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Acta Pharmacologica Sinica logoLink to Acta Pharmacologica Sinica
. 2012 Sep 3;33(9):1147–1158. doi: 10.1038/aps.2012.105

Discovery of structurally diverse and bioactive compounds from plant resources in China

Sheng-ping Yang 1, Jian-min Yue 1,*
PMCID: PMC4003105  PