (51) | 1994 | 3.1.1 |
| idarubicin (56) | daunorubicin (52) | 1990 | 3.1.1 |
| etoposide (58) | podophyllotoxin (57) | 1980 | 3.1.1 |
| teniposide (59) | podophyllotoxin (57) | 1967 | 3.1.1 |
| sabarubicin (61) | doxorubicin (51) | 2004 | 3.1.1 |
| nemorubicin (62) | doxorubicin (51) | 2005 | 3.1.1 |
| docetaxel (65) | paclitaxel (1) | 1995 | 3.1.2 |
| cabazitaxel (66) | paclitaxel (1) | 2010 | 3.1.2 |
| pralatrexate (79) | folic acid (78) | 2006 | 3.1.3 |
| raltitrexed (80) | folic acid (78) | 1996 | 3.1.3 |
| pemetrexed (81) | folic acid (78) | 2004 | 3.1.3 |
| octreotide (83) | somatostatin (82) | 1988 | 3.1.3 |
| lanreotide (84) | somatostatin (82) | 1994 | 3.1.3 |
| vorinostat (86) | trichostatin A (85) | 2006 | 3.1.3 |
| belinostat (89) | trichostatin A (85) | 2014 | 3.1.3 |
| estramustine (96) | estradiol | 1980 | 3.1.3 |
| topotecan (101) | camptothecin (100) | 1996 | 3.2.1 |
| belotecan (102) | camptothecin (100) | 2004 | 3.2.1 |
| carfilzomib (108) | epoxomicin (106) | 2012 | 3.2.1 |
| tanespimycin (110) | geldanamycin (109) | 2004 | 3.2.1 |
| becatecarin (115) | rebeccamycin (114) | 2004 | 3.2.1 |
| elliptinium (117) | ellipticine (116) | 1983 | 3.2.1 |
| berubicin (127) | doxorubicin (51) | 1995 | 3.2.2 |
| tamibarotene (129) | all-trans-retinoic acid (128) | 2005 | 3.2.3 |
| bexarotene (131) | 9-cis-retinoic acid (130) | 2000 | 3.2.3 |
| mifamurtide (134) | muramyl dipeptide (135) | 2010 | 3.2.3 |
| irinotecan (138) | camptothecin (100) | 1994 | 3.2.5 |
| combretastatin A-1 | combretastatin A-1 | 2012 | 3.2.5 |
| diphosphate (145) | |||
| etopophos (148) | podophyllotoxin (57) | 1996 | 3.2.5 |
| estramustine phosphate (150) | estradiol | 1980 | 3.2.5 |
| abiraterone (152) acetate | abiraterone (152) | 2011 | 3.2.5 |
| doxifluridine (153) | fluorouracil (2) | 1987 | 3.2.5 |
| capecitabine (154) | fluorouracil (2) | 1998 | 3.2.5 |
| eribulin (157) mesylate | halichondrin B (158) | 2010 | 3.3.1 |
| enzastaurin (165) | staurosporine (20) | 2005 | 3.3.2 |
Data from Thomson Reuters Integrity. It indicates the year, in which the drug was first introduced as a clinical anticancer drug.
Information from reference 17.
Table 3.
Investigational anticancer drugs optimized from natural leads
| Investigational drug | Lead compound | Mechanism of action | Highest Phase * | Current status * | Section cited |
|---|---|---|---|---|---|
| HTI-286 (15) | hemiasterlin (14) | tubulin polymerization inhibitor | I | no active development | 3.1.1 |
| (R)-roscovitine (23) | olomoucine (22) | CDK inhibitor | II | under active development | 3.1.1 |
| phenoxodiol (29) | daidzein (28) | BIRC4 expression inhibitor tumor NADH oxidase (tNOX) inhibitor sphingosine kinase inhibitor | III | no active development | 3.1.1 |
| beloranib (34) | fumagillin (33) | methionine aminopeptidase-2 (MetAP2) inhibitor | I | no active development | 3.1.1 |
| PPI-2458 (35) | fumagillin (33) | methionine aminopeptidase-2 (MetAP2) inhibitor | I | no active development | 3.1.1 |
| diacetate S23906-1 (37) | acronycine (36) | DNA alkylating drug | -$ | discontinued | 3.1.1 |
| vadimezan (42) | flavone-8-acetic acid (41) | vascular disrupting agent | III | discontinued | 3.1.1 |
| KOS-1584 (44) | epothilone D (43) | microtubule-stabilizing agent | II | no active development | 3.1.1 |
| plinabulin (46) | (−)-Phenylahistin (45) | tubulin polymerization inhibitor | II | no active development | 3.1.1 |
| tafluposide (60) | podophyllotoxin (57) | DNA topoisomerase I & II Inhibitor | I | no active development | 3.1.1 |
| terameprocol (64) | meso-nordihydroguaiaretic acid (63) | tat inhibitor; antimitotic drug | II | no active development | 3.1.1 |
| iso-fludelone (68) | epothilone D (43) | microtubule-stabilizing agent | I | under active development# | 3.1.2 |
| BMS-310705 (69) | epothilone B (12) | microtubule-stabilizing agent | I | no active development | 3.1.2 |
| ABJ879 (70) | epothilone B (12) | microtubule-stabilizing agent | I | discontinued | 3.1.2 |
| sagopilone (71) | epothilone B (12) | microtubule-stabilizing agent | II | under active development | 3.1.2 |
| soblidotin (74) | dolastatin 10 (72) | tubulin polymerization inhibitor | II | no active development | 3.1.2 |
| cematodin (75) | dolastatin 15 (73) | tubulin polymerization inhibitor | - | discontinued | 3.1.2 |
| synthadotin (76) | dolastatin 15 (73) | tubulin polymerization inhibitor | I | discontinued | 3.1.2 |
| dacinostat ( 87) | trichostatin A (85) | histone deacetylase (HDAC) inhibitor | - | discontinued | 3.1.3 |
| panobinostat (88) | trichostatin A (85) | histone deacetylase (HDAC) inhibitor | III | under active development | 3.1.3 |
| givinostat (90) | trichostatin A (85) | histone deacetylase (HDAC) inhibitor | II | under active development | 3.1.3 |
| abexinostat (91) | trichostatin A (85) | histone deacetylase (HDAC) inhibitor | II | under active development | 3.1.3 |
| quisinostat (92) | trichostatin A (85) | histone deacetylase 1 (HDAC 1) inhibitor | II | under active development | 3.1.3 |
| entinostat (93) | trichostatin A (85) | histone deacetylase (HDAC) inhibitor | III | under active development | 3.1.3 |
| mocetinostat (94) | trichostatin A (85) | histone deacetylase (HDAC) inhibitor | II | under active development | 3.1.3 |
| tallimustine (98) | distamycin A (97) | DNA-damaging drug | II | no active development | 3.1.3 |
| brostallicin (99) | distamycin A (97) | apoptosis inducers | II | under active development | 3.1.3 |
| exatecan (103) | camptothecin (100) | DNA topoisomerase I inhibitor | III | no active development | 3.2.1 |
| lurtotecan (104) | camptothecin (100) | DNA topoisomerase I inhibitor | II | no active development | 3.2.1 |
| namitecan (105) | camptothecin (100) | DNA topoisomerase I inhibitor | I | under active development | 3.2.1 |
| alvespimycin (111) | geldanamycin (109) | heat shock protein 90 (Hap90) inhibitor | II | discontinued | 3.2.1 |
| retaspimycin (112) | geldanamycin (109) reblastatin (113) |
heat shock protein 90 (Hap90) inhibitor | II | discontinued | 3.2.1 |
| datelliptium (118) | ellipticine (116) | DNA-intercalating drug DNA topoisomerase II inhibitor |
III | no active development | 3.2.1 |
| retelliptine (119) | ellipticine (116) | DNA-intercalating drug DNA topoisomerase II inhibitor |
II | no active development | 3.2.1 |
| meisoindigo (121) | indirubin (120) | signal transduction modulator STAT-3 inhibitor |
II | under active development | 3.2.1 |
| SDZ-LAP-977 (125) | lavendustin A (122) | tyrosine kinase inhibitor | II | no active development | 3.2.2 |
| SDZ-LAV-694 (126) | lavendustin A (122) | antimitotic drug | I | under active development | 3.2.2 |
| diflomotecan (132) | camptothecin (100) | DNA topoisomerase I inhibitor | II | under active development | 3.2.3 |
| elomotecan (133) | camptothecin (100) | DNA topoisomerases I & II inhibitor | I | under active development | 3.2.3 |
| β-lapachone (137) | β-lapachol (136) | - | II | no active development | 3.2.4 |
| omtriptolide (141) | triptolide (140) | - | I | under active development | 3.2.5 |
| minnelide (142) | triptolide (140) | heat shock protein 70 inhibitor angiogenesis inhibitor |
I | under active development | 3.2.5 |
| combretastatin A-4 phosphate (144) | combretastatin A-4 (143) | vascular disrupting agent | III | under active development | 3.2.5 |
| ombrabulin (146) | combretastatin A-4 (143) | vascular disrupting agent | III | discontinued | 3.2.5 |
| F14512 (149) | podophyllotoxin (57) | DNA topoisomerase II inhibitor | I | under active development | 3.2.5 |
| zalypsis (163) | trabectedin (160) | - | II | under active development | 3.3.1 |
Data from Thomson Reuters Integrity (updated by September 2014).
Data from clinicaltrials.gov
-$Information unavailable
3 Development of anticancer drugs or drug candidates from natural leads
Due to their great contribution to anticancer drug discovery, natural products have been extensively investigated as potential anticancer agents in both phenotypic and target-focused approaches. Although numorous natural leads with significant biological activity have been identified, most of them are unsuitable for direct therapeutic application and structural optimization are required. In this section, we will discuss the optimization strategies to develop anticancer drugs or drug candidates from natural leads, and case studies with various optimization purposes will be covered.
3.1 Optimization of drug efficacy
The optimization of drug efficacy is conventionally the major goal for structural modification of bioactive natural products. As afore-mentioned, three different levels of chemical modification are involved in the optimization of drug efficacy. In this section, we will illustrate the effects of individual optimization approaches on the improvement of drug efficacy. However, it is worthwhile to point out that since structural alteration could lead to multi-dimentional optimization, discussion in this section may go beyond the purpose of optimizing drug efficacy.
3.1.1 Chemical manipulation of functional groups
The most straightforward approach to improve the efficacy of natural products is through appropriate chemical manipulation of the functional groups. The basic underlying principle is that similar structures will present similar biological activity. In fact, early anticancer drugs classified as antimetabolites are usually generated by mimicking endogenous metabolites. The nucleotide and nucleoside analogues are particularly indicative. Fluorouracil or 5-FU (2) 36 is a pyrimidine analog, in which a hydrogen atom in uracil is replaced by a fluoro atom through the isosterism strategy. 5-FU irreversibly inhibits thymidylate synthase and is used in the treatment of cancer. Similarly, mercaptopurine (3) 37 and thioguanine (4) 38 were developed from hypoxanthine and guanine, respectively, through the isosterism strategy. Nucleoside mimetics can contain structural modification on either base or sugar component of the natural nucleosides. Substitution of the deoxyribose in deoxycytidine by an arabinose sugar produced cytarabine (5), 39 a chemotherapy agent mainly for treating acute myeloid leukemia (AML) and non-Hodgkin lymphoma. In contrast, decitabine (6), 40 in which the cytosine in deoxycytidine is changed to 5-aza-cytosine, is a drug for the treatment of myelodysplastic syndromes and AML. Cladribine (7) 41 is used to treat hairy cell leukemia (HCL) and multiple sclerosis. It contains structural alterations in both base and sugar moieties of the adenosine, and inhibits adenosine deaminase. Clofarabine (8) 42,43 is modified from cladribine via isosteric replacement, which makes it more stable in acidic solution and more resistant to phosphorolytic cleavage. Other endogenous substances, such as folic acid and steroids, have also served as key prototypes for early cancer chemotherapeutics. Methotrexate (9) 44, a folate analog, inhibits the metabolism of folic acid and is an effective chemotherapy against a variety of cancers. Calusterone (10) 45 and fluoxymesterone (11) 46 are testosterone analogs known as anabolic steroids, and are used for the treatment of cancers.
Besides endogenous “natural products”, the optimization of exogenous natural leads also involves various chemical manipulations of functional groups in the lead structures. Generally, extra chemical moieties could be grafted to the original natural structure to produce additional interaction with the macromolecule target and enhance the efficacy. Derivation, substitution as well as other modification of the functional groups is a straightforward approach to make the prototype molecules fit the binding sites better. Isosterism is another approach to optimize efficacy, although this strategy could also be used to improve metabolic stability of natural molecules (cf. Section 3.2.3).
As a classic medicinal chemistry principle, bioisosterism is often the first resort for structural optimization. Epothilone B (12) is a natural microtubule−stabilizing agent isolated from Sorangium cellulosum. This compound and related epothilones exhibit a mode of action similar to that of paclitaxel, which kindled extensive research interest. 47 Ixabepilone (13) was developed from 12 by changing the ester oxygen atom to a nitrogen atom. This isosteric replacement made 13 more resistant to esterases than 12. Ixabepilone was the most effective epothilone in vitro and in vivo, 48,49 and it was approved by the US Food and Drug Administration (FDA) in 2007 for the treatment of metastatic or locally advanced breast cancer. Similarly, hemiasterlin (14), a tripeptide of marine origin, was reported to be active against murine leukemia cells, 50 and was later identified as an anti-microtubule agent. 51 In the synthetic efforts to prepare 14 and its analogs, one analog, HTI-286 (15), 52 has been found to be more potent and more synthetically accessible than 14. The phenyl ring could be considered as a bioisostere of the 1-methylindole moiety. Compound 15 entered clinical trials as an oncolytic drug in 2005; however, no further results have been reported after the completion of phase I trial.
Derivation of functional groups in natural molecules is also a common strategy to improve pharmacological efficacy. Sirolimus (16), 53 also known as rapamycin, is a natural macrolide used as an immunosuppressant drug for preventing rejection in organ transplantation. Similar to the case of paclitaxel, the discovery of rapamycin also led to the disclosure of a novel mechanism of action, mTOR inhibition, and therefore pioneered a new era in drug discovery. As a prototype structure for mTOR inhibitors, rapamycin was later recognized for its anticancer activity. However, the therapeutic application of 16 for the treatment of cancer was hindered by its low aqueous solubility and poor chemical stability. To provide better solutions for cancer therapy, novel analogs of 16 were developed by taking advantage of a hydroxyl group in the structure. Temsirolimus (17) 54,55 is an ester derivative of 16. It is a prodrug (cf. Section 3.2.5) of 16 and the first mTOR inhibitor approved for cancer therapy. Everolimus (18), 56 an ether derivative of 16, was used as an immunosuppressant and cancer therapy for advanced renal carcinoma. As compared to 16, 18 showed greater solubility and better pharmacokinetic profile, it was thereby marketed as an oral anticancer drug. Ridaforolimus (19, formerly known as deforolimus), a phosphinate of 16, is an mTOR inhibitor approved as an orphan drug in 2005 for the treatment of bone sarcoma. 57 It is a non-prodrug analog of 16 with favorable pharmacokinetic properties. Staurosporine (20) is a bis-indole alkaloid originally isolated from the bacterium Streptomyces staurosporeus. 58 It was later recognized as an ATP-competitive protein kinase inhibitor with strong affinity for many kinases. 59 Midostaurin (21, PKC412), a N-benzoyl derivative of 20, (PKC412) is a multi-target protein kinase inhibitor and has been approved as an orphan drug for the treatment of acute myeloid leukemia (AML). 60
Addition or alteration of functional groups in natural molecules may enhance the interaction with macromolecule targets and increase potency. The efficiency of this strategy was illustrated by the discovery and development of purine derivartives as cyclin-dependent kinase (CDK) inhibitors. 61 The plant hormone isopentenyladenine and another purine derivative, 6-dimethylaminopurine, were first identified as weak inhibitors of CDK1/cyclin B, which led to extensive medicinal efforts to improve their potency. 61 Olomoucine (22) was then identified as a CDK inhibitor with a unique selectivity profile. However, its potency against CDKs was still relatively weak and the best IC50 values were only at micromolar level. 62 The potency was successfully improved by incorporating additional alkyl substitutions in the molecule, and (R)-roscovitine (23) was proven to be a potent CDK inhibitor and is currenly in clinical trials for the treatment of various cancers. 63 One further example of natural product-derived CDK inhibitors is flavopiridol (24). This semisynthetic flavonoid is derived from rohitukine (25), 64 a natural chromane alkaloid first isolated from an indigenous Indian plant in 1979. SAR studies on 25 resulted in the discovery of 24, which was identified as a potent CDK inhibitor with broad specificity. By changing the methyl group on the chromone skeleton to a bulkier ortho-chloro-benzene ring, flavopiridol fits better into the ATP binding site of CDKs than the parent structure and its potency was significantly enhanced. Favopiridol was later became the first CDK inhibitor to enter clinical trials, and it was also the first clinical drug targeting CDK. 65 K-252a (26) is an indolocarbazole structurally related to staurosporine (20). 66 It was isolated from microbial origin and identified as a potent inhibitor of protein kinase C. Lestaurtinib (27, also known as CEP-701) 67,68 is an analog of 26 with the methyl ester in 26 reduced to a hydroxymethyl group. This analog was reported to inhibit Fms-like tyrosine kinase 3 (FLT-3) among other kinases. It was approved as an orphan drug for the treatment of acute myeloid leukemia and Philadelphia-negative classic myeloproliferative diseases. As a natural product family with extensive biological activities, flavonoids have drawn intense research interests. The isoflavone daidzein (28) is a key component of food and dietary supplements derived from soy. Phenoxodiol (29) is a synthetic analog of 28, in which the 4H-chromen-4-one core in 28 was altered to 2H-chromene. Phenoxodiol exhibited significant antitumor activity. 69 Although its primary mode of action remains to be elucidated, 29 was investigated in clinical trials intensively. 70 Triphendiol (30) 71, 72 is another derivative of 29, which incorporates a p-methoxy phenyl substitution and has a 2H-chromene rather than chromane skeleton in the structure. Triphendiol has superior anticancer activity, especially against pancreatic and bile duct cancers, and it was approved for the treatment of several solid tumors in 2008. Illudin S (31) 73 is a sesquiterpene toxin found in mushrooms of the genus Omphalotus. It belongs to the sesquiterpene family of illudins, which are generally highly toxic and not applicable for clinical use in their natural form. SAR studies on illudins resulted in the discovery of irofulven (32), 74,75 an analog of 31, with improved therapeutic index. Irofulven is a DNA-alkylating agent with a unique mechanism of action. It interferes with DNA replication and targets malignant tumor cells, especially rapidly differentiating malignant cells. Irofulven was approved as a clinical drug for the treatment of renal cell carcinoma and ovarian cancer. Fumagillin (33) was originally isolated from the microbial organism Aspergillus fumigatus. It was later identified as a methionine aminopeptidase 2 (MetAP2) inhibitor, and therefore, 33 as well as its derivatives were investigated as angiogenesis inhibitors for the treatment of cancer. 76 Beloranib (34, CKD-732) 77,78 and PPI-2458 (35) 79,80 are semisynthetic derivatives of 33, in which the tetraenoic acid moiety in 33 is replaced. These compounds were designed as MetAP2 inhibitors and were tested for the clinical treatment of cancer. With the understanding on the biological relevance of MetAP2 advanced, 34 and 35 were later investigated for the treatment of rheumatoid arthritis and obesity. Beloranib was approved for the treatment of Prader-Willi syndrome in 2013.
Another structural optimization strategy is to modify the ring systems in natural molecules by adding, removing, or altering ring structures so as to make the molecules in better shape complementarity with their target macromolecules. Acronycine (36), an alkaloid isolated from Sarcomelicope simplicifolia, showed broad spectrum antitumor activity. 81 However, the clinical trials on 36 as cancer chemotherapy were discontinued due to insufficient response rate and undesirable toxicities. Subsequently, the structure of 36 was modified by grafting two esters at the C1 and C2 positions of the pyran ring and extending the molecule with an extra benzene ring. A series of diester benzo[b]acronycine derivatives were prepared and were found to be more potent than 36. Among them, the diacetate S23906-1 (37) 82 was identified as one of the most potent derivatives both in vitro and in vivo, and was investigated clinically for the treatment of cancer. Streptorubin B (38) and prodigiosin (39) are pyrrole alkaloids originated from bacteria. 83 Streptorubin B and its analogs were later revealed as small-molecule inhibitors of Bcl-2. 84,85 Extensive structural modification of 38 and 39 resulted in the discovery of obatoclax (40, GX15-070) 86,87 as a clinical drug for the treatment of chronic lymphocytic leukemia. As compared to 38, the pyrrole ring in 38 is replaced by an indole moiety in 40 and the fused cyclodecane ring in 38 is simplified to two methyl groups on the pyrrole ring. Obatoclax is a more potent Bcl-2 inhibitor than 38 and binds to the hydrophobic pocket of the BH3 domain. It was also investigated in clinical trials for the treatment of various types of cancer, but there are currently no active clinical development of this drug. As mentioned previously, natural flavonoids exhibit a wide range of biological properties. In a screening program initialized by the National Cancer Institute (NCI), flavone acetic acid ester was identified as a potent antitumor agent and tested in clinical trials. Flavone-8-acetic acid (41) was regarded as the active form of flavone acetic acid ester and possessed unique activity and toxicity profiles, which implicated a novel mechanism of action. 88 Although 41 may represent a new chemotype of anticancer drugs, it showed low potency in human. Structural modification and SAR study on 41 resulted in the discovery of vadimezan (42, ASA404), which has the flavone scaffold altered to xanthenone. 89,90 Vadimezan was found to be a tumor-vascular disrupting agent and was tested clinically for the treatment of various cancers. 91,92
Alteration of the saturation status of natural skeletons is another chemical strategy for natural lead optimization. The overall molecular conformation might be changed by either saturation or unsaturation of the skeleton. Epothilone D (43), a natural polyketide isolated from Sorangium cellulosum, is a desoxy analog of epothilone B (12). As revealed by the crystal structures as well as conformational analysis, the C8-C12 carbon backbone of 43 adopts a nearly anti-periplanar conformation. Accordingly, KOS-1584 (9,10-didehydroepothilone D, 44), a highly active trans olefin analog of 43 with an unsaturated C9-C10 bond, is assumed to resemble the active conformation of 43. Compound 44 is an investigational anticancer compound exhibiting improved potency and pharmacokinetic properties. 93,94 (−)-Phenylahistin (45) is a fungal 2,5-diketopiperazine isolated from Aspergillus ustus. 95 It is a microtubule binding agent cytotoxic against a number of tumor cells. 96 To optimize the biological activity of 45, various dehydrogenated analogs were synthesized and evaluated. Plinabulin (NPI-2358, 46) was discovered through these efforts. It is active against multidrug-resistant (MDR) tumor cell lines and entered clinical trials for the treatment of non-small cell lung cancer. 97,98
Frequently, multiple alterations of the prototype structure may be involved to finely tune the biological profiles of natural leads. Vinblastine (47) 99 is a natural drug from the family of vinca alkaloids and it is an anti-mitotic chemotherapy drug used for the treatment of various cancers, including Hodgkin's lymphoma, non-small cell lung cancer, breast cancer, head and neck cancer, and testicular cancer. Structural modifications of 47 have generated several new analogs with higher potency and less toxicity. Vindesine (48) 100,101 is one of the most impressive analogs. It only presents minor structural differences on the vindoline ring of 47, where the methyl ester is changed to an amide group and the acetyl group is removed. However, 48 is less neurotoxic and showed no cross-resistance with vincristine. Compound 48 is used to treat different types of cancer, including leukaemia, lymphoma, melanoma, breast cancer and lung cancer. Vinorelbine (49) 102, the first 5′-nor semi-synthetic vinca alkaloid, is another important analog of 47. The structural modifications in 49 include the transformation of the tryptamine moiety in 47 to gramine by reducing one carbon in the ring system and eliminating a water molecule to give a double bond in the piperidine ring. Vinorelbine exhibited better pharmacological and pharmacokinetic profiles. It is used to treat breast cancer and non-small cell lung cancer. Vinflunine (50) 103,104 is a novel 5′-nor vinca alkaloid with a gem-difluoro moiety. It showed superior in vivo preclinical antitumor activity and was investigated for the treatment of various solid tumors. It was approved as a clinical anticancer drug in UK in 2010 and is currently under active phase III clinical trials for the treatment of locally recurrent or metastatic Her-2 negative carcinoma of the breast in combination with capecitabine.
Doxorubicin (51) belongs to the family of anthracycline aminoglycosides. It was originally obtained by fermentation of Streptomyces strains and was isolated together with the major fermentation product daunorubicin (52). 105 The discovery of 51 and 52 provides an important chemotype for anticancer drugs. Doxorubicin is a topoisomerase II inhibitor used widely for cancer chemotherapy. However, problems of drug resistance and cardiotoxicity associated with 51 stimulated extensive structural modification. Such efforts revealed that minor structural changes in 51 could result in significant changes in biological effects, particularly the antitumor spectra and toxicity profiles. Several new anthracyclines with either altered aglycone or sugar moieties were discovered. Epirubicin (53) 106 is a diastereomer of 51, and it differs from 51 only in the chirality of the 4′ carbon. Epirubicin showed better therapeutic profiles than 51, and the minor change in stereochemistry resulted in faster elimination and, therefore, reduced toxicity. The efficacy of anthracyclines could be improved by increasing molecular lipophilicity and thereby facilitating cellular uptake. Pirarubicin (54) 107 is a 4′-O-tetrahydropyranyl derivative of 51. It interacts with topoisomerase II like the parent structure 51, but is less cardiotoxic and also exhibits activity against some 51-resistant cell lines. Valrubicin (55), 108 an N-trifluoroacetyl-14-valerate derivative of 51, is used to treat bladder cancer, and idarubicin (56) 109 is a 4-demethoxy derivative of 52 used against acute myelogenous leukemia. The structures of 54–56 are characterized by their higher lipophilicity, which is responsible for their increased potency and decreased cardiotoxicity.
Derivation of functional groups in a natural molecule may also cause a shift in the mechanism of action. The structural modification of the natural lignan podophyllotoxin (57) serves as a good example. Podophyllotoxin was originally discovered as a cytotoxic agent inhibiting the assembly of the mitotic spindle. 110 Although unacceptable side effects, particularly gastrointestinal toxicity, associated with 57 prevented its clinical use as cancer therapy, extensive structural modification efforts on this natural chemotype eventually led to the discovery of etoposide (58) and teniposide (59). 111,112 Interestingly, instead of inhibiting the assembly of microtubules, 58 and 59 exert their cytotoxicity by inducing DNA breaks mediated by topoisomerase II. The successful marketing of 58 and 59 has prompted further structural modification of 57. Tafluposide (60) 113 is a fluorinated phosphate of 58, which uniquely acts as a dual inhibitor of topoisomerases I and II. Tafluposide demonstrated high in vivo antitumor activity with a superior therapeutic spectrum and has been advanced to clinical trials. These 57-derived anticancer drugs exhibited divergent molecular mechanisms, different antitumor spectra, and distinct therapeutic profiles.
As mentioned earlier, the natural product doxorubicin (51) is a topoisomerase II inhibitor. Sabarubicin (61), a disaccharide analog of 51, exhibits superior antitumor efficacy and is used for the treatment of small cell lung cancer (SCLC). The unique antitumor profiles of 61 could result from activation of p53-independent apoptosis. 114 Nemorubicin (62) is another derivative of 51, which has the 3′-NH2 group in 51 replaced with a 3′-methoxymorpholinyl group. This substitution increases the lipophilicity of the molecule and improves cellular permeability. Nemorubicin differs significantly from 51 in terms of antitumor, metabolic, and toxicity profiles. Its mechanism of action involves the nucleotide excision repair (NER) pathway, as well as topoisomerase I inhibition. 115 Both 61 and 62 were approved as anticancer drugs in European Union.
Structural modification of a natural molecule can also lead to new therapeutic applications. The naturally occurring lignan meso-nordihydroguaiaretic acid (63) and other nordihydroguaiaretic acid (NDGA) derivatives were initially investigated as transcription inhibitors with effects against various viral infections. 116–119 However, a semi-synthetic NGDA derivative, terameprocol (64), was unexpectedly found to be a novel site-specific transcription inhibitor affecting the cell cycle and thereby exhibiting tumoricidal activity in vivo. Terameprocol was studied for the clinical treatment of cancers. 120,121
3.1.2 Structure-activity relationship-directed optimization
For many natural products with novel structure and unique mechanism of action, the prototype molecule will be subjected to extensive structural modification and conclusive SAR correlations can be established based on the resulting data, which can guide further optimization of the natural structures. Many examples are present in the literature, and SAR discussions on major classes of clinically useful anticancer natural products as well as their application in structural optimization are elucidated in many monographs, such as those cited herein. 31,32 Thus, our coverage of SAR-directed optimization in this section is intended to be selective rather than comprehensive. Tubulin-interactive natural products are of great research interest and have produced many therapeutic agents. 29,122 The microtubule-targeting natural products, paclitaxel, epothilones, and dolastatins will be briefly discussed as the most illustrative examples to highlight the importance of SAR study in structural optimization.
As mentioned earlier, the discovery of paclitaxel (1) initialized a new era in anticancer drug research. The recogition of its unique mechanism of action not only stimulated extensive structural modification and SAR study on this prototype molecule, but also prompted the search for new microtubule binding agents. Despite its high efficacy, 1 suffers from poor solubility and high toxicity, therefore, numerous 1-analogs have been synthesized to overcome these drawbacks and SAR has been thoroughly studied. 123,124 Major structural components required for antitumor activity include the diterpene taxane core, the phenylisoserine side chain at C13 position, the N-acyl group at the 3′ position of the side chain, and the oxetane ring incorporating C4, C5 and C20. Structural modifications of functional groups on both the taxane core and the C13 side chain have been examined for their effects on antitumor activity, and the key SAR correlations for cytotoxic taxoids are summarized in Figure 1. 124 Based on these SAR clues, several new analogs with improved therapeutic profiles have been developed. 125 Docetaxel (65) is a 1-analog used for the treatment of breast, ovarian, prostate and non-small cell lung cancers. Structurally, it differs from 1 only at the C10 and C3′ positions. Such structural alterations increase the water solubility of 65. 126 Cabazitaxel (66) is a semisynthetic dimethoxy derivative of 65. The modification of the C7 and C10 hydroxyls to dimethoxy groups might alter the P-glycoprotein (P-gp) affinity, and thereby, overcome the drug resistance problem associated with 65. Cabazitaxel was approved for the treatment of hormone-refractory prostate cancer in 2010. 127 Although many other taxoids also entered clinical trials and currently there are still literally thousands of clinical trials ongoing, no more new taxoids have been marketed since the approval of cabazitaxel. The emergence of novel non-taxane tubulin interactive agents, such as epothilones, could further toughen the competition in this field. Recent reviews have underscored future efforts on both “synthetic repurposing” of this compound class 128 and the search for simplified molecules based on the pharmacophore of paclitaxel 129.
Figure 1.
Summary of key SAR for taxoid analogs (modified from ref. 124).
The epothilones are polyketide macrolactones of bacterial origin, and they represent another important family of natural product-derived microtubule-stabilizing anticancer agents. Although they share the same binding site and exhibit similar biological effects as paclitaxel (1), the epothilones showed better efficacy and milder adverse effects than 1 in early trials. 27,130 Extensive structural modifications on this chemical family have revealed some SAR features (Figure 2). 27,131,132 Basically, the 16-membered macrocycle and the configuration of the seven chiral centers are essential for biological activity. However, alteration, addition and reduction of various functionalities in the prototype molecule epothilone B (12) could be readily accommodated (Figure 2).131 Guided by such SAR, several new epothilone analogs have been developed for therapeutic uses or clinical trials. Ixabepilone (13) was obtained by isosteric replacement of the lactone moiety in 12 with a lactam. This structural alteration slightly reduced cytotoxic and tubulin binding activities, while it improved the resistance to esterase cleavage and expanded the therapeutic window. Ixabepilone was approved for use in the treatment of breast cancer in 2007. 133 As demonstrated by the efficient microtubule stabilization and potent antiproliferative activity of epothilone D (43), the epothilone C12–C13 epoxide moiety is not an absolute requirement for bioactivity, and it can be changed to a double bond. Further incorporation of a trans double bond between C9 and C10 or C10 and C11 can also improve the antitumor activity. KOS-1584 (44) is a (E)-9,10-dehydro derivative of 43. KOS-1584 exhibited enhanced in vivo potency and was tested in clinic. 134 This SAR feature also led to the discovery of the C26-fluorinated analog fludelone (67), which has proved to be a potent antitumor agent in vivo. 135 To further improve potency, another epothilone congener iso-fludelone (68) was prepared by substituting the thiazole moiety in 67 with an iso-oxazole group. Iso-fludelone showed excellent biological stability, water solubility, and potency as compared with other epothilones. 136 This new analog has recently entered Phase I clinical study in patients with advanced solid tumors. 137 Modifications of the C20 methyl on the thiazole ring of 12 to small or moderate size substituents were generally well tolerated. Two new analogs, BMS-310705 (69) and ABJ879 (70), were developed for clinical trials by following this SAR observation. BMS-310705 contains an amino group at C21 of 12, which increases chemical stability and water solubility. 138 ABJ879 is a 20-desmethyl-20-methylsulfanyl derivative of 12, and it is more potent than 12 against human tumor cell lines. 139 The side chain at C15 and the methyl at C6 of 12 were also modified to improve the multi-drug resistant profiles and antitumor efficacy. Sagopilone (71, ZK-EPO) is a lipophilic analog of 12, in which the thiazole ring is changed to a benzothiazole ring and the C6 methyl is replaced by propenyl. This compound not only showed significant antitumor activity and efficacy, but also was distinguished from other epothilones by its capability to cross blood-brain barrier and the lack of recognition by efflux mechanisms. 140 A comparison of data from preclinical and phase I clinical studies on seven epothilone analogs was reported. 141 Currently, there are still three epothilones, epothilone B (12, phase II), iso-fludelone (68, phase I) and sagopilone (71, phase II) under active clinical trials.
Figure 2.
Summary of key SAR for epothilone analogs (modified from ref. 131).
Dolastatins are a series of antineoplastic peptides of marine origin. Dolastatin 10 (72), the most potent compound in this structural family, showed subnanomolar inhibitory activity against murine P388 lymphocytic leukemia. 142 It was identified as an antimitotic agent binding at the vinca alkaloid site, and was tested in clinical trials. 143 Although the clinical studies were terminated due to an unacceptable toxicity profile, its high in vitro activity and novel mode of action promoted extensive structural modification studies on 72 as well as another structurally related natural depsipeptide, dolastatin 15 (73),144 to retain anticancer activity and reduce toxicity. The effects of structural modifications on 72 and 73 are briefly summarized in Figure 3, and the SAR studies resulted in the discovery of several synthetic analogs as potent anticancer agents for clinical trials. 145 Soblidotin (74) 146 is an analog of 72 with the thiazole ring removed. Cematodin (75) 147 and synthadotin (76) 148 are synthetic analogs of 73. In these compounds, the unique 2-hydroxyisovaleric acid–dolapyrrolidone (Hiva–Dpy2) terminal moieties in 73 have been changed to benzylamino and tert-butylamino groups, respectively. Analogs 74–76 exhibited potent antimitotic activity with significant antiproliferative and preclinical antitumor effects. They were investigated in clinic for the treatment of various cancers, but failed to reach market as anticancer chemotherapy. However, another 72-analog, monomethyl auristatin E (MMAE, 77), was chemically conjugated to a chimeric anti-CD30 antibody to provide the antibody-drug conjugate (ADC) brentuximab vedotin, which was approved for treatment of relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. 149
Figure 3.
Summary of key SAR for dolastatins analogs (modified from ref. 145).
3.1.3 Pharmacophore-oriented molecular design
A further strategy to optimize natural leads is to design and synthesize natural product mimetics based on pharmacophores of the natural leads. In this approach, the key pharmacophoric features of the natural leads are first identified. Then, novel structures with scaffolds different from those of the natural leads are designed, while the pharmacophoric features are retained. Compared with the previous two strategies, this approach has the obvious advantages of enhanced structural novelty and potentially better chemical accessibility. In a broader view, this strategy can be termed as a pharmacophore-oriented molecular design. As illustrated in Table 1, the number of NCEs derived from this approach (S*, S*/NM and S/NM) is comparable to that of natural product-derivatives (ND), and account for another one third of small-molecule anticancer drugs.
Kinase inhibitors binding at the ATP site constitute a prominent example of pharmacophore-oriented molecular design based on endogenous substances. Most kinase inhibitors could be regarded as ATP mimetics with the pharmacophoric features preserved (e.g., hydrogen bond forming atoms interacting with the hinge region of the ATP site), but the basic skeleton (e.g., the hydrophobic core) altered to improve structural novelty and chemical accessibility. The discovery and development of antimetabolites as anticancer drugs is another example of pharmacophore-oriented molecular design in the area of cancer chemotherapy. Folic acid (78) is an endogenous substance essential for numerous body functions, particularly for cells and tissues that divide rapidly. Therefore, antifolates with structural similarity to folic acid can interfere with folate metabolism and be used to treat cancer. Methotrexate (MTX, 9) 44 is a folate analog widely used as an effective therapeutic agent against many solid tumors. However, in spite of the development of new drug delivery systems to improve the distribution of MTX,150 the poor pharmacokinetics and narrow safety margin of the drug limit its therapeutic application. Therefore, novel folate analogs are being actively sought as better therapeutic drugs. Pralatrexate (79) is a derivative of 10-deazaaminopterin, an isosteric congener of MTX. It selectively inhibits cancerous cells that express reduced folate carrier type 1 (RFC-1), a plasma membrane transporter responsible for cellular uptake of folate. Pralatrexate was approved as the first drug for relapsed or refractory peripheral T-cell lymphoma (PTCL). 151 In addition to 79, other folate analogs have been discovered through pharmacophore-oriented molecular design, in which glutamate, the key pharmacophoric feature in 78, is retained, while the aromatic pteridine ring and the para-aminobenzoic acid moieties are altered to other scaffolds. Raltitrexed (80) 152 is a thymidylate synthase inhibitor used in cancer chemotherapy. 80 differs from the prototype molecule 78 in both the pteridine and benzene rings. Similarly, pemetrexed (81) is also a folate analog with the pteridine and benzene rings in 78 altered. Pemetrexed inhibits three enzymes that use folate derivatives as substrates, namely thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT). It has been developed as a multi-targeted anti-folate for the treatment of a variety of cancers. 153
The pharmacophore-oriented molecular design strategy was also applied to design synthetic analogs of endogenous hormones. The tetradecapeptide somatostatin (SRIF14, 82) is a cyclic peptide hormone that regulates the endocrine system and affects neurotransmission as well as cell proliferation. The potential medicinal applications of 82 make it an attractive template for peptidomimetic drug design. The residues Phe7-Trp8-Lys9-Thr10 were identified as the pharmacophore of SRIF14. 154 Two truncated peptide analogs of 82, octreotide (83) and lanreotide (84), were designed accordingly, in which the pharmacophoric residues were either maintained (for 83) or slightly modified (for 84). Both octreotide and lanreotide are long-acting analogs of 82, and are used for the treatment of neuroendocrine tumors. 155,156
The development of histone deacetylase inhibitors as anticancer drugs is another good example for pharmacophore-oriented drug design based on natural leads. Trichostatin A (TSA, 85) is a Streptomyces product with significant in vivo effects on cell proliferation and differentiation. It was identified as a potent and selective inhibitor against mammalian histone deacetylase (HDAC). 157 The hydroxamate group in TSA was regarded as a pharmacophoric feature for HDAC inhibition. Vorinostat (suberoylanilide hydroxamic acid, SAHA, 86) 158 is a simplified analog of 85 in which the hydroxamate moiety was retained, while the conjugated trans double bonds as well as the chiral center were eliminated. Vorinostat was the first HDAC inhibitor approved by the FDA for the treatment of cutaneous T cell lymphoma (CTCL). The resolution of the structures formed by 85 or 86 complexed with an HDAC homologue revealed the interaction mode of these HDAC inhibitors, and suggested a three-part pharmacophore: a zinc-binding moiety, a hydrophobic linker, and a surface recognition group (Figure 4). 159 The hydroxamate group and the substituted aromatic ring serve as the zinc-binding moiety and the surface recognition group, respectively, which are crucial for high-affinity to HDAC. In contrast, the hydrophobic linker plays an important role to appropriately position the former two moieties, while variation in the linker could also affect the inhibitory activity. Identification of this pharmacophore facilitated further molecular design of HDAC inhibitors. Several cinnamic hydroxamates that meet the pharmacophoric structural requirements have been successfully developed into investigational drugs. Dacinostat (LAQ-824, 87) 160,161 and panobinostat (LBH-589, 88) 162 are two HDAC inhibitors tested in clinical trials. In both molecules, the hydroxamate moiety was kept, a styrene group was incorporated as the hydrophobic linker, and a tryptamine-containing fragment was designed for surface recognition. Belinostat (PXD101, 89) 163 is another cinnamic hydroxamate analog, in which an N-phenyl sulfonamide group is featured as the recognition cap group. Belinostat has been approved recently for the treatment of relapsed or refractory peripheral T-cell lymphoma. Givinostat (ITF2357, 90) 164 and abexinostat (PCI-24781, 91) 165 represent a new generation of HDAC inhibitors, and they are currently under active clinical trials. Structurally, they are benzoic hydroxamates with either a carbamate or an ether linkage extending the hydrophobic linker to the recognition cap groups. Tertiary amines are added to the recognition moieties to improve solubility. Quisinostat (JNJ-26481585, 92) 166 is closely related to 90 and 91, in which the benzene ring in 91 was changed to a pyrimidine ring, the aromatic benzofuran ring was changed to indole, and the ether linkage was replaced by a pyridine ring. o-Phenylenediamine is another effective zinc-binding group in addition to hydroxamate. Therefore, benzamide derivatives with o-phenylenediamine as the zinc-binding group have been designed as HDAC inhibitors, and two of them, entinostat (MS-275, 93) 167 and mocetinostat (MGCD0103, 94), 168 are being investigated in clinical trials as oral anticancer drugs.
Figure 4.
TSA and its pharmacohporic features
The pharmacophore-oriented molecular design strategy can also involve the hybridization or merging of pharmacophores from distinct chemical classes of anticancer-agents to generate new chemotypes. Uramustine (uracil mustard, 95) is a hybrid structure of nitrogen mustard and uracil. 169 It is a DNA alkylating agent and works by damaging DNA, primarily in cancer cells that preferentially take up the compound due to its structural similarity to uracil. Uramustine is a chemotherapeutic drug used for lymphatic malignancies such as non-Hodgkin's lymphoma, and was later withdrawn. 170 Similarly, estramustine (96) is a hybrid structure of estradiol and nitrogen mustard combined through a carbamate linkage, giving the compound both alkylating capability and estrogen-induced specificity. Estramustine is marketed as a chemotherapy agent for the treatment of prostate cancer. 171 Distamycin A (97) is a naturally occurring antibiotic isolated from cultures of Streptomyces distallicus. 172 It is a prototype of the polyamide minor groove binder (MGB) with a strong preference for AT rich sequences. When the pyrrole-amide skeleton of 97 is linked to other DNA interactive agents, it can serve as a DNA sequence selective vehicle and improve the cytotoxicity as well as therapeutic index of the hybrid molecule. The use of 97 in the design of hybrid molecules as potential antitumor agents with alkylating functions has been previously reviewed. 173 Tallimustine (98) was designed by combining the key DNA-interacting components of 97 and the alkylating agent nitrogen mustard. 174 Brostallicin (99) was designed by adding a latent alkylating functional group, a α,β-unsaturated bromoamide, to the pyrrole-amide skeleton of 97. The α-bromoacrylic moiety could be activated to an alkylating agent by Michael addition to the glutathione in tumor cells. 175 Both 98 and 99 have been tested in clinical trials for the treatment of a variety of cancers, and 99 is still under active development.
3.2 Optimization of ADMET profiles
Although the structural optimization of natural products has conventionally been dominated by efforts to improve efficacy, attempts to address poor pharmacokinetic profiles and unacceptable toxicity have been gradually emphasized. Efforts to increase the bioactivity of natural leads generally involve the refinement of structural details in the prototype molecule to enhance specific interaction with a certain macromolecule. However, the ADME profile of a molecule is often associated with molecular properties of the entire molecule. Consequently, structural modifications to tune the ADME profiles usually involve chemical modifications that can improve the physico-chemical properties of the molecule, which are often introduced at sites that can tolerate structural alteration. Toxicity is more complicated. Except for structural alerts or toxicophores, which are well-defined structural motifs with increased incidence of adverse outcomes, overall molecular properties, particularly lipophilicity, can also contribute to drug accumulation and thereby affect the toxicity of the drug. General approaches to improve solubility, enhance cellular permeability, increase chemical or metabolic stability, and decrease toxicity will be discussed with illustrative examples in this section. The prodrug approach, which is an important approach in medicinal chemistry to address the ADME and toxicity issues, will be discussed separately.
3.2.1 Approaches to improve solubility
Poor solubility, especially the lack of water-solubility, is frequently a hurdle in developing natural products into therapeutic drugs, and it can present a huge challenge to the formulation and administration of drugs. The most straightforward approach to improve water-solubility is to intentionally incorporate hydrophilic groups into the natural leads. The development of camptothecin (CPT, 100) analogs as effective anticancer drugs is a good example of this approach. CPT is a cytotoxic alkaloid isolated from the bark and stems of Camptotheca acuminata. 176 CPT inhibits the DNA enzyme topoisomerase I. It showed remarkable anticancer activity in preliminary clinical trials. However, adverse drug reaction and low solubility are major disadvantages of this natural lead, which limits its therapeutic application. The SAR studies on CPT analogs indicated that the conjugated fused ABCD rings, the lactone E ring, the hydroxyl and the (S)-configuration at C-20 are essential for cytotoxic activity. However, positions 7, 9, and 10 can tolerate structural alterations. 177 Accordingly, several water-soluble CPT analogs were developed with hydrophilic fragments incorporated at these positions. Topotecan (101) 178 is a water-soluble derivative of CPT with hydroxy and dimethylaminomethyl groups present at C10 and C7, respectively. Topotecan is used in the form of its hydrochloride salt to treat ovarian, cervical, and small cell lung cancers. Belotecan (102) 179 is another water-soluble CPT analog bearing an isopropylaminoethyl moiety at position 7. It is in clinical use for the treatment of ovarian and small cell lung cancers. Other water-soluble CPT analogs, such as exatecan (103), 180 lurtotecan (104), 181 and namitecan (105), 182 are all featured by the inclusion of aliphatic amino substitution at the C7 position, although structural alteration at other positions may also exist. Furthermore, the prodrug approach has also been successfully exploited to improve water-solubility of CPT derivatives and has led to the development of the clinical drug irinotecan (cf. Section 3.2.5).
The bacterial natural product epoxomicin (106) was identified as an inhibitor of the chymotrypsin-like activity of the 20S proteasome. 183 To improve proteasome inhibitory activity, a series of epoxyketone derivatives were synthesized and evaluated. YU-101 (107), which is a tetrapeptide slightly different from 106, was discovered as a more potent proteasome inhibitor than the natural compound. 184 YU-101 was further modified by adding a morpholino substitution on the acetyl group of its N-terminus. This modification was intended to improve the ADME properties, especially water-solubility, and eventually led to the discovery of carfilzomib (108). Carfilzomib was approved as a therapeutic drug for the treatment of multiple myeloma in 2012. 185 The interesting story on the discovery and development of 108 from the natural lead 106 has been recently described. 186
Geldanamycin (GM, 109) is a benzoquinone ansamycin antibiotic first isolated from a strain of Streptomyces hygroscopicus. It inhibits the function of heat shock protein 90 (Hsp90) by binding to its ADP/ATP-binding pocket. 187 Although the clinical trials of 109 were discontinued due to hepatotoxicity and poor solubility, SAR and X-ray crystal studies suggested that structural alterations at the C17 position of 109 would be well tolerated. 188 Therefore, several 109-analogs with various substitutions at C17 were subsequently developed and tested in clinical trials. Tanespimycin (17-AAG, 110) is a 17-allylamino-GM developed by Bristol-Myers Squibb, 189 which was approved for the treatment of multiple myeloma in 2004. However, further clinical trials of 110 were impeded by the major obstacle of poor solubility. Later structural optimization of 109 focused mainly on improving water-solubility through C17 modification. Alvespimycin (17-DMAG, 111) 190 is a water-soluble 109-derivative with dimethylaminoethylamino substitution at C17. Its hydrochloride salt was tested for the treatment of advanced solid tumors. The realization that reduction of the p-benzoquinone skeleton in 109 to a hydroquinone would make the C17 amino group sufficiently basic to form stable salts prompted the conversion of 110 to its hydroquinone congener retaspimycin (112). 191 This compound is a water-soluble analog of 109 and also structurally related to the hydroquinone natural product reblastatin (113). 192
Rebeccamycin (114) is a natural bis-indole alkaloid originated from bacteria. 193 While it is structurally similar to staurosporine (20), 114 did not inhibit protein kinases. Instead, it was a weak topoisomerase I inhibitor. 194 Becatecarin (115) is a semisynthetic water-soluble derivative of 114 with a diethylaminoethyl substituent on the imide nitrogen. Becatecarin showed dual inhibition of topoisomerases I and II, and was approved for the treatment of bile duct tumors. 195
Ellipticine (116) is a natural alkaloid isolated from the plant family Apocynaceae. This planar heterocyclic structure showed high antineoplastic activity and it acts through DNA intercalation and topoisomerase II inhibition. 196 However, water insolubility hampered its progression to clinical trials. Accordingly, a number of water soluble derivatives with either a quaternary ammonium ion at N-2 or an amino-alkyl substituent at C-1 have been designed to overcome this problem. Elliptinium (117) is a 2-methyl-9-hydroxyl derivative of 116 with improved water-solubility. 197 It was used for the treatment of metastatic breast cancer. Similarly, datelliptium (118), an ellipticine derivative bearing a diethylaminoethyl substituent at N-2, was tested clinically as the water soluble hydrochloride salt. 198 Retelliptine (119) contains a diethyl-aminopropylamino substituent at the C-1 position and this compound reached clinical investigation in the form of a water-soluble dihydrochloride salt. 199
Indirubin (120) is the active ingredient of the traditional Chinese prescription Danggui Longhui Wan. As a bis-indole natural product isolated from Indigo naturalis (leaves of Indigofera tinctoria or baphicacanthus cusia), 120 was found to be effective against chronic myelogenous leukemia. 200 However, the poor solubility of 120 resulted in low bioavailability when administered orally. 201 The introduction of a methyl group on one amide nitrogen of 120 led to the discovery of meisoindigo (121), an analog with higher antineoplastic activity and better absorption properties. 202 The presence of the methyl group in 121 decreases the possibility of intra-molecular hydrogen bonding and increases water-solubility, which contributes to the improved pharmacokinetic profiles of 121.
3.2.2 Approaches to enhance cellular permeability
The poor cellular permeability of some natural leads could cause insufficient exposure to macromolecule targets, and thereby, failure to achieve cellular as well as in vivo activity. To increase cellular permeability, the overall lipophilicity of the entire molecule must be modulated by either eliminating polar, hydrophilic moieties or adding lipophilic fragments.
Lavendustin A (122) is a microbial secondary metabolite. It showed potent inhibition against the epidermal growth factor receptor (EGFR) tyrosine kinase in cell-free extracts, but not in intact cells. 203 The discrepancy was attributed to poor cellular permeability resulting from the multiple polar groups and high polar surface area of 122. 204 Medicinal chemistry efforts to improve cellular penetration and antiproliferative activity of 122 were initiated. 205 The partial structure 123 was prepared, in which the o-cresol moiety was removed to decrease polarity, however, it was still inactive in cells. Further esterification of the carboxylic acid and O-methylation of the 2,5-dihydroxyphenyl moiety in 123 produced compound 124, which did exhibit antiproliferative activity in the micromolar range. Substantial increases in cellular activity were achieved by replacing the nitrogen in 124 with a carbon atom to further increase lipophilicity and cellular penetration. The resulting structure SDZ-LAP-977 (125) exhibited high antiproliferative activity against tumor and keratinocyte cell lines. 206 Based on the fact that the hydroxyl and carbonyl of the methyl salicylate portion in 125 could form a pseudo six-membered ring through intra-molecular hydrogen bonding, this portion of the molecule was changed to 4-ethylquinazoline, which further decreased polarity. Interestingly, the resultant compound SDZ-LAV-694 (126) was inactive against the EGF-R tyrosine kinase. Instead, it blocks the cell cycle in mitosis and inhibits tubulin polymerization by binding to the colchicine binding site on tubulin. Compound 126 was a potent tubulin inhibitor with a nanomolar IC50 value. The optimization of 125 to 126 is also a good example of scaffold hopping (cf. Section 3.3.3). Both 125 and 126 have been tested in clinical trials. 206,207
Structural optimization to enhance cellular permeability could also facilitate penetration through the blood-brain barrier (BBB). Berubicin (127) is a 4′-O-benzylated doxorubicin (51) analog designed to circumvent drug resistance. However, the presence of an additional benzyl group also allowed 127 to penetrate the BBB, which distinguished this compound from other anthracycline derivatives and made it applicable for the treatment of brain tumors. 208
3.2.3 Approaches to increase chemical or metabolic stability
A lack of chemical or metabolic stability can present severe challenges for the development of natural leads into therapeutic drugs. The all-trans-retinoic acid (ATRA, 128) is a therapeutic drug mainly used for the treatment of acute promyelocytic leukemia. However, this agent is chemically unstable at room temperature, especially in the presence of UV light, air, and oxidizing agents. ATRA acts as a retinoic acid receptor (RAR) agonist, and the pharmacophore for RAR agonists comprises a hydrophobic tail and a polar end. Accordingly, tamibarotene (129) was designed by incorporating a tetramethyltetralin group as a hydrophobic tail. This compound was a potent and orally active RAR agonist with significantly improved chemical stability as compared to 128, and has been successfully developed as an anti-leukemia drug. 209 Similarly, 9-cis-retinoic acid (130) is also an antineoplastic agent with poor chemical stability. Its tetramethyltetralin analog, bexarotene (131), 210 was approved as an oral antineoplastic agent for the treatment of cutaneous T cell lymphoma.
Isosteric replacement is also a strategy to improve metabolic stability of natural leads. As mentioned earlier in Section 3.1.1, substituting the ester oxygen in epothilone B (12) with a nitrogen atom produced ixabepilone (13). Compound 13 is more resistant to cellular esterases than 12 and, consequently, has better metabolic stability, as well as higher efficacy. 49 Such a subtle change also granted intellectual property status to 13 and made it possible for Bristol-Myers Squibb to develop it as a new chemical entity.
The lactone ring in camptothecin (CPT, 100) is susceptible to hydrolysis, which is potentiated by the electron-withdrawing effect of the hydroxyl at C20. Hence, homocamptothecin (hCPT) derivatives with an extra methylene unit between C20 and C21, which expands the six-membered lactone ring to a seven-membered ring, were designed to improve plasma stability. Two of these compounds, diflomotecan (132) and elomotecan (133), reached clinical trials. Diflomotecan, a 10,11-difluoro-hCPT, was the first hCPT tested in clinical studies. It is a potent topo I inhibitor with high oral bioavailability, but in contrast to other topoisomerase I inhibitors, it did not cause severe gastrointestinal toxicity. 211 Elomotecan is an hCPT derivative, which inhibits both topoisomerases I and II. 212 It exhibited potent antiproliferative effects against a panel of tumor cell lines, including drug-resistant lines, and also showed high in vivo efficiency in tumor xenograft studies. 213
Mifamurtide (134) is a synthetic lipophilic analog of muramyl dipeptide (MDP, 135), 214 the smallest naturally-occurring immune stimulatory component of cell walls from Mycobacterium species. When conjugated with alanyl-2-aminoethyl-2,3-dipalmitoylglycerylphosphoric acid, mifamurtide exhibited similar immune-stimulatory effects as natural MDP, but has the advantage of a longer half-life in plasma. The phospholipid side chain of 134 makes it accumulate in the lipid bilayer of the liposomes. Liposome-entrapped 134 is designed for in vivo targeted delivery to macrophages and stimulates them to kill various tumor cells. Mifamurtide was approved as a drug against osteosarcoma, a kind of bone cancer mainly affecting children and young adults. 215,216
3.2.4 Approaches to decrease toxicity
Unacceptable toxicity is another problem that impedes the development of natural products into therapeutic drugs. Two sources of toxicity are generally involved: off-target effects and the so-called idiosyncratic drug reactions. The first type of toxicity generally requires structural optimization to improve a compound’s specificity, which usually relates to structural alteration in certain molecular areas of the prototype molecules. This issue can generally be addressed in the optimization efforts to improve efficacy, as illustrated by many examples in Section 3.1. The second source of toxicity usually involves nonspecific adverse effects caused by unpredictable stimulation of endogenous biomolecules. Such toxicity is usually caused by structural alerts with either inherent or metabolic chemical reactivity. 217 Two alternative approaches are usually taken to overcome toxicity caused by structural alerts. Firstly, the toxicity could be reduced by increasing potency or local accumulation so as to decrease exposure duration of the drug. Secondly, it is possible to avoid toxicity by modifying the structural alerts.
The development of doxorubicin (51) analogs as new therapeutic drugs with less cardiotoxicity is a good example for reducing toxicity by increasing local accumulation and potency. As mentioned earlier in Section 3.1.1, pirarubicin (54), valrubicin (55) and idarubicin (56) are all highly lipophilic analogs of 51. Such a change in molecular property allows the compounds to accumulate more readily in the nuclei, and therefore, increases potency as well as decreases cardiotoxicity.
The natural product β-lapachol (136) is a relatively simple naphthoquinone with significant antitumor activity. The naphthoquinone skeleton is generally considered as a structural alert, since it is a reactive electrophile susceptible to endogenous nucleophiles. β-Lapachol was advanced to clinical status by NCI in the 1970s, but was later withdrawn due to unacceptable toxicity. 218 β-Lapachone (137) is a structurally related o-naphthoquinone and can be obtained by treating 136 with sulfuric acid. The intra-molecular cyclization reduces the susceptibility to nucleophilic attack due to decreased electrophilicity and increased steric effects. β-Lapachone showed strong anticancer activity both in vitro and in vivo, and was tested in clinical trials for advanced solid tumors. 219 Although there is no further report on the clinical development of β-lapachone as an anticancer drug, it is currently being investigated as a potential therapy for the treatment of non-alcoholic fatty liver disease (information from Thomson Reuters Integrity).
3.2.5 Prodrug approaches
By definition, a prodrug is an inactive molecule that can be converted to its active form through in vivo metabolic processes. The prodrug approach is often used to improve ADME properties, especially oral bioavailability. It can also reduce adverse effects, facilitate formulation efforts, and even improve the taste of intended drugs. The prodrug approach is an important strategy in developing natural leads into therapeutic anticancer drugs. This approach is used most frequently to enhance oral bioavailability, improve metabolic stability, or facilitate target delivery. A “straightforward” design of prodrugs takes advantage of ubiquitous enzymes, such as esterases or amidases, while a “smart” design involves cleavage reactions only induced by enzymes unique to the target tissue or even cascade enzymatic reactions. 220
In the field of natural products, a prodrug approach is most frequently applied to improve solubility and enhance oral bioavailability. As mentioned in Section 3.2.1, the clinical application of camptothecin (CPT, 100) was hampered by low solubility. Irinotecan (138) is a water-soluble prodrug of CPT with a bispiperidine functionality incorporated at C10 via a carbamate linkage. Enzymatic cleavage of the C10 side chain by carboxylesterases mainly in the liver affords the active metabolite SN-38 (139), which is 1000-fold more potent as a topoisomerase I inhibitor and also more cytotoxic than 138. Irinotecan was approved for the treatment of cancer, especially colon cancer. 221, 222
Triptolide (140) is a diterpenoid epoxide isolated from Tripterygium wilfordii. It demonstrated a unique bioactivity spectrum and was evaluated clinically in China for the treatment of rheumatoid arthritis and leukemia. However, its poor water solubility and severe toxicity limited its therapeutic application. 223 Omtriptolide (PG-490-88Na, 141), 14-succinyl triptolide sodium salt, is a prodrug designed to improve water solubility. It is highly water soluble and can be converted into 140 in vivo. It entered phase I clinical trials to treat solid tumors, but was later discontinued due to a similar toxicity profile to 140. Minnelide (142), another water-soluble prodrug of 140, bears an O-methyl phosphate disodium salt on the C-14β hydroxyl of 140. It was investigated mainly for potential treatment of pancreatic cancer and gastrointestinal tumors. 224
Combretastatins are a family of natural phenols isolated from Combretum caffrum. Combretastatin A-4 (CA-4, 143), 225 the most potent naturally occurring combretastatin known, is a strong vascular disrupting agent, binds at the colchicine site of β-tubulin, and shows significant cytotoxicity against human cancer cell lines. Structurally, CA-4 is a stilbenoid with two substituted aromatic rings linked by an ethene bridge, which is a relatively rigid structure with poor water solubility. To overcome the solubility problem, prodrugs based on 143 and its analogs have been designed and investigated. Combretastatin A-4 phosphate (CA-4P, 144) is a water-soluble phosphate prodrug of 143. It can be converted to its active metabolite 143 by phosphatases, and acts as a vascular disrupting agent and significantly reduces the blood flow to tumor cells. 226 Similarly, combretastatin A-1 diphosphate (CA-1P, 145) is a phosphate prodrug of CA-1. 227 Ombrabulin (AVE8062, 146) is another combretastatin prodrug, which has a serine conjugated with the synthetic CA-4 analog RPR-258063 (147) through an amide linkage to improve water-solubility. Ombrabulin can be rapidly converted into its active metabolite 147 in vivo, and exerts its antitumor effect by disrupting the formation of blood vessels needed for tumor growth. Ombrabulin is being investigated clinically for the treatment of soft tissue sarcoma. 228
Etopophos (etoposide phosphate, 148) is a water-soluble prodrug developed to overcome the poor water solubility of etoposide (58). Etopophos can be efficiently converted in vivo by endogenous phosphatase to the active drug 58, and exhibits pharmacological and pharmacokinetic profiles similar to those of 58. Notably, the prodrug approach increased the in vivo bioavailability from 0.04% to over 50%, and also resulted in more predictable oral bioavailability. 111
F14512 (149) is a water-soluble derivative of epipodophyllotoxin, the synthetic precursor of 58. It is a prodrug designed for targeted delivery. The spermine moiety present in the side chain facilitates selective uptake of 149 by tumor cells via the polyamine transport system, which is generally over-activated in tumor cells. F14512 has been characterized as a potent drug candidate and is currently in Phase I clinical trials. 229
Estramustine phosphate (estramustine phosphate sodium, 150) is an oral oncolytic drug used for the treatment of advanced prostatic carcinoma. It is a prodrug of estramustine (151), which can be prepared directly from estradiol with a carbamate ester linkage to nor-nitrogen mustard. Estramustine phosphate can be readily metabolized to estramustine and a closely related structure, estromustine in vivo, and exert its cytotoxic activity as a microtubule inhibitor. 230,231
Abiraterone (152) is a derivative of steroidal progesterone featured by a 3-pyridyl substituent at C-17 and a Δ16,17 double bond. It is a potent and selective cytochrome P450 17α-hydroxylase-17,20-lyase (CYP17A1) inhibitor and inhibits CYP17A1 in an irreversible manner via a covalent binding mechanism. However, 152 has very poor bioavailability and is susceptible to hydrolysis; thus, it was marketed as an acetate prodrug, which is orally active and also less susceptible to hydrolysis than 152. As an innovative drug, 152-acetate was used for castration-resistant prostate cancer. 232
As mentioned earlier, 5-fluorouracil (5-FU, 2) is an anti-metabolite designed from uracil by isomeric replacement. A critical limitation of 2 is its rapid degradation and inactivation by dihydropyrimidine dehydrogenase (DPD) in vivo. To overcome the metabolic instability of 2, a series of prodrugs was developed by making use of thymidine phosphorylase (TP), an enzyme highly expressed in tumor issues. Doxifluridine (5′-DFUR, 153) is an oral prodrug designed for this purpose. 5′-DFUR circumvents the degradation by DPD in the gut wall, and is converted into 2 by TP in tumor tissue. Since 2 is produced in situ in tumor tissue, 153 could be considered as a target delivery device to deliver 2 selectively to tumor tissue. 233 Capecitabine (154) is a novel carbamate derivative of 153 rationally designed to generate 2 preferentially in tumors. It is metabolized to 153 by carboxyl esterases and is further enzymatically converted to 2 in tumor tissue. Capecitabine has even higher tumor-selectivity than 153 and is an oral chemotherapeutic agent used in the treatment of metastatic breast and colorectal cancers. 234
3.3 Improving chemical accessibility
Besides efficacy and ADMET profiles, another bottleneck in developing natural products into therapeutic drugs is chemical accessibility. Many natural products have only limited supply from nature, and the situation can be even worse under the pressure of environmental protection issues. On the other hand, although total synthesis can be an alternative way to produce natural products, it is more likely to be an academic triumph rather than an alternative source for drug supply, due to the complexity of many natural structures. Biosynthetic technology could be a potential solution. However, it still faces severe technical challenges before it is truly applicable on industrial scales. It is worth to note that semi-synthesis from reproducible natural precursors is a practical strategy to solve the chemical accessibility problem. This has been vividly demonstrated by the successful example of paclitaxel (1), which can be obtained in large-scale though semi-synthesis from 10-deacetylbaccatin III (10-DAB), a synthetic precursor of paclitaxel abundant in yew needles. 124 Another example is omacetaxine mepesuccinate (homoharringtonine, 155), a protein synthesis inhibitor approved by FDA for the treatment of chronic myeloid leukemia (CML) in 2012. 155 was isolated from the whole plant of Cephalotaxus harringtonia. 235 As a natural ester of cephalotaxine (156), 155 is now manufactured by direct esterification of cephalotaxine, which is extracted from dry leaves of Cephalotaxus species and serves as a reproducible natural precursor of 155. 236
The preparation of simplified analogs based on complex natural structures represents a rational way to improve the chemical accessibility of natural products. As illustrated by the example of morphine alkaloids, simplified analogs of morphine, including morphinanes, benzomorphanes, phenylpiperidines, and even methadone, all retain analgesic activity, while they have significantly decreased structural complexity and improved chemical accessibility. Chemically, the strategies to make simplified analogs of a natural product include dissection of the complex natural template, elimination of redundant chiral centers, and pharmacophore-oriented scaffold hopping.
3.3.1 Dissection of complex natural templates
Complex natural structures are usually secondary metabolites produced during the evolution of an organism, and are intended for self-defense of the organism rather than as medicines for humans. Therefore, it is possible that not all of the structural features in a natural molecule are required for bioactivity, and structural redundancy may exist. Intense efforts have been devoted to reduce the structural complexity of natural products through truncation by organic synthesis, and some studies have successfully produced anticancer drugs with improved chemical accessibility. 237 The most telling example for this approach is the development of the anticancer drug eribulin (157) from the natural product halichondrin B (158).
Halichondrin B (158), a polyether macrolide isolated from the marine sponge Halichondra okadai, exhibited potent anticancer activity against murine cancer cells both in culture and in vivo. 238 Compound 158 was identified as a tubulin-targeted mitotic inhibitor by analyzing its cytotoxicity data against 60 different human tumor cell lines. 239 It attracted much attention due to its intriguing structural architecture and extraordinary antitumor activity. In spite of its structural complexity and the presence of 32 chiral centers, its first total synthesis was achieved in 1992. 240 When synthetic 158 and several intermediates were tested for antitumor activity, intermediate 159 with only the right half of 158 showed in vitro activity identical to that of 158, however, it showed no in vivo efficacy. This exciting discovery eventually led to the discovery and development of the structurally simplified and pharmaceutically optimized analog eribulin (157). 241,242 Compounds 157 and 158 exhibited comparable in vitro and in vivo activities, but due to the absence of an ester linkage, 157 showed improved metabolic stability. More notably, its significantly simplified structure made large-scale synthesis possible, and adequate supplies could be provided by chemical synthesis. Eribulin mesylate was approved for the treatment of refractory metastatic breast cancer in 2010. The synthesis of halichondrins and the case history for the development of eribulin mesylate have been nicely reviewed. 243,244
Trabectedin (ecteinascidin 743 or ET-743, 160) was identified as an antitumor component from the sea squirt Ecteinascidia turbinata. It has a unique molecular architecture characterized by the presence of three tetrahydroisoquinoline moieties and one of them connected with the other two through a ten-membered lactone ring incorporating a cysteine residue. 245 Trabectidin has been approved in Europe as Yondelis for the treatment of soft tissue sarcoma and ovarian cancer. Due to its scarcity in nature, total synthesis of trabectedin was attempted and was first achieved in 1996. 246 Although the total synthesis failed to provide an adequate supply of 160, it led to the discovery of simplified analogs with in vitro potency and mode of action similar to those of 160. The simplified structure phthalascidin (PT-650, 161) is characterized by the elimination of one tetrahydroisoquinoline moiety and the bridging lactone ring of 160 as well as the addition of a phthalimide side chain. Phthalascidin showed significant antiproliferative activity, even in camptothecin- and etoposide-resistant cells, and was more readily synthesized and more chemically stable than 160. 247 Compounds 160 and 161 can be obtained efficiently through a semisynthetic process starting from cyanosafracin B (162), a fermentation product from Pseudomonas fluorescens. 248 Zalypsis (163) is a synthetic simplified dimeric isoquinoline alkaloid structurally related to 160, 161 and several other tetrahydroisoquinoline marine products, such as jorumycin from Jorunna funebris, and renieramycins from sponges and tunicates. Again, the lactone ring is absent and a substituted trans-cinnamamide side chain is present. Zalypsis showed potent cytotoxic activity against a 24-cell line panel, and could form covalent bonds with guanines in the DNA double helix. 249 It is currently under active phase II clinical trials for various cancers, including cervical cancer, metastatic endometrial cancer and bladder cancer.
3.3.2 Diminishing stereogenic centers
The presence of multiple stereogenic centers is a key feature of many natural products and is also a major challenge in the total synthesis of natural products. Therefore, an important way to improve chemical accessibility is to reduce the number of chiral centers in the natural prototype molecule. The bis-indole alkaloid staurosporine (20) is a potent protein kinase C (PKC) inhibitor of bacterial origin. Although its lack of specificity has precluded the clinical use of 20, it still serves as a critical prototype structure and a valuable research tool, especially for anticancer drug discovery. Macrocyclic 250 and acyclic derivatives 251 were designed and synthesized as simplified analogs of 20 to improve PKC isozyme selectivity and increase the pharmacological benefits. Ruboxistaurin (LY333531, 164) is a bisindolylmaleimide macrocycle structure, in which the aminosugar moiety in 20 is replaced with a 14-membered N-N' bridged macrocyclic ether and the number of chiral centers is reduced from four to one. Enzastaurin (165) is an acyclic derivative of 20. It is an achiral molecule with all four chiral centers in the natural structure eliminated. Both 164 and 165 showed significant selectivity for PKCβ and also exhibited kinase selectivity for PKC in comparison to other ATP-dependent kinases. 250,251 Ruboxistaurin is an investigational drug for diabetic peripheral retinopathy sponsored by Eli Lilly. Enzastaurin has been tested in the clinic as an oral small molecule for the treatment of cancer, either as stand-alone therapy or in combination with traditional cancer therapies. 252
3.3.3 Scaffold hopping
The concept of scaffold hopping was first introduced in 1999 as a technique to identify different molecular backbones with similar biological activities. 253 Virtually, scaffold hopping is a technique to identify novel bioactive chemotypes by modifying the central core structure of known active compounds. Even before the introduction of the concept, the scaffold hopping strategy has been widely applied to discover novel lead structures with better therapeutic profiles based on known active molecules. Theoretically, scaffold hopping can be an effective approach to improve efficacy and pharmacokinetic properties as well as chemical accessibility. The application and classification of scaffold hopping strategies in drug discovery have been recently reviewed. 254,255 Usually, functional or topological pharmacophores are identified and maintained during the operation of scaffold hopping. Therefore, the case studies cited in Section 3.1.3 could also serve as examples for scaffold hopping. Scaffold hopping is less frequently applied in the optimization of natural leads than in synthetic molecules. This is probably because the scarcity of chemical and biological information on natural leads makes it difficult for efficient detection of pharmacophores. We will only highlight a few examples using the scaffold hopping strategy intently to improve chemical accessibility. However, it is worth noting that the application of scaffold hopping could be an important trend in the field of natural product-based drug discovery. Octreotide (83) and lanreotide (84) are simplified analogs of the tetradecapeptide somatostatin (SRIF14, 82). The pharmacophoric residues Phe7-Trp8-Lys9-Thr10 were preserved and the cyclic peptide backbone SRIF14 was truncated to improve chemical accessibility. Both 83 and 84 are long-acting analogs of 82 and are used for the treatment of neuroendocrine tumors. 155,156 Trichostatin A (TSA, 85) is a selective inhibitor of mammalian histone deacetylase (HDAC). In the simplified analog vorinostat (SAHA, 86), the hydroxamate pharmacophore is preserved, but the natural linker moiety containing conjugated trans double bonds and a chiral center has been changed to a simple linear alkyl chain. 158 The compound resulting from this scaffold hopping was more chemically accessible and retained the HDAC inhibition of the natural compound.
4 Highlights of natural product research in NPRL
The Natural Products Research Laboratories (NPRL) at the University of North Carolina at Chapel Hill have been engaged in the discovery and development of natural product-derived chemotherapeutic agents based on medicinal chemistry approaches since 1971, and have discovered several thousands of bioactive natural products and their synthetic derivatives/analogs. Several reviews have featured major achievements in natural products-based drug discovery, particularly research performed in the NPRL on the discovery of novel anticancer drugs. 256–259 We will highlight herein only the case studies that successfully led to the discovery and development of anticancer drug candidates.
As mentioned earlier, the structural modification of the natural lignan podophyllotoxin (57) successfully led to the discovery of three therapeutic drugs, etoposide (58), teniposide (59), and etopophos (148). However, the therapeutic application of these drugs is often hampered by problems such as poor water-solubility, acquired drug resistance, and metabolic inactivation. In extensive efforts to overcome the above problems, several novel podophyllotoxin analogs, NK 611 (166), GL-331 (167), and TOP-53 (168), were discovered and reached clinical trials. 260 Among them, GL-331 was initially discovered by the NPRL and investigated in clinical trials by Genelabs Technologies, Inc. In an effort to improve the antitumor profile, especially to overcome multidrug resistance, various aniline substitutions were introduced at the C7 position of 4′-demethyl-epipodophyllotoxin and a series of novel 4β-arylamino derivatives with superior DNA topo II inhibitory activity were identified. 261 GL-331 was one of the most potent topo II inhibitors in this series. As compared to 58, GL-331 is a DNA topo II inhibitor with superior activity both in vitro and in vivo. It also overcame multidrug resistance in many cell lines, and showed toxicological and pharmacokinetic profiles similar to those of 58. In addition, formulated GL-331 has desirable stability and biocompatibility. After being tested in phase I clinical trials at M. D. Anderson Cancer Center, GL-331 was progressed to phase II clinical trials against small cell lung cancers. However, currently, there is no active development of this compound (information from Thomson Reuters Integrity).
The fluorinated 2-phenyl-4-quinolone derivative 169 was originally developed as an antimitotic agent bearing the (methylenedioxy)benzene moiety, which is a common motif in natural antimitotic agents, such as cornigerine, podophyllotoxin (57), steganacin, and combretastatin A-2. 262 Compound 169 showed potent cytotoxicity against the NCI’s 60 human tumor cell lines (HTCL) panel with an average logGI50 value of -6.47. It is also a potent inhibitor of tubulin polymerization with an IC50 value of 0.85 μM. This compound exhibited good in vivo activity against OVCAR-3 ovarian cell line, and prolonged the life span of treated mice by 130%. 263 Compound 169 was later found to inhibit hepatocyte growth factor-induced invasion of SK-Hep-1 human hepatocellular carcinoma cells at micromolar concentrations by suppressing matrix metalloproteinase-9 expression, and was regarded as a potential therapeutic agent against tumor invasion. 264 Unfortunately, compound 169 is poorly water soluble, and thus, the monosodium phosphate salt of 169 (170) was developed as a prodrug of 169. Compound 170 was rapidly converted into 169 following iv and po administration and exhibited excellent antitumor activity in the SKOV-3 xenograft nude mice model. Due to its superior pharmacological profiles, compound 170 is highly promising for development as an anticancer candidate and is licensed to Effpha Corporation of Taiwan for further investigation in clinical trials. 265
Curcumin (171) is a yellow diarylheptanoid isolated from Curcuma longa (Zingiberaceae). Based on this natural chemotype, a number of synthetic curcumin analogs have been synthesized and evaluated as anticancer agents by the NPRL. 266–269 Some analogs were identified as potent androgen receptor antagonists with strong cytotoxic activity against prostate cancer cells as well as other tumor cell lines. Among them, JC-9 (172), a curcumin analog with high efficacy in vitro and in vivo, was licensed to Androscience Corporation, San Diego, CA for further preclinical and clinical studies. So far, JC-9 succeeded in Phase II clinical trials for treating acne in August 2012, and clinical trials for treating prostate cancer are being planned.
5 Conclusions
Natural products have historically been and will continue to be a precious source for anticancer drug discovery. Sometimes, the natural products themselves are used directly as therapeutic drugs, but more often, they need careful structural optimization to improve their efficacy, pharmacokinetic and safety profiles, as well as chemical accessibility. We have reviewed herein the general strategies for the evolution of natural leads into anticancer drug candidates or therapeutic drugs. It is also important to be aware of the benefits brought to natural product-based drug discovery by the development of new concepts and technologies, especially the strategy of diverted total synthesis 270 to efficiently prepare natural product-inspired chemical libraries as well as the application of chemoinformatic tools 271,272 to extract useful information for natural product-based drug discovery.
Acknowledgments
This work was supported in part by the National Natural Science Foundation of China (81172985 and 81261120391) awarded to Z Xiao, and by US NIH grant CA177584 from the National Cancer Institute awarded to K.H. Lee.
References
- 1.Newman DJ, Cragg GM, Snader KM. The influence of natural products upon drug discovery. Nat Prod Rep. 2000;17:215–234. doi: 10.1039/a902202c. [DOI] [PubMed] [Google Scholar]
- 2.Buss AD, Cox B, Waigh RD. Natural products as leads for new pharmaceuticals. In: Abraham DJ, editor. Burger’s Medicinal Chemistry and Drug Discovery, Sixth Edition, Volume 1: Drug Discovery. New Jersey: Wiley, Hoboken; 2003. pp. 847–900. [Google Scholar]
- 3.Henkel T, Brunne RM, Muller H, Reichel F. Statistical investigation into the structural complementarity of natural products and synthetic compounds. Angew Chem Int Ed. 1999;38:643–647. doi: 10.1002/(SICI)1521-3773(19990301)38:5<643::AID-ANIE643>3.0.CO;2-G. [DOI] [PubMed] [Google Scholar]
- 4.Feher M, Schmidt JM. Property distributions: Differences between drugs, natural products, and molecules from combinatorial chemistry. J Chem Inf Comput Sci. 2003;43:218–227. doi: 10.1021/ci0200467. [DOI] [PubMed] [Google Scholar]
- 5.Grabowski K, Schneider G. Properties and architecture of drugs and natural products revisited. Curr Chem Biol. 2007;1:115–127. [Google Scholar]
- 6.Wetzel S, Schuffenhauer A, Roggo S, Ertl P, Waldmann H. Cheminformatic analysis of natural products and their chemical space. Chimia. 2007;61:355–360. [Google Scholar]
- 7.Singh N, Guha R, Giulianotti MA, Pinilla C, Houghten RA, Medina-Franco JL. Chemoinformatic analysis of combinatorial libraries, drugs, natural products, and molecular libraries small molecule repository. J Chem Inf Model. 2009;49:1010–1024. doi: 10.1021/ci800426u. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nat Rev Drug Discov. 2005;4:206–220. doi: 10.1038/nrd1657. [DOI] [PubMed] [Google Scholar]
- 9.Newman DJ. Natural products as leads to potential drugs: An old process or the new hope for drug discovery? J Med Chem. 2008;51:2589–2599. doi: 10.1021/jm0704090. [DOI] [PubMed] [Google Scholar]
- 10.Nicolaou KC, Chen JS, Dalley SM. From nature to the laboratory and into the clinic. Bioorg Med Chem. 2009;17:2290–2303. doi: 10.1016/j.bmc.2008.10.089. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Kinghorn AD, Pan L, Fletcher JN, Chai H. The relevance of higher plants in lead compound discovery programs. J Nat Prod. 2011;74:1539–1555. doi: 10.1021/np200391c. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Mishra BB, Tiwari VK. Natural products: An evolving role in future drug discovery. Eur J Med Chem. 2011;46:4769–4807. doi: 10.1016/j.ejmech.2011.07.057. [DOI] [PubMed] [Google Scholar]
- 13.Cragg GM, Newman DJ. Natural products: A continuing source of novel drug leads. Biochim Biophys Acta, Gen Subj. 2013;1830:3670–3695. doi: 10.1016/j.bbagen.2013.02.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Cragg GM, Newman DJ, Snader KM. Natural products in drug discovery and development. J Nat Prod. 1997;60:52–60. doi: 10.1021/np9604893. [DOI] [PubMed] [Google Scholar]
- 15.Newman DJ, Cragg GM, Snader KM. Natural products as sources of new drugs over the period 1981–2002. J Nat Prod. 2003;66:1022–1037. doi: 10.1021/np030096l. [DOI] [PubMed] [Google Scholar]
- 16.Newman DJ, Cragg GM. Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007;70:461–477. doi: 10.1021/np068054v. [DOI] [PubMed] [Google Scholar]
- 17.Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod. 2012;75:311–335. doi: 10.1021/np200906s. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Shu Y-Z. Recent natural products based drug development: A pharmaceutical industry perspective. J Nat Prod. 1998;61:1053–1071. doi: 10.1021/np9800102. [DOI] [PubMed] [Google Scholar]
- 19.Butler MS. Natural products to drugs: natural product derived compounds in clinical trials. Nat Prod Rep. 2005;22:162–195. doi: 10.1039/b402985m. [DOI] [PubMed] [Google Scholar]
- 20.Butler MS. Natural products to drugs: natural product-derived compounds in clinical trials. Nat Prod Rep. 2008;25:475–516. doi: 10.1039/b514294f. [DOI] [PubMed] [Google Scholar]
- 21.Mann J. Natural products in cancer chemotherapy: past, present and future. Nat Rev Cancer. 2002;2:143–148. doi: 10.1038/nrc723. [DOI] [PubMed] [Google Scholar]
- 22.Gordaliza M. Natural products as leads to anticancer drugs. Clin Transl Oncol. 2007;9:767–776. doi: 10.1007/s12094-007-0138-9. [DOI] [PubMed] [Google Scholar]
- 23.Cragg GM, Grothaus PG, Newman DJ. Impact of natural products on developing new anticancer agents. Chem Rev. 2009;109:3012–3043. doi: 10.1021/cr900019j. [DOI] [PubMed] [Google Scholar]
- 24.Das B, Satyalakshmi G. Natural products based anticancer agents. Mini-Rev Org Chem. 2012;9:169–177. [Google Scholar]
- 25.Cragg GM, Newman DJ. A tale of two tumor targets: Topoisomerase I and tubulin. The Wall and Wani contribution to cancer chemotherapy. J Nat Prod. 2004;67:232–244. doi: 10.1021/np030420c. [DOI] [PubMed] [Google Scholar]
- 26.Oberlies NH, Kroll DJ. Camptothecin and Taxol: Historic achievements in natural products research. J Nat Prod. 2004;67:129–135. doi: 10.1021/np030498t. [DOI] [PubMed] [Google Scholar]
- 27.Altmann K-H, Gertsch J. Anticancer agents from nature - Natural products as a unique source of new microtubule-stabilizing agents. Nat Prod Res. 2007;24:327–357. doi: 10.1039/b515619j. [DOI] [PubMed] [Google Scholar]
- 28.Wall ME. Camptothecin and Taxol: Discovery to clinic. Med Res Rev. 2008;18:299–314. doi: 10.1002/(sici)1098-1128(199809)18:5<299::aid-med2>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
- 29.Kingston DGI. Tubulin-interactive natural products as anticancer agents. J Nat Prod. 2009;72:507–515. doi: 10.1021/np800568j. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Salvador JAR, Carvalho JFS, Neves MAC, Silvestre SM, Leitao AJ, Silva MMC, Sa eMML. Anticancer steroids: linking natural and semi-synthetic compounds. Nat Prod Rep. 2013;30:324–374. doi: 10.1039/c2np20082a. [DOI] [PubMed] [Google Scholar]
- 31.Cragg GM, Kingston DGI, Newman DJ, editors. Anticancer agents from natural products. London, UK: CRC Press, Taylor & Francis Group; 2005. [Google Scholar]
- 32.Cragg GM, Kingston DGI, Newman DJ, editors. Anticancer agents from natural products. 2. London, UK: CRC Press, Taylor & Francis Group; 2011. [Google Scholar]
- 33.Cragg GM. Paclitaxel (Taxol): A success story with valuable lessons for natural product drug discovery and development. Med Res Rev. 1998;18:315–331. doi: 10.1002/(sici)1098-1128(199809)18:5<315::aid-med3>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
- 34.Itokawa H, Lee KH, editors. Taxus–the genus Taxus. London, UK: CRC Press, Taylor & Francis Group; 2003. and literature cited therein. [Google Scholar]
- 35.Chashoo G, Singh SK. Holistic molecular approaches for anticancer therapy. J Biomed Pharm Res. 2012;1:5–29. [Google Scholar]
- 36.Cohen SS, Flaks JG, Barner HD, Loeb MR, Lichtenstein J. The mode of action of 5-fluorouracil and its derivatives. Proc Natl Acad Sci U S A. 1958;44:1004–1012. doi: 10.1073/pnas.44.10.1004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Burchenal JH, Murphy ML, Ellison RR, Sykes MP, Tan TC, Leone LA, Karnofsky DA, Craver LF, Dargeon HW, Rhoads CP. Clinical evaluation of a new antimetabolite, 6-mercaptopurine, in the treatment of leukemia and allied diseases. Blood. 1953;8:965–999. [PubMed] [Google Scholar]
- 38.Clarke DA, Hamilton LD, Philips FS, Sternberg SS. Effects of thioguanine in mammals. Cancer. 1956;9:1092–1101. doi: 10.1002/1097-0142(195611/12)9:6<1092::aid-cncr2820090605>3.0.co;2-1. [DOI] [PubMed] [Google Scholar]
- 39.Chu MY, Fischer GA. A proposed mechanism of action of 1-β-D-arabinofuranosylcytosine as an inhibitor of the growth of leukemic cells. Biochem Pharmacol. 1962;11:423–430. doi: 10.1016/0006-2952(62)90225-3. [DOI] [PubMed] [Google Scholar]
- 40.Cihak A, Vesely J, Hynie S. Transformation and metabolic effects of 5-aza-2′-deoxycytidine in mice. Biochem Pharmacol. 1980;29:2929–2932. doi: 10.1016/0006-2952(80)90039-8. [DOI] [PubMed] [Google Scholar]
- 41.Nelson MC, Hogan DK. The role of cladribine in the treatment of lymphoid malignancies. Oncol Nurs Forum. 1995;22:1395–1400. [PubMed] [Google Scholar]
- 42.Qian M, Wang X, Shanmuganathan K, Chu CK, Gallo JM. Pharmacokinetics of the anticancer agent 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine in rats. Cancer Chemother Pharmacol. 1994;33:484–488. doi: 10.1007/BF00686505. [DOI] [PubMed] [Google Scholar]
- 43.Takahashi T, Kanazawa J, Akinaga S, Tamaoki T, Okabe M. Antitumor activity of 2-chloro-9-(2- deoxy-2-fluoro-β-D-arabinofuranosyl)adenine, a novel deoxyadenosine analog, against human colon tumor xenografts by oral administration. Cancer Chemother Pharmacol. 1999;43:233–240. doi: 10.1007/s002800050889. [DOI] [PubMed] [Google Scholar]
- 44.Hertz R, Li MC, Spencer DB. Effect of methotrexate therapy upon choriocarcinoma and chorioadenoma. Proc Soc Exp Biol Med. 1956;93:361–366. doi: 10.3181/00379727-93-22757. [DOI] [PubMed] [Google Scholar]
- 45.Horn Y, Halden A, Gordan GS. The platelet-stimulating effects of 7-beta, 17-alpha-dimethyltestosterone (calusterone) Blood. 1972;40:684–687. [PubMed] [Google Scholar]
- 46.Kennedy BJ. Fluoxymesterone in the treatment of advanced breast cancer. Cancer. 1957;10:813–818. doi: 10.1002/1097-0142(195707/08)10:4<813::aid-cncr2820100430>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
- 47.Goodin S. Novel cytotoxic agents: epothilones. Am J Health Syst Pharm. 2008;65:S10–S15. doi: 10.2146/ajhp080089. [DOI] [PubMed] [Google Scholar]
- 48.Lee FY, Borzilleri R, Fairchild CR, Kim SH, Long BH, Reventos-Suarez C, Vite GD, Rose WC, Kramer RA. BMS-247550: A novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res. 2001;5:1429–37. [PubMed] [Google Scholar]
- 49.Conlin A, Fornier M, Hudis C, Kar S, Kirkpatrick P. Ixabepilone. Nat Rev Drug Discov. 2007;6:953–954. [Google Scholar]
- 50.Talpir R, Benayahu Y, Kashman Y, Pannell L, Schleyer M. Hemiasterlin and geodiamolide TA; two new cytotoxic peptides from the marine sponge Hemiasterella minor (Kirkpatrick) Tetrahedron Lett. 1994;35:4453–4456. [Google Scholar]
- 51.Anderson HJ, Coleman JE, Andersen RJ, Roberge M. Cytotoxic peptides hemiasterlin, hemiasterlin A and hemiasterlin B induce mitotic arrest and abnormal spindle formation. Cancer Chemother Pharmacol. 1997;39:223–226. doi: 10.1007/s002800050564. [DOI] [PubMed] [Google Scholar]
- 52.Andersen RJ, Williams DE, Strangman WK, Roberge M. HTI-286 (Taltobulin), a synthetic analog of the antitumor natural product Hemiasterlin. In: Cragg GM, Kingston DGI, Newman DJ, editors. Anticancer agents from natural products. 2. London, UK: CRC Press, Taylor & Francis Group; 2011. pp. 347–362. [Google Scholar]
- 53.Mallinson J, Collins I. Macrocycles in new drug discovery. Future Med Chem. 2012;4:1409–1438. doi: 10.4155/fmc.12.93. [DOI] [PubMed] [Google Scholar]
- 54.Kwitkowski VE, Prowell TM, Ibrahim A, Farrell AT, Justice R, Mitchell SS, Sridhara R, Pazdur R. FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma. Oncologist. 2010;15:428–435. doi: 10.1634/theoncologist.2009-0178. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Raymond E, Alexandre J, Faivre S, Vera K, Materman E, Boni J, Leister C, Korth-Bradley J, Hanauske A, Armand JP. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol. 2004;22:2336–2347. doi: 10.1200/JCO.2004.08.116. [DOI] [PubMed] [Google Scholar]
- 56.Sedrani R, Cottens S, Kallen J, Schuler W. Chemical modification of rapamycin: the discovery of SDZ RAD. Transplant Proc. 1998;30:2192–2194. doi: 10.1016/s0041-1345(98)00587-9. [DOI] [PubMed] [Google Scholar]
- 57.Mita MM, Mita AC, Chu QS, Rowinsky EK, Fetterly GJ, Goldston M, Patnaik A, Mathews L, Ricart AD, Mays T, Knowles H, Rivera VM, Kreisberg J, Bedrosian CL, Tolcher AW. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol. 2008;26:361–367. doi: 10.1200/JCO.2007.12.0345. [DOI] [PubMed] [Google Scholar]
- 58.Omura S, Iwai Y, Hirano A, Nakagawa A, Awaya J, Tsuchiya H, Takahashi Y, Masuma R. A new alkaloid AM-2282 of Streptomyces origin taxonomy, fermentation, isolation and preliminary characterization. J Antibiot. 1977;30:275–282. doi: 10.7164/antibiotics.30.275. [DOI] [PubMed] [Google Scholar]
- 59.Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008;26:127–132. doi: 10.1038/nbt1358. [DOI] [PubMed] [Google Scholar]
- 60.Zaugg K, Rocha S, Resch H, Hegyi I, Oehler C, Glanzmann C, Fabbro D, Bodis S, Pruschy M. Differential p53-dependent mechanism of radiosensitization in vitro and in vivo by the protein kinase C-specific inhibitor PKC412. Cancer Res. 2001;61:732–738. [PubMed] [Google Scholar]
- 61.Meijer L, Raymond E. Roscovitine and other purines as kinase inhibitors. From starfish oocytes to clinical trials. Acc Chem Res. 2003;36:417–425. doi: 10.1021/ar0201198. [DOI] [PubMed] [Google Scholar]
- 62.Veselý J, Havlíček L, Strnad M, Blow JJ, Donella-Deana A, Pinna L, Letham DS, Kato JY, Detivaud L, Leclerc S, Meijer L. Inhibition of cyclin-dependent kinases by purine analogues. Eur J Biochem. 1994;224:771–786. doi: 10.1111/j.1432-1033.1994.00771.x. [DOI] [PubMed] [Google Scholar]
- 63.Havlíček L, Hanuš J, Veselý J, Leclerc S, Meijer L, Shaw G, Strnad M. Cytokinin-derived cyclin-dependent kinase inhibitors: Synthesis and cdc2 inhibitory activity of Olomoucine and related compounds. J Med Chem. 1997;40:408–412. doi: 10.1021/jm960666x. [DOI] [PubMed] [Google Scholar]
- 64.Harmon AD, Weiss U. The structure of Rohiturine, the main alkaloid of Amoora rohituka (Syn. Aphanafhxis polystachya) (Meliaceae) Tetrahedron Lett. 1979;20:721–724. [Google Scholar]
- 65.Senderowicz AM. Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials. Invest New Drugs. 1999;17:313–320. doi: 10.1023/a:1006353008903. [DOI] [PubMed] [Google Scholar]
- 66.Kase H, Iwahashi K, Matsuda Y. K-252a, a potent inhibitor of protein kinase C from microbial origin. J Antibiot. 1986;39:1059–65. doi: 10.7164/antibiotics.39.1059. [DOI] [PubMed] [Google Scholar]
- 67.Prudhomme M. Biological targets of antitumor indolocarbazoles bearing a sugar moiety. Curr Med Chem Anticancer Agents. 2004;4:509–521. doi: 10.2174/1568011043352650. [DOI] [PubMed] [Google Scholar]
- 68.Pratz KW, Sato T, Murphy KM, Stine A, Rajkhowa T, Mark Levis. FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood. 2010;115:1425–1432. doi: 10.1182/blood-2009-09-242859. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69.Mahoney S, Rfuso F, Rogers P, Hisheh S, Rown DB, Millward M, Dharmarajan Cytotoxic effects of the novel isoflavone, phenoxodiol on prostate cancer cell lines. J Biosci. 2012;37:73–84. doi: 10.1007/s12038-011-9170-6. [DOI] [PubMed] [Google Scholar]
- 70.Howes JB, de Souza PL, West L, Huang LJ, Howes LG. Pharmacokinetics of phenoxodiol, a novel isoflavone, following intravenous administration to patients with advanced cancer. BMC Clin Pharmacol. 2011;11:1. doi: 10.1186/1472-6904-11-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71.Saif MW, Tytler E, Lansigan F, Brown DM, Husband AJ. Flavonoids, phenoxodiol, and a novel agent, triphendiol, for the treatment of pancreaticobiliary cancers. Expert Opin Investig Drugs. 2009;18:469–479. doi: 10.1517/13543780902762835. [DOI] [PubMed] [Google Scholar]
- 72.Wang X, McKernan R, Kim KH, Alvero AB, Whiting A, Thompson JA, Mor G, Saif MW, Husband AJ, Brown DM, Tytler EM. Triphendiol (NV-196), development of a novel therapy for pancreatic cancer. Anticancer Drugs. 2011;22:719–31. doi: 10.1097/CAD.0b013e328346f3b4. [DOI] [PubMed] [Google Scholar]
- 73.McMorris TC, Kelner MJ, Wang W, Estes LA, Montoya MA, Taetle R. Structure-activity relationship of illudins: Analogs with improved therapeutic index. J Org Chem. 1992;57:6876–6883. [Google Scholar]
- 74.McMorris TC, Staake MD, Kelner MJ. Synthesis and biological activity of enantiomers of antitumor irofulven. J Org Chem. 2004;69:619–623. doi: 10.1021/jo035084j. [DOI] [PubMed] [Google Scholar]
- 75.Wang Y, Wiltshire T, Senft J, Reed E, Wang W. Irofulven induces replication-dependent CHK2 activation related to p53 status. Biochem Pharmacol. 2007;73:469–480. doi: 10.1016/j.bcp.2006.10.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76.Ingber D, Fujita T, Kishimoto S, Sudo K, Kanamaru T, Brem H, Folkman J. Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature. 1990;348:555–557. doi: 10.1038/348555a0. [DOI] [PubMed] [Google Scholar]
- 77.Chun E, Han CK, Yoon JH, Sim TB, Kim YK, Lee KY. Novel inhibitors targeted to methionine aminopeptidase 2 (MetAP2) strongly inhibit the growth of cancers in xenografted nude model. Int J Cancer. 2005;114:124–130. doi: 10.1002/ijc.20687. [DOI] [PubMed] [Google Scholar]
- 78.Kim EJ, Shin WH. General pharmacology of CKD-732, a new anticancer agent: effects on central nervous, cardiovascular, and respiratory system. Biol Pharm Bull. 2005;28:217–23. doi: 10.1248/bpb.28.217. [DOI] [PubMed] [Google Scholar]
- 79.Bernier SG, Lazarus DD, Clark E, Doyle B, Labenski MT, Thompson CD, Westlin WF, Hannig G. A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis. Proc Natl Acad Sci USA. 2004;101:10768–10773. doi: 10.1073/pnas.0404105101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 80.Hannig G, Lazarus DD, Bernier SG, Karp RM, Lorusso J, Qiu D, Labenski MT, Wakefield JD, Thompson CD, Westlin WF. Inhibition of melanoma tumor growth by a pharmacological inhibitor of MetAP-2, PPI-2458. Int J Oncol. 2006;28:955–63. [PubMed] [Google Scholar]
- 81.Tillequin F. Rutaceous alkaloids as models for the design of novel antitumor drugs. Phytochem Rev. 2007;6:65–79. [Google Scholar]
- 82.Léonce S, Kraus-Berthier L, Golsteyn RM, David-Cordonnier M-H, Tardy C, Lansiaux A, Poindessous V, Larsen AK, Pierré A. Generation of replication-dependent double-strand breaks by the novel N2-G-alkylator S23906-1. Cancer Res. 2006;66:7203–7210. doi: 10.1158/0008-5472.CAN-05-3946. [DOI] [PubMed] [Google Scholar]
- 83.Fürstner A. Chemistry and biology of roseophilin and the prodigiosin alkaloids: A survey of the last 2500 years. Angew Chem Int Ed. 2003;42:3582–3603. doi: 10.1002/anie.200300582. [DOI] [PubMed] [Google Scholar]
- 84.Murthy MSR, Steenaart NAE, Johnson RA, Shore GC. Prodigiosin-derivatives as neoplastic and anti-viral agents. 2001055131. PCT Int Appl WO. 2001:267.
- 85.Zhai D, Jin C, Satterthwait AC, Reed JC. Comparison of chemical inhibitors of antiapoptotic Bcl-2-family proteins. Cell Death Differ. 2006;13:1419–1421. doi: 10.1038/sj.cdd.4401937. [DOI] [PubMed] [Google Scholar]
- 86.Nguyen M, Marcellus RC, Roulston A, Watson M, Serfass L, Murthy Madiraju SR, Goulet D, Viallet J, Bélec L, Billot X, Acoca S, Purisima E, Wiegmans A, Cluse L, Johnstone RW, Beauparlant P, Shore GC. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci USA. 2007;104:19512–19517. doi: 10.1073/pnas.0709443104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 87.Trudel S, Li ZH, Rauw J, Tiedemann RE, Wen XY, Stewart AK. Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma. Blood. 2007;109:5430–5438. doi: 10.1182/blood-2006-10-047951. [DOI] [PubMed] [Google Scholar]
- 88.Bibby MC. Flavone acetic acid - an interesting novel therapeutic agent or just another disappointment? Br J Cancer. 1991;63:3–5. doi: 10.1038/bjc.1991.2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 89.Rewcastle GW, Atwell GJ, Baguley BC, Calveley SB, Denny WA. Potential antitumor agents. 58. Synthesis and structure-activity relationships of substituted xanthenone-4-acetic acids active against the colon 38 tumor in vivo. J Med Chem. 1989;32:793–799. doi: 10.1021/jm00124a012. [DOI] [PubMed] [Google Scholar]
- 90.Rewcastle GW, Atwell GJ, Zhuang L, Baguley BC, Denny WA. Potential antitumor agents. 61. Structure-activity relationships for in vivo colon 38 activity among disubstituted 9-oxo-9H-xanthene-4-acetic. J Med Chem. 1991;34:217–222. doi: 10.1021/jm00105a034. [DOI] [PubMed] [Google Scholar]
- 91.Wallace A, LaRosa DF, Kapoor V, Sun J, Cheng G, Jassar A, Blouin A, Ching LM, Albelda SM. The vascular disrupting agent, DMXAA, directly activates dendritic cells through a MyD88-independent mechanism and generates antitumor cytotoxic T lymphocytes. Cancer Res. 2007;67:7011–7019. doi: 10.1158/0008-5472.CAN-06-3757. [DOI] [PubMed] [Google Scholar]
- 92.McKeage MJ. The potential of DMXAA (ASA404) in combination with docetaxel in advanced prostate cancer. Expert Opin Invest Drugs. 2008;17:23–29. doi: 10.1517/13543784.17.1.23. [DOI] [PubMed] [Google Scholar]
- 93.Yoshimura F, Rivkin A, Gabarda AE, Chou T-C, Dong H, Sukenick G, Morel FF, Taylor RE, Danishefsky SJ. Synthesis and conformational analysis of (E)-9,10-dehydroepothilone B: A suggestive link between the chemistry and biology of epothilones. Angew Chem Int Ed. 2003;42:2518–2521. doi: 10.1002/anie.200351407. [DOI] [PubMed] [Google Scholar]
- 94.Rivkin A, Yoshimura F, Gabarda AE, Chou T-C, Dong H, Tong WP, Danishefsky SJ. Complex target-oriented total synthesis in the drug discovery process: The discovery of a highly promising family of second generation epothilones. J Am Chem Soc. 2003;125:2899–2901. doi: 10.1021/ja029695p. [DOI] [PubMed] [Google Scholar]
- 95.Kanoh K, Kohno S, Asari T, Harada T, Katada J, Muramatsu M, Kawashima H, Sekiya H, Uno I. (−)-Phenylahistin: A new mammalian cell cycle inhibitor produced by aspergillus ustus. Bioorg Med Chem Lett. 1997;7:2847–2852. [Google Scholar]
- 96.Kanoh K, Kohno S, Katada J, Hayash Y, Muramatsu M, Uno I. Antitumor activity of phenylahistin in vitro and in vivo. Biosci Biotechnol Biochem. 1999;63:1130–1133. doi: 10.1271/bbb.63.1130. [DOI] [PubMed] [Google Scholar]
- 97.Nicholson B, Lloyd GK, Miller BR, Palladino MA, Kiso Y, Hayashi Y, Neuteboom ST. NPI-2358 is a tubulin-depolymerizing agent: in-vitro evidence for activity as a tumor vascular-disrupting agent. Anticancer Drug. 2006;17:25–31. doi: 10.1097/01.cad.0000182745.01612.8a. [DOI] [PubMed] [Google Scholar]
- 98.Borthwick AD. 2,5-Diketopiperazines: Synthesis, reactions, medicinal chemistry, and bioactive natural products. Chem Rev. 2012;112:3641–3716. doi: 10.1021/cr200398y. [DOI] [PubMed] [Google Scholar]
- 99.Roussi F, Guéritte F, Fahy J. The vinca alkaloids. In: Cragg GM, Kingston DGI, Newman DJ, editors. Anticancer agents from natural products. 2. London, UK: CRC Press, Taylor & Francis Group; 2011. pp. 177–198. [Google Scholar]
- 100.Barnett CJ, Cullinan GJ, Gerzon K, Hoying RC, Jones WE, Newlon WM, Poore GA, Robison RL, Sweeney MJ. Structure-activity relationships of dimeric Catharanthus alkaloids. 1. Deacetyl vinblastine amide (vindesine) sulfate. J Med Chem. 1978;21:88–96. doi: 10.1021/jm00199a016. [DOI] [PubMed] [Google Scholar]
- 101.Joel S. The comparative clinical pharmacology of vincristine and vindesine: Does vindesine offer any advantage in clinical use? Cancer Treat Rev. 1995;21:513–525. doi: 10.1016/0305-7372(95)90015-2. [DOI] [PubMed] [Google Scholar]
- 102.Mano M. Vinorelbine in the management of breast cancer: New perspectives, revived role in the era of targeted therapy. Cancer Treat Rev. 2006;32:106–118. doi: 10.1016/j.ctrv.2005.12.008. [DOI] [PubMed] [Google Scholar]
- 103.Fahy J, Duflos A, Ribet J-P, Jacquesy J-C, Berrier C, Jouannetaud M-P, Zunino F. Vinca alkaloids in superacidic media: A method for creating a new family of antitumor derivatives. J Am Chem Soc. 1997;119:8576–8577. [Google Scholar]
- 104.Kruczynski A, Barret JM, Etiévant C, Colpaert F, Fahy J, Hill BT. Antimitotic and tubulin-interacting properties of vinflunine, a novel fluorinated Vinca alkaloid. Biochem Pharmacol. 1998;55:635–48. doi: 10.1016/s0006-2952(97)00505-4. [DOI] [PubMed] [Google Scholar]
- 105.Arcamone F, Cassinelli G, Fantini G, Grein A, Orezzi P, Pol C, Spalla C. Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius. Biotechnol Bioeng. 1969;11:1101–1110. doi: 10.1002/bit.260110607. [DOI] [PubMed] [Google Scholar]
- 106.Bonfante V, Bonadonna G, Villani F, Martini A. Preliminary clinical experience with 4-epidoxorubicin in advanced human neoplasia. Recent Results Cancer Res. 1980;74:192–199. doi: 10.1007/978-3-642-81488-4_24. [DOI] [PubMed] [Google Scholar]
- 107.Miller AA, Salewski E. Prospects for pirarubicin. Med Pediatr Oncol. 1994;22:261–268. doi: 10.1002/mpo.2950220410. [DOI] [PubMed] [Google Scholar]
- 108.Kuznetsov DD, Alsikafi NF, O'Connor RC, Steinberg GD. Intravesical valrubicin in the treatment of carcinoma in situ of the bladder. Expert Opin Pharmacother. 2001;2:1009–1013. doi: 10.1517/14656566.2.6.1009. [DOI] [PubMed] [Google Scholar]
- 109.Cortés-Funes H, Coronado C. Role of anthracyclines in the era of targeted therapy. Cardiovasc Toxicol. 2007;7:56–60. doi: 10.1007/s12012-007-0015-3. [DOI] [PubMed] [Google Scholar]
- 110.Seidlova-Massinova V, Malinsky J, Santavy F. The biological effect of some podophyllotoxin compounds and their dependence on chemical structure. J Natl Cancer Inst. 1957;18:359–371. [PubMed] [Google Scholar]
- 111.Hande KR. Etoposide: Four decades of development of a topoisomerase II inhibitor. Eur J Cancer. 1998;34:1514–1521. doi: 10.1016/s0959-8049(98)00228-7. [DOI] [PubMed] [Google Scholar]
- 112.Cragg GM, Newman DJ. Plants as a source of anticancer agents. J Ethnopharmacol. 2005;100:72–79. doi: 10.1016/j.jep.2005.05.011. [DOI] [PubMed] [Google Scholar]
- 113.Sargent JM, Elgie AW, Williamson CJ, Hill BT. Ex vivo effects of the dual topoisomerase inhibitor tafluposide (F 11782) on cells isolated from fresh tumor samples taken from patients with cancer. Anticancer Drugs. 2003;14:467–473. doi: 10.1097/00001813-200307000-00013. [DOI] [PubMed] [Google Scholar]
- 114.Arcamone F-M, Sabarubicin Anthracycline chemistry and biology II. Top Curr Chem. 2008;283:171–189. doi: 10.1007/128_2007_1. [DOI] [PubMed] [Google Scholar]
- 115.Broggini M. Nemorubicin. Anthracycline chemistry and biology II. Top Curr Chem. 2008;283:191–206. doi: 10.1007/128_2007_6. [DOI] [PubMed] [Google Scholar]
- 116.Gnabre JN, Brady JN, Clanton DJ, Ito Y, Dittmer J, Bates RB, Huang RC. Inhibition of human immunodeficiency virus type 1 transcription and replication by DNA sequence-selective plant lignans. Proc Natl Acad Sci USA. 1995;92:11239–11243. doi: 10.1073/pnas.92.24.11239. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 117.Hwu JR, Tseng WN, Gnabre JG, Giza P, Huang RC. Antiviral activities of methylated nordihydroguaiaretic acids. 1. Synthesis, structure identification, and inhibition of Tat-regulated HIV transactivation. J Med Chem. 1998;41:2994–3000. doi: 10.1021/jm970819w. [DOI] [PubMed] [Google Scholar]
- 118.Chen H, Teng L, Li J, Park R, Mold DE, Gnabre J, Hwu JR, Tseng WN, Huang RC. Antiviral activities of methylated nordihydroguaiaretic acids. 2. Targeting herpes simplex virus replication by the mutation insensitive transcription inhibitor tetra-O-methyl-NDGA. J Med Chem. 1998;41:3001–3007. doi: 10.1021/jm980182w. [DOI] [PubMed] [Google Scholar]
- 119.Craigol J, Callahan M, Huang RC, DeLucia A. Inhibition of human papillomavirus type 16 gene expression by nordihydroguaiaretic acid plant lignin derivatives. Antiviral Res. 2000;47:19–28. doi: 10.1016/s0166-3542(00)00089-9. [DOI] [PubMed] [Google Scholar]
- 120.Heller JD, Kuo J, Wu TC, Kast WM, Huang RCC. Tetra-O-methyl nordihydroguaiaretic acid induces G2 arrest in mammalian cells and exhibits tumoricidal activity in vivo. Cancer Res. 2001;61:5499–5504. [PubMed] [Google Scholar]
- 121.Lopez RA, Goodman AB, Rhodes M, Blomberg JAL, Heller J. The anticancer activity of the transcription inhibitor terameprocol (meso-tetra-O-methyl nordihydroguaiaretic acid) formulated for systemic administration. Anticancer Drugs. 2007;18:933–939. doi: 10.1097/CAD.0b013e32813148e0. [DOI] [PubMed] [Google Scholar]
- 122.Mishra RC. Microtubule binding natural substances in cancer chemotherapy. In: Tiwari VK, Mishra BB, editors. Opportunity, challenge and scope of natural products in medicinal chemistry. Kerala, India: Research Signpost; 2011. pp. 269–282. [Google Scholar]
- 123.Kingston DGI. Taxol: The chemistry and structure-activity relationships of a novel anticancer agent. Trends in Biotech. 1994;12:222–227. doi: 10.1016/0167-7799(94)90120-1. [DOI] [PubMed] [Google Scholar]
- 124.Kingston DGI. Taxol and its Analogs. In: Cragg GM, Kingston DGI, Newman DJ, editors. Anticancer agents from natural products. 2. London, UK: CRC Press, Taylor & Francis Group; 2011. pp. 123–175. [Google Scholar]
- 125.Yared JA, Tkaczuk KHR. Update on taxane development: new analogs and new formulations. Drug Des Dev Ther. 2012;6:371–384. doi: 10.2147/DDDT.S28997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 126.Pazdur R, Kudelka AP, Kavanagh JJ, Cohen PR, Raber MN. The taxoids: paclitaxel (Taxol) and docetaxel (Taxotere) Cancer Treat Rev. 1993;19:351–386. doi: 10.1016/0305-7372(93)90010-o. [DOI] [PubMed] [Google Scholar]
- 127.Malhotra M, Dhingra R, Sharma T, Deep A, Narasimhan B, Phogat P, Sharma PC. Cabazitaxel: a novel drug for hormone-refractory prostate cancer. Mini-Rev Med Chem. 2013;13:915–920. doi: 10.2174/1389557511313060011. [DOI] [PubMed] [Google Scholar]
- 128.Cragg GM, Grothaus PG, Newman DJ. New horizons for old drugs and drug leads. J Nat Prod. 2014;77:703–723. doi: 10.1021/np5000796. [DOI] [PubMed] [Google Scholar]
- 129.Kingston DGI, Snyder jp. The quest for a simple bioactive analog of paclitaxel as a potential anticancer agent. Acc Chem Res. 2014;47:2682–2691. doi: 10.1021/ar500203h. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 130.Goodin S, Kane MP, Rubin EH. Epothilones: mechanism of action and biologic activity. J Clin Oncol. 2004;22:2015–2025. doi: 10.1200/JCO.2004.12.001. [DOI] [PubMed] [Google Scholar]
- 131.Höfle G, Reichenbach H. Epothilone, a myxobacterial metabolite with promising antitumor activity. In: Cragg GM, Kingston DGI, Newman DJ, editors. Anticancer agents from natural products. 2. London, UK: CRC Press, Taylor & Francis Group; 2011. pp. 513–573. [Google Scholar]
- 132.Kaiser S, Muller JJ, Froehlich PE, Cristina Baggio Gnoatto S, Bergold AM. From bacteria to antineoplastic: Epothilones, a successful history. Anticancer Agents Med Chem. 2013;13:1057–1068. doi: 10.2174/18715206113139990133. [DOI] [PubMed] [Google Scholar]
- 133.http://www.cancer.gov/cancertopics/druginfo/fda-ixabepilone
- 134.Rivkin A, Yoshimura F, Fumihiko G, Gabarda AE, Cho YS, Chou T-C, Dong H, Danishefsky SJ. Discovery of (E)-9,10-dehydroepothilones through chemical synthesis:_ On the emergence of 26-trifluoro-(E)-9,10-dehydro-12,13-desoxyepothilone B as a promising anticancer drug candidate. J Am Chem Soc. 2004;126:10913–10922. doi: 10.1021/ja046992g. [DOI] [PubMed] [Google Scholar]
- 135.Rivkin A, Chou TC, Danishefsky SJ. On the remarkable antitumor properties of fludelone: how we got there. Angew Chem Int Ed Engl. 2005;44:2838–2850. doi: 10.1002/anie.200461751. [DOI] [PubMed] [Google Scholar]
- 136.Chou TC, Zhang X, Zhong ZY, Li Y, Feng L, Eng S, Myles DR, Johnson R, Jr, Wu N, Yin YI, Wilson RM, Danishefsky SJ. Therapeutic effect against human xenograft tumors in nude mice by the third generation microtubule stabilizing epothilones. Proc Natl Acad Sci USA. 2008;105:13157–13162. doi: 10.1073/pnas.0804773105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 137.http;//clinicaltrials.gov/show/NCT01379287.
- 138.Trivedi M, Budihardjo I, Loureiro K, Reid TR, Ma JD. Epothilones: A novel class of microtubule-stabilizing drugs for the treatment of cancer. Future Oncol. 2008;4:483–500. doi: 10.2217/14796694.4.4.483. [DOI] [PubMed] [Google Scholar]
- 139.Nicolaou KC, King NP, Finlay MRV, He Y, Roschangar F, Vourloumis D, Vallberg H, Sarabia F, Ninkovic S, Hepworth D. Total synthesis of Epothilone E and related side-chain modified analogues via a stille coupling based strategy. Bioorg Med Chem. 1999;7:665–697. doi: 10.1016/s0968-0896(98)00153-9. [DOI] [PubMed] [Google Scholar]
- 140.Galmarini CM. Sagopilone, a microtubule stabilizer for the potential treatment of cancer. Curr Opin Investig Drugs. 2009;10:1359–1371. [PubMed] [Google Scholar]
- 141.Fumoleau P, Coudert B, Isambert N, Ferrant E. Novel tubulin-targeting agents: anticancer activity and pharmacologic profile of epothilones and related analogues. Ann Oncol. 2007;18:v9–v15. doi: 10.1093/annonc/mdm173. [DOI] [PubMed] [Google Scholar]
- 142.Pettit GR, Kamano Y, Herald CL, Tuinman AA, Boettner FE, Kizu H, Schmidt JM, Baczynskyj L, Tomer KB, Bontems RJ. The isolation and structure of a remarkable marine animal antineoplastic constituent: dolastatin 10. J Am Chem Soc. 1987;109:6883–6885. [Google Scholar]
- 143.Bai RL, Pettit GR, Hamel E. Binding of dolastatin 10 to tubulin at a distinct site for peptide antimitotic agents near the exchangeable nucleotide and vinca alkaloid sites. J Biol Chem. 1990;265:17141–17149. [PubMed] [Google Scholar]
- 144.Bai R, Friedman SJ, Pettit GR, Hamel E. Dolastatin 15, a potent antimitotic depsipeptide derived from Dolabella auricularia Interaction with tubulin and effects of cellular microtubules. Biochem Pharmacol. 1992;43:2637–45. doi: 10.1016/0006-2952(92)90153-a. [DOI] [PubMed] [Google Scholar]
- 145.Flahive E, Srirangam J. The dolastatins: novel antitumor agents from Dolabella auricularia. In: Cragg GM, Kingston DGI, Newman DJ, editors. Anticancer agents from natural products. 2. London, UK: CRC Press, Taylor & Francis Group; 2011. pp. 263–289. [Google Scholar]
- 146.Miyazaki K, Kobayashi M, Natsume T, Gondo M, Mikami T, Sakakibara K, Tsukagoshi S. Synthesis and antitumor activity of novel dolastatin 10 analogs. Chem Pharm Bull. 1995;43:1706–1718. doi: 10.1248/cpb.43.1706. [DOI] [PubMed] [Google Scholar]
- 147.Supko JG, Lynch TJ, Clark JW, Fram R, Allen LF, Velagapudi R, Kufe DW, Eder JP., Jr A phase I clinical and pharmacokinetic study of the dolastatin analogue cemadotin administered as a 5-day continuous intravenous infusion. Cancer Chemother Pharmacol. 2000;46:319–328. doi: 10.1007/s002800000152. [DOI] [PubMed] [Google Scholar]
- 148.Ebbinghaus S, Hersh E, Cunningham CC, O'Day S, McDermott D, Stephenson J, Richards DA, Eckardt J, Haider OL, Hammond LA. Phase II study of synthadotin (SYN-D; ILX651) administered daily for 5 consecutive days once every 3 weeks (qdx5q3w) in patients (Pts) with inoperable locally advanced or metastatic melanoma. J Clin Oncol. 2004;22:7530–7530. [Google Scholar]
- 149.Naumovski L, Junutula JR. Glembatumumab vedotin, a conjugate of an anti-glycoprotein non-metastatic melanoma protein B mAb and monomethyl auristatin E for the treatment of melanoma and breast cancer. Curr Opin Mol Ther. 2010;12:248–257. [PubMed] [Google Scholar]
- 150.Abolmaali SS, Tamaddon AM, Dinarvand R. A review of therapeutic challenges and achievements of methotrexate delivery systems for treatment of cancer and rheumatoid arthritis. Cancer Chemoth Pharm. 2013;71:1115–1130. doi: 10.1007/s00280-012-2062-0. [DOI] [PubMed] [Google Scholar]
- 151.O'Connor OA. Pralatrexate: an emerging new agent with activity in T-cell lymphomas. Curr Opin Oncol. 2006;18:591–597. doi: 10.1097/01.cco.0000245309.74767.20. [DOI] [PubMed] [Google Scholar]
- 152.Jackman AL, Taylor GA, Gibson W, Kimbell R, Brown M, Calvert AH, Judson IR, Hughes LR. ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: a new agent for clinical study. Cancer Res. 1991;51:5579–5586. [PubMed] [Google Scholar]
- 153.Manegold C. Pemetrexed (Alimta, MTA, multitargeted antifolate, LY231514) for malignant pleural mesothelioma. Semin Oncol. 2003;30:32–36. doi: 10.1016/s0093-7754(03)00283-5. [DOI] [PubMed] [Google Scholar]
- 154.Veber DF, Holly FW, Paleveda WJ, Nutt RF, Bergstrand SJ, Torchiana M, Glitzer MS, Saperstein R, Hirschmann R. Conformationally restricted bicyclic analogs of somatostatin. Proc Natl Acad Sci USA. 1978;75:2636–2640. doi: 10.1073/pnas.75.6.2636. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 155.Sideris L, Dube P, Rinke A. Antitumor effects of somatostatin analogs in neuroendocrine tumors. Oncologist. 2012;17:747–755. doi: 10.1634/theoncologist.2011-0458. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 156.Melen-Mucha G, Lawnicka H, Kierszniewska-Stepien D, Komorowski J, Stepien H. The place of somatostatin analogs in the diagnosis and treatment of the neuroendocrine glands tumors. Front Anticancer Drug Discov. 2010;1:241–272. doi: 10.2174/157489206777442197. [DOI] [PubMed] [Google Scholar]
- 157.Yoshida M, Kijima M, Akita M, Beppu T. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem. 1990;265:17174–17179. [PubMed] [Google Scholar]
- 158.Stowell JC, Huot RI, Voast LV. The synthesis of N-hydroxy-N′-phenyloctanediamide and its inhibitory effect on proliferation of AXC rat prostate cancer cells. J Med Chem. 1996;38:1411–1413. doi: 10.1021/jm00008a020. [DOI] [PubMed] [Google Scholar]
- 159.Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA, Breslow R, Pavletich NP. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature. 1999;401:188–193. doi: 10.1038/43710. [DOI] [PubMed] [Google Scholar]
- 160.Remiszewski SW, Sambucetti LC, Bair KW, Bontempo J, Cesarz D, Chandramouli N, Chen R, Cheung M, Cornell-Kennon S, Dean K, Diamantidis G, France D, Green MA, Howell KL, Kashi R, Kwon P, Lassota P, Martin MS, Mou Y, Perez LB, Sharma S, Smith T, Sorensen E, Taplin F, Trogani N, Versace RW, Walker H, Weltchek-Engler S, Wood A, Wu A, Atadja P. N-Hydroxy-3-phenyl-2-propenamides as novel inhibitors of human histone deacetylase with in vivo antitumor activity:_ Discovery of (2E)-N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl) ethyl]amino]methyl]phenyl]-2-propenamide (NVP-LAQ824) J Med Chem. 2003;46:4609–4624. doi: 10.1021/jm030235w. [DOI] [PubMed] [Google Scholar]
- 161.Catley L, Weisberg E, Tai Y-T, Atadja P, Remiszewski S, Hideshima T, Mitsiades N, Shringarpure R, LeBlanc R, Chauhan D, Munshi NC, Schlossman R, Richardson P, Griffin J, Anderson KC. NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma. Blood. 2003;102:2615–2622. doi: 10.1182/blood-2003-01-0233. [DOI] [PubMed] [Google Scholar]
- 162.Revill P, Mealy N, Serradell N, Bolos J, Rosa E. Panobinostat. Drugs Future. 2007;32:315–322. [Google Scholar]
- 163.Plumb JA, Finn PW, Williams RJ, Bandara MJ, Romero MR, Watkins CJ, La Thangue NB, Brown R. Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol Cancer Ther. 2003;2:721–728. [PubMed] [Google Scholar]
- 164.Guerini V, Barbui V, Spinelli O, Salvi A, Dellacasa C, Carobbio A, Introna M, Barbui T, Golay J, Rambaldi A. The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F) Leukemia. 2008;22:740–747. doi: 10.1038/sj.leu.2405049. [DOI] [PubMed] [Google Scholar]
- 165.Buggy JJ, Cao ZA, Bass KE, Verner E, Balasubramanian S, Liu L, Schultz BE, Young PR, Dalrymple SA. CRA-024781: A novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo. Mol Cancer Ther. 2006;5:1309–1317. doi: 10.1158/1535-7163.MCT-05-0442. [DOI] [PubMed] [Google Scholar]
- 166.Tong W-G, Wei Y, Stevenson W, Kuang S-Q, Fang Z, Zhang M, Arts J, Garcia-Manero G. Preclinical antileukemia activity of JNJ-26481585, a potent second-generation histone deacetylase inhibitor. Leukemia Res. 2010;34:221–228. doi: 10.1016/j.leukres.2009.07.024. [DOI] [PubMed] [Google Scholar]
- 167.Hess-Stumpp H, Bracker TU, Henderson D, Politz O. MS-275, a potent orally available inhibitor of histone deacetylases – the development of an anticancer agent. Int J Biochem Cell Biol. 2007;39:1388–1405. doi: 10.1016/j.biocel.2007.02.009. [DOI] [PubMed] [Google Scholar]
- 168.Siu LL, Pili R, Duran I, Messersmith WA, Chen EX, Sullivan R, MacLean M, King S, Brown S, Reid GK, Li Z, Kalita AM, Laille EJ, Besterman JM, Martell RE, Carducci MA. Phase I study of MGCD0103 given as a three-times-per-week oral dose in patients with advanced solid tumors. J Clin Oncol. 2008;26:1940–1947. doi: 10.1200/JCO.2007.14.5730. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 169.Lane M, Kelly MG. The antitumor activity of 5-bis-2′-chlorethyl)-aminouracil (uracil mustard) Cancer Res. 1960;20:511–517. [PubMed] [Google Scholar]
- 170.Kennedy BJ, Torkelson JL, Torlakovic E. Uracil mustard revisited. Cancer. 1999;85:2265–2272. [PubMed] [Google Scholar]
- 171.Nilsson T, Muntzing J. Histochemical and biochemical investigation of advanced prostatic carcinoma treated with estramustine phosphate, Estracyt. Scand J Urol Nephrol. 1973;7:18–22. doi: 10.3109/00365597309133665. [DOI] [PubMed] [Google Scholar]
- 172.Arcamone F, Penco S, Orezzi P, Nicolella V, Pirelli A. Structure and synthesis of distamycin A. Nature. 1964;203:1064–1065. doi: 10.1038/2031064a0. [DOI] [PubMed] [Google Scholar]
- 173.Baraldi PG, Zaid AN, Preti D, Fruttarolo F, Tabrizi MA, Iaconinoto A, Pavani MG, Carrion MD, Cara CL, Romagnoli R. Hybrid molecules based on distamycin A as potential antitumor agents. Arkivoc. 2006;7:20–34. [Google Scholar]
- 174.Weiss GR, Poggesi I, Rocchetti M, DeMaria D, Mooneyham T, Reilly D, Vitek LV, Whaley F, Patricia E, Von Hoff DD, O’Dwyer P. A phase I and pharmacokinetic study of tallimustine [PNU152241 (FCE 24517)] in patients with advanced cancer. Clin Cancer Res. 1998;4:53–59. [PubMed] [Google Scholar]
- 175.Geroni C, Marchini S, Cozzi P, Galliera E, Ragg E, Colombo T, Battaglia R, Howard M, D'Incalci M, Broggini M. Brostallicin, a novel anticancer agent whose activity is enhanced upon binding to glutathione. Cancer Res. 2002;62:2332–2336. [PubMed] [Google Scholar]
- 176.Wall ME, Wani MC, Cook CE, Palmer KH, McPhail AI, Sim GA. Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from camptotheca acuminate. J Am Chem Soc. 1966;88:3888–3890. [Google Scholar]
- 177.Rahier NJ, Thomas CJ, Hecht SM. Camptothecin and its analogs. In: Cragg GM, Kingston DGI, Newman DJ, editors. Anticancer agents from natural products. 1. London, UK: CRC Press, Taylor & Francis Group; 2005. pp. 5–21. [Google Scholar]
- 178.Mattern MR, Hofmann GA, McCabe FL, Johnson RK. Synergistic cell killing by ionizing radiation and topoisomerase I inhibitor topotecan (SK&F 104864) Cancer Res. 1991;51:5813–5816. [PubMed] [Google Scholar]
- 179.Lee JH, Lee JM, Kim JK, Ahn SK, Lee SJ, Kim MY, Jew SS, Park JG, Hong CI. Antitumor activity of 7-[2-(N-isopropylamino)ethyl]-(20S)-camptothecin, CKD602, as a potent DNA topoisomerase I inhibitor. Arch Pharm Res. 1998;21:581–590. doi: 10.1007/BF02975379. [DOI] [PubMed] [Google Scholar]
- 180.Mitsui I, Kumazawa E, Hirota Y, Aonuma M, Sugimori M, Ohsuki S, Uoto K, Ejima A, Terasawa H, Sato K. A new water-soluble camptothecin derivative, DX-8951f, exhibits potent antitumor activity against human tumors in vitro and in vivo. Jpn J Cancer Res. 1995;86:776–782. doi: 10.1111/j.1349-7006.1995.tb02468.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 181.Seiden MV, Muggia F, Astrow A, Matulonis U, Campos S, Roche M, Sivret J, Rusk J, Barrett E. A phase II study of liposomal lurtotecan (OSI-211) in patients with topotecan resistant ovarian cancer. Gynecol Oncol. 2004;93:229–232. doi: 10.1016/j.ygyno.2003.12.037. [DOI] [PubMed] [Google Scholar]
- 182.Beretta GL, Zuco V, De Cesare M, Perego P, Zaffaroni N. Namitecan: a hydrophilic camptothecin with a promising preclinical profile. Curr Med Chem. 2012;19:3488–3501. doi: 10.2174/092986712801323252. [DOI] [PubMed] [Google Scholar]
- 183.Meng L, Mohan R, Kwok BH, Elofsson M, Sin N, Crews CM. Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. Proc Natl Acad Sci USA. 1999;96:10403–10408. doi: 10.1073/pnas.96.18.10403. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 184.Elofsson M, Splittgerber U, Myung J, Mohan R, Crews CM. Towards subunit-specific proteasome inhibitors: synthesis and evaluation of peptide α′,β′-epoxyketones. Chem Biol. 1999;6:811–822. doi: 10.1016/s1074-5521(99)80128-8. [DOI] [PubMed] [Google Scholar]
- 185.Kortuem KM, Stewart AK. Carfilzomib. Blood. 2013;121:893–897. doi: 10.1182/blood-2012-10-459883. [DOI] [PubMed] [Google Scholar]
- 186.Halford B. Carfilzomib: From discovery to drug. C&EN. 2012;90:34–35. [Google Scholar]
- 187.Schulte TW, Akinaga S, Soga S, Sullivan W, Stensgard B, Toft D, Neckers LM. Antibiotic radicicol binds to the N-terminal domain of Hsp90 and shares important biologic activities with geldanamycin. Cell Stress Chaperon. 1998;3:100–108. doi: 10.1379/1466-1268(1998)003<0100:arbttn>2.3.co;2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 188.Snader KM. Benzoquinone ansamycins. In: Cragg GM, Kingston DGI, Newman DJ, editors. Anticancer agents from natural products. 1. London, UK: CRC Press, Taylor & Francis Group; 2005. pp. 339–356. [Google Scholar]
- 189.Dimopoulos MA, Mitsiades CS, Anderson KC, Richardson PG. Tanespimycin as antitumor therapy. Clin Lymphoma Myeloma Leuk. 2011;11:17–22. doi: 10.3816/CLML.2011.n.002. [DOI] [PubMed] [Google Scholar]
- 190.Lancet JE, Gojo I, Burton M, Quinn M, Tighe SM, Kersey K, Zhong Z, Albitar MX, Bhalla K, Hannah AL, Baer MR. Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia. Leukemia. 2010;24:699–705. doi: 10.1038/leu.2009.292. [DOI] [PubMed] [Google Scholar]
- 191.Ge J, Normant E, Porter JR, Ali JA, Dembski MS, Gao Y, Georges AT, Grenier L, Pak RH, Patterson J, Sydor JR, Tibbitts TT, Tong JK, Adams J, Palombella VJ. Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J Med Chem. 2006;49:4606–4615. doi: 10.1021/jm0603116. [DOI] [PubMed] [Google Scholar]
- 192.Takatsu T, Ohtsuki M, Muramatsu A, Enokita R, Kurakata SI. Reblastatin, a novel benzenoid ansamycin-type cell cycle inhibitor. J Antibiot. 2000;53:1310–1312. doi: 10.7164/antibiotics.53.1310. [DOI] [PubMed] [Google Scholar]
- 193.Bush JA, Long BH, Catino JJ, Bradner WT, Tomita K. Production and biological activity of rebeccamycin, a novel antitumor agent. J Antibiot (Tokyo) 1987;40:668–78. doi: 10.7164/antibiotics.40.668. [DOI] [PubMed] [Google Scholar]
- 194.Anizon F, Belin L, Moreau P, Sancelme M, Voldoire A, Prudhomme M, Ollier M, Sevère D, Riou JF, Bailly C, Fabbro D, Meyer T. Syntheses and biological activities (topoisomerase inhibition and antitumor and antimicrobial properties) of rebeccamycin analogues bearing modified sugar moieties and substituted on the imide nitrogen with a methyl group. J Med Chem. 1997;40:3456–3465. doi: 10.1021/jm9702084. [DOI] [PubMed] [Google Scholar]
- 195.Schwandt A, Mekhail T, Halmos B, O'Brien T, Ma PC, Fu P, Ivy P, Dowlati A. Phase-II trial of rebeccamycin analog, a dual topoisomerase-I and -II inhibitor, in relapsed "sensitive" small cell lung cancer. J Thorac Oncol. 2012;7:751–754. doi: 10.1097/JTO.0b013e31824abca2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 196.Kohn KW, Waring MJ, Glaubiger D, Friedman CA. Intercalative binding of ellipticine to DNA. Cancer Res. 1975;35:71–76. [PubMed] [Google Scholar]
- 197.Rouëssé J, Spielmann M, Turpin F, Le Chevalier T, Azab M, Mondésir JM. Phase II study of elliptinium acetate salvage treatment of advanced breast cancer. Eur J Cancer. 1993;29:856–859. doi: 10.1016/s0959-8049(05)80424-1. [DOI] [PubMed] [Google Scholar]
- 198.Khayat D, Borel C, Azab M, Paraisot D, Malaurie E, Bouloux C, Weil M. Phase I study of datelliptium chloride, hydrochloride given by 24-h continuous intravenous infusion. Cancer Chemother Pharmacol. 1992;30:226–228. doi: 10.1007/BF00686318. [DOI] [PubMed] [Google Scholar]
- 199.Kattan J, Durand M, Droz JP, Mahjoubi M, Marino JP, Azab M. Phase I study of retelliptine dihydrochloride (SR 95325 B) using a single two-hour intravenous infusion schedule. Am J Clin Oncol. 1994;17:242–245. doi: 10.1097/00000421-199406000-00013. [DOI] [PubMed] [Google Scholar]
- 200.Xiao Z, Hao Y, Liu B, Qian L. Indirubin and meisoindigo in the treatment of chronic myelogenous leukemia in China. Leuk Lymphoma. 2002;43:1763–1768. doi: 10.1080/1042819021000006295. [DOI] [PubMed] [Google Scholar]
- 201.Ji XJ, Zhang FR. Studies on antineoplastic action of indirubin derivatives and analogues and their structure-activity relationship. Acta Pharm Sin. 1985;20:137–139. [PubMed] [Google Scholar]
- 202.Ji XJ, Liu XM, Li K, Chen RH, Wang LG. Pharmacological studies of meisoindigo: absorption and mechanism of action. Biomed Environ Sci. 1991;4:332–337. [PubMed] [Google Scholar]
- 203.Onoda T, Iinuma H, Sasaki Y, Hamada M, Isshiki IC, Naganawa H, Takeuchi T, Tatsuta R, Umezawa R. Isolation of a novel tyrosine kinase inhibitor, lavendustin A, from Streptomyces griseolavendus. J Nat Prod. 1989;52:1252–1257. doi: 10.1021/np50066a009. [DOI] [PubMed] [Google Scholar]
- 204.Onoda T, Isshiki K, Takeuchi T, Tatsuta K, Umezawa K. Inhibition of tyrosine kinase and epidermal growth factor receptor internalization by lavendustin A methyl ester in cultured A431 cells. Drugs Exp Clin Res. 1990;16:249–253. [PubMed] [Google Scholar]
- 205.Nussbaumer P, Winiski AP, Cammisuli S, Hiestand P, Weckbecker G, Stutzt A. Novel antiproliferative agents derived from lavendustin A. J Med Chem. 1994;37:4079–4084. doi: 10.1021/jm00050a005. [DOI] [PubMed] [Google Scholar]
- 206.Nussbaumer P, Winiski AP. Structure–activity relationship studies on a novel class of antiproliferative agents derived from lavendustin A. Part I: Ring A modifications. Bioorg Med Chem. 2008;16:7552–7560. doi: 10.1016/j.bmc.2008.07.039. [DOI] [PubMed] [Google Scholar]
- 207.Medina J, Picarles V, Greiner B, Elsaesser C, Kolopp M, Mahl A, Roman D, Vogel B, Nussbaumer P, Winiski A, Meingassner J, de Fraissinette AB. LAV694, a new antiproliferative agent showing improved skin tolerability vs. clinical standards for the treatment of actinic keratosis. Biochem Pharmacol. 2003;66:1885–1895. doi: 10.1016/s0006-2952(03)00369-1. [DOI] [PubMed] [Google Scholar]
- 208.Kazerooni R, Conrad C, Baud C, Johansen M, Thapar N, Meyer C, Priebe W, Madden T. Phase I clinical pharmacokinetics of RTA 744: A blood brain barrier penetrating anthracycline active against high-grade glioma. J Clin Oncol. 2007;25(18S):2045. [Google Scholar]
- 209.Sanda T, Kuwano T, Nakao S, Iida S, Ishida T, Komatsu H, Shudo K, Kuwano M, Ono M, Ueda R. Antimyeloma effects of a novel synthetic retinoid Am80 (tamibarotene) through inhibition of angiogenesis. Leukemia. 2005;19:901–909. doi: 10.1038/sj.leu.2403754. [DOI] [PubMed] [Google Scholar]
- 210.Boehm MF, Zhang L, Zhi L, McClurg MR, Berger E, Wagoner M, Mais DE, Suto CM, Davies PJA, Heyman RA, Nadzant AM. Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells. J Med Chem. 1995;38:3146–3155. doi: 10.1021/jm00016a018. [DOI] [PubMed] [Google Scholar]
- 211.Kroep JR, Gelderblom H. Diflomotecan, a promising homocamptothecin for cancer therapy. Expert Opin Invest Drugs. 2009;18:69–75. doi: 10.1517/13543780802571674. [DOI] [PubMed] [Google Scholar]
- 212.Lavergne O, Harnett J, Rolland A, Lanco C, Lesueur-Ginot L, Demarquay D, Huchet M, Coulomb H, Bigg DCH. BN 80927: A novel homocamptothecin with inhibitory activities on both topoisomerase I and topoisomerase II. Bioorg Med Chem Lett. 1999;9:2599–2602. doi: 10.1016/s0960-894x(99)00428-x. [DOI] [PubMed] [Google Scholar]
- 213.Demarquay D, Huchet M, Coulomb H, Lesueur-Ginot L, Lavergne O, Camara J, Kasprzyk PG, Prévost G, Bigg DC. BN80927: a novel homocamptothecin that inhibits proliferation of human tumor cells in vitro and in vivo. Cancer Res. 2004;64:4942–4949. doi: 10.1158/0008-5472.CAN-03-3872. [DOI] [PubMed] [Google Scholar]
- 214.Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, Fukase K, Inamura S, Kusumoto S, Hashimoto M, Foster SJ, Moran AP, Fernandez-Luna JL, Nuñez G. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's Disease. J Biol Chem. 2003;278:5509–5512. doi: 10.1074/jbc.C200673200. [DOI] [PubMed] [Google Scholar]
- 215.Hisano G, Fidler IJ. Systemic activation of macrophages by liposome-entrapped muramyl tripeptide in mice pretreated with the chemotherapeutic agent adriamycin. Cancer Immunol Immunother. 1982;14:61–66. doi: 10.1007/BF00200168. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 216.Meyers PA. Muramyl tripeptide (mifamurtide) for the treatment of osteosarcoma. Expert Rev Anticancer Ther. 2009;9:1035–1049. doi: 10.1586/era.09.69. [DOI] [PubMed] [Google Scholar]
- 217.Blagg J. Structural alerts for toxicity. In: Abraham DJ, Rotella DP, editors. Burger’s Medicinal Chemistry, Drug Discovery, and Development. 7. New York, USA: John Wiley & Sons, Inc; 2010. pp. 301–334. [Google Scholar]
- 218.Morrison RK, Brown DE, Oleson JJ, Cooney DA. Oral toxicology studies with lapachol. Toxicol Appl Pharm. 1970;17:1–11. doi: 10.1016/0041-008x(70)90126-2. [DOI] [PubMed] [Google Scholar]
- 219.Li Y, Sun X, LaMont JT, Pardee AB, Li CJ. Selective killing of cancer cells by β-lapachone: direct checkpoint activation as a strategy against cancer. Proc Natl Acad Sci USA. 2003;100:2674–2678. doi: 10.1073/pnas.0538044100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 220.Wu K-M. A new classification of prodrugs: Regulatory perspectives. Pharmaceuticals. 2009;2:77–81. doi: 10.3390/ph2030077. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 221.Kunimoto T, Nitta K, Tanaka T, Uehara N, Baba H, Takeuchi M, Yokokura T, Sawada S, Miyasaka T, Mutai M. Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Res. 1987;47:5944–5947. [PubMed] [Google Scholar]
- 222.Sawada S, Okajima S, Aiyama R, Nokata K, Furuta T, Yokokura T, Sugino E, Yamaguchi K, Miyasaka T. Synthesis and antitumor activity of 20(S)-camptothecin derivatives: carbamate-linked, water-soluble derivatives of 7-ethyl-10-hydroxycamptothecin. Chem Pharm Bull. 1991;39:1446–1454. doi: 10.1248/cpb.39.1446. [DOI] [PubMed] [Google Scholar]
- 223.Leuenroth S. Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease. Proc Natl Acad Sci USA. 2007;104:4389–4394. doi: 10.1073/pnas.0700499104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 224.Zhou Z-L, Yang Y-X, Ding J, Li Y-C, Miao Z-H. Triptolide: structural modifications, structure–activity relationships, bioactivities, clinical development and mechanisms. Nat Prod Rep. 2012;29:457–475. doi: 10.1039/c2np00088a. [DOI] [PubMed] [Google Scholar]
- 225.Pettit GR, Sheo BS, Boyd MR, Hamel E. Antineoplastic Agents. 291. Isolation and synthesis of combretastatins A-4, A-5, and A-6. J Med Chem. 1995;38:1666–1672. doi: 10.1021/jm00010a011. [DOI] [PubMed] [Google Scholar]
- 226.Chaplin DJ, Pettit GR, Hill SA. Anti-vascular approaches to solid tumour therapy: evaluation of combretastatin A4 phosphate. Anticancer Res. 1999;19:189–195. [PubMed] [Google Scholar]
- 227.Tozer GM, Kanthou C, Parkins CS, Hill SA. The biology of the combretastatins as tumour vascular targeting agents. Int J Exp Pathol. 2002;83:21–38. doi: 10.1046/j.1365-2613.2002.00211.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 228.Hori K, Saito S, Kubota K. A novel combretastatin A-4 derivative, AC7700, strongly stanches tumour blood flow and inhibits growth of tumours developing in various tissues and organs. Br J Cancer. 2002;86:1604–1614. doi: 10.1038/sj.bjc.6600296. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 229.Kruczynski A, Pillon A, Créancier L, Vandenberghe I, Gomes B, Brel V, Fournier E, Annereau JP, Currie E, Guminski Y, Bonnet D, Bailly C, Guilbaud N. F14512, a polyamine-vectorized anticancer drug, currently in clinical trials exhibits a marked preclinical anti-leukemic activity. Leukemia. 2013;27:2139–2148. doi: 10.1038/leu.2013.108. [DOI] [PubMed] [Google Scholar]
- 230.Bergenheim AT, Henriksson R. Pharmacokinetics and pharmacodynamics of estramustine phosphate. Clin Pharmacokinet. 1998;34:163–72. doi: 10.2165/00003088-199834020-00004. [DOI] [PubMed] [Google Scholar]
- 231.Simpson D, Wagstaff AJ. Estramustine phosphate sodium. Am J Cancer. 2003;2:373–390. [Google Scholar]
- 232.Ang JE, Olmos D, Bono JSD. CYP17 blockade by abiraterone: further evidence for frequent continued hormone-dependence in castration-resistant prostate cancer. Br J Cancer. 2009;100:671–675. doi: 10.1038/sj.bjc.6604904. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 233.Bollag W, Hartmann HR. Tumor inhibitory effects of a new fluorouracil derivative: 5′-deoxy-5-fluorouridine. Eur J Cancer. 1980;16:427–432. doi: 10.1016/0014-2964(80)90221-2. [DOI] [PubMed] [Google Scholar]
- 234.Schüller J, Cassidy J, Dumont E, Roos B, Durston S, Banken L, Utoh M, Mori K, Weidekamm E, Reigner B. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol. 2000;45:291–297. doi: 10.1007/s002800050043. [DOI] [PubMed] [Google Scholar]
- 235.Grem JL, Cheson BD, King SA, Leyland-Jones B, Suffness M. Cephalotaxine esters: anti-leukemic advance or therapeutic failure? J Natl Cancer Inst. 1988;80(14):1095–103. doi: 10.1093/jnci/80.14.1095. [DOI] [PubMed] [Google Scholar]
- 236.Robin J, Dhal R, Dujardin G, Girodier L, Mevellec L, Poutot S. The first semi-synthesis of enantiopure homoharringtonine via anhydrohomoharringtonine from a preformed chiral acyl moiety. Tetrahedron Lett. 1999;40:2931–2934. [Google Scholar]
- 237.Wach J-Y, Gademann K. Reduce to the maximum: truncated natural products as powerful modulators of biological processes. Synlett. 2012;23:163–170. [Google Scholar]
- 238.Hirata Y, Uemura D. Halichondrins --- antitumor polyether macrolides from a marine sponge. Pure Appl Chem. 1986;58:701–710. [Google Scholar]
- 239.Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E. Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data. J Biol Chem. 1991;266:15882–15889. [PubMed] [Google Scholar]
- 240.Aicher TD, Buszek KR, Fang FG, Forsyth CJ, Jung SH, Kishi Y, Matelich MC, Scola PM, Spero DM, Yoon SK. Total synthesis of halichondrin B and norhalichondrin B. J Am Chem Soc. 1992;114:3162–3164. [Google Scholar]
- 241.Zheng W, Seletsky BM, Palme MH, Lydon PJ, Singer LA, Chase CE, Lemelin CA, Shen Y, Davis H, Tremblay L, Towle MJ, Salvato KA, Wels BF, Aalfs KK, Kishi Y, Littlefield BA, Yu MJ. Macrocyclic ketone analogues of halichondrin B. Bioorg Med Chem Lett. 2004;14:5551–5554. doi: 10.1016/j.bmcl.2004.08.069. [DOI] [PubMed] [Google Scholar]
- 242.Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsk BM, Palme MH, Habgood GJ, Singer LA, Dipietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA. In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res. 2001;61:1013–1021. [PubMed] [Google Scholar]
- 243.Choi H-W, Demeke D, Kang F-A, Kishi Y, Nakajima K, Nowak P, Wan Z-K, Xie C. Synthetic studies on the marine natural product halichondrins. Pure Appl Chem. 2003;75:1–17. [Google Scholar]
- 244.Huyck TK, Gradishar W, Manuguid F, Kirkpatrick P. Eribulin mesylate. Nat Rev Drug Discovery. 2011;10:173–174. doi: 10.1038/nrd3389. [DOI] [PubMed] [Google Scholar]
- 245.Rinehart KL. Antitumor compounds from tunicates. Med Res Rev. 2000;20:1–27. doi: 10.1002/(sici)1098-1128(200001)20:1<1::aid-med1>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
- 246.Corey EJ, Gin DY, Kania RS. Enantioselective total synthesis of ecteinascidin 743. J Am Chem Soc. 1996;118:9202–9203. [Google Scholar]
- 247.Martinez EJ, Owa T, Schreiber SL, Corey EJ. Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743. Proc Natl Acad Sci USA. 1999;96:3496–3501. doi: 10.1073/pnas.96.7.3496. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 248.Cuevas C, Pérez M, Martín MJ, Chicharro JL, Fernández-Rivas C, Flores M, Francesch A, Gallego P, Zarzuelo M, de la Calle F, García J, Polanco C, Rodríguez I, Manzanares I. Synthesis of ecteinascidin ET-743 and phthalascidin Pt-650 from cyanosafracin B. Org Lett. 2000;2:2545–2548. doi: 10.1021/ol0062502. [DOI] [PubMed] [Google Scholar]
- 249.Leal JF, García-Hernández V, Moneo V, Domingo A, Bueren-Calabuig JA, Negri A, Gago F, Guillén-Navarro MJ, Avilés P, Cuevas C, García-Fernández LF, Galmarini CM. Molecular pharmacology and antitumor activity of Zalypsis in several human cancer cell lines. Biochem Pharmacol. 2009;78:162–170. doi: 10.1016/j.bcp.2009.04.003. [DOI] [PubMed] [Google Scholar]
- 250.Jirousek MR, Gillig JR, Gonzalez CM, Heath WF, McDonald JH, III, Neel DA, Rito CJ, Singh U, Stramm LE, Melikian-Badalian A, Baevsky M, Ballas LM, Hall SE, Winneroski LL, Faul MM. (S)-13-[(Dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyr rolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione (LY333531) and related analogues: Isozyme selective inhibitors of protein kinase Cβ. J Med Chem. 1996;39:2664–2671. doi: 10.1021/jm950588y. [DOI] [PubMed] [Google Scholar]
- 251.Faul MM, Gillig JR, Jirousek MR, Ballas LM, Schotten T, Kahl A, Mohr M. Acyclic N- (azacycloalkyl)bisindolylmaleimides: isozyme selective inhibitors of PKCβ. Bioorg Med Chem Lett. 2003;13:1857–1859. doi: 10.1016/s0960-894x(03)00286-5. [DOI] [PubMed] [Google Scholar]
- 252.Rizvi MA, Ghias K, Davies KM, Ma C, Weinberg F, Munshi HG, Krett NL, Rosen ST. Enzastaurin (LY317615), a protein kinase CB inhibitor, inhibits the AKT pathway andinduces apoptosis in multiple myeloma cell lines. Mol Cancer Ther. 2006;5:1783–1789. doi: 10.1158/1535-7163.MCT-05-0465. [DOI] [PubMed] [Google Scholar]
- 253.Schneider G, Neidhart W, Giller T, Schmid G. "Scaffold-hopping" by topological pharmacophore search: A contribution to virtual screening. Angew Chem Int Ed. 1999;38:2894–2896. [PubMed] [Google Scholar]
- 254.Sekhon BS, Bimal N. Scaffold hopping in drug discovery. RGUHS J Pharm Sci. 2012;2:10–16. [Google Scholar]
- 255.Sun H, Tawa G, Wallqvist A. Classification of scaffold-hopping approaches. Drug Discov Today. 2012;17:310–324. doi: 10.1016/j.drudis.2011.10.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 256.Lee K-H. Novel antitumor agents from higher plants. Med Res Rev. 1999;19:569–596. doi: 10.1002/(sici)1098-1128(199911)19:6<569::aid-med7>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
- 257.Lee K-H. Current developments in the discovery and design of new drug candidates from plant natural product leads. J Nat Prod. 2004;67:273–283. doi: 10.1021/np030373o. [DOI] [PubMed] [Google Scholar]
- 258.Itokawa H, Morris-Natschke SL, Akiyama T, Lee K-H. Plant-derived natural product research aimed at new drug discovery. J Nat Med. 2008;62:263–280. doi: 10.1007/s11418-008-0246-z. [DOI] [PubMed] [Google Scholar]
- 259.Lee K-H. Discovery and development of natural product-derived chemotherapeutic agents based on a medicinal chemistry approach. J Nat Prod. 2010;73:500–516. doi: 10.1021/np900821e. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 260.Lee KH, Xiao Z. Antitumor agents 277. Podophyllotoxins and analogs. In: Cragg GM, Kingston DGI, Newman DJ, editors. Anticancer agents from natural products. 2. London, UK: CRC Press, Taylor & Francis Group; 2011. pp. 95–122. and literature cited therein. [Google Scholar]
- 261.Wang ZQ, Kuo YH, Schnur D, Bowen JP, Liu SY, Han FS, Chang JY, Cheng YC, Lee K-H. Antitumor agents. 113. New 4β-arylamino derivatives of 4′-O-demethylepipodophyllotoxin and related compounds as potent inhibitors of human DNA topoisomerase II. J Med Chem. 1990;33:2660–2666. doi: 10.1021/jm00171a050. [DOI] [PubMed] [Google Scholar]
- 262.Li L, Wang H-K, Kuo S-C, Wu T-S, Lednicer D, Lin CM, Hamel E, Lee K-H. Antitumor Agents. 150. 2′,3′,4′,5′,5,6,7-Substituted 2-phenyl-4-quinolones and related compounds: Their synthesis, cytotoxicity, and inhibition of tubulin polymerization. J Med Chem. 1994;37:1126–1135. doi: 10.1021/jm00034a010. [DOI] [PubMed] [Google Scholar]
- 263.Xia Y, Yang Z-Y, Xia P, Hackl T, Hamel E, Mauger A, Wu J-H, Lee K-H. Antitumor Agents. 211. Fluorinated 2-phenyl-4-quinolone derivatives as antimitotic antitumor agents. J Med Chem. 2001;44:3932–3936. doi: 10.1021/jm0101085. [DOI] [PubMed] [Google Scholar]
- 264.Wang S-W, Pan S-L, Peng C-Y, Huang D-Y, Tsai A-C, Chang Y-L, Guh J-H, Kuo S-C, Lee K-H, Teng C-M. CHM-1 inhibits hepatocyte growth factor-induced invasion of SK-Hep-1 human hepatocellular carcinoma cells by suppressing matrix metalloproteinase-9 expression. Cancer Lett. 2007;257:87–96. doi: 10.1016/j.canlet.2007.07.002. [DOI] [PubMed] [Google Scholar]
- 265.Chou L-C, Chen C-T, Lee J-C, Way T-D, Huang C-H, Huang S-M, Teng C-M, Yamori T, Wu T-S, Sun C-M, Chien D-S, Qian K, Morris-Natschke SL, Lee K-H, Huang L-J, Kuo S-C. Synthesis and preclinical evaluations of 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one monosodium phosphate (CHM-1-P-Na) as a potent antitumor agent. J Med Chem. 2010;53:1616–1626. doi: 10.1021/jm901292j. [DOI] [PubMed] [Google Scholar]
- 266.Ohtsu H, Xiao Z, Ishida J, Nagai M, Wang H-K, Itokawa H, Su C-Y, Shih C, Chiang T, Chang E, Lee Y, Tsai M-Y, Chang C, Lee K-H. Antitumor agents. 217. Curcumin analogues as novel androgen receptor antagonists with potential as anti-prostate cancer agents. J Med Chem. 2002;45:5037–5042. doi: 10.1021/jm020200g. [DOI] [PubMed] [Google Scholar]
- 267.Ohtsu H, Itokawa H, Xiao Z, Su C-Y, Shih CCY, Chiang T, Chang E, Lee Y, Chiu S-Y, Chang C, Lee K-H. Antitumor agents 222. Synthesis and anti-androgen activity of new diarylheptanoids. Bioorg Med Chem. 2003;11:5083–5090. doi: 10.1016/j.bmc.2003.08.029. [DOI] [PubMed] [Google Scholar]
- 268.Lin L, Shi Q, Su C-Y, Shih CCY, Lee K-H. Antitumor agents 247. New 4-ethoxycarbonylethyl curcumin analogs as potential antiandrogenic agents. Bioorg Med Chem. 2006;14:2527–2534. doi: 10.1016/j.bmc.2005.11.034. [DOI] [PubMed] [Google Scholar]
- 269.Lin L, Shi Q, Nyarko AK, Bastow KF, Wu C-C, Su C-Y, Shih CCY, Lee K-H. Antitumor Agents. 250. Design and synthesis of new curcumin analogues as potential anti-prostate cancer agents. J Med Chem. 2006;49:3963–3972. doi: 10.1021/jm051043z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 270.Wilson RM, Danishefsky SJ. Small molecule natural products in the discovery of therapeutic agents: the synthesis connection. J Org Chem. 2006;71:8329–8351. doi: 10.1021/jo0610053. [DOI] [PubMed] [Google Scholar]
- 271.Over B, Wetzel S, Gruetter C, Nakai Y, Renner S, Rauh D, Waldmann H. Natural-product-derived fragments for fragment-based ligand discovery. Nat Chem. 2013;5:21–28. doi: 10.1038/nchem.1506. [DOI] [PubMed] [Google Scholar]
- 272.Lachance H, Wetzel S, Kumar K, Waldmann H. Charting, navigating, and populating natural product chemical space for drug discovery. J Med Chem. 2012;55:5989–6001. doi: 10.1021/jm300288g. [DOI] [PubMed] [Google Scholar]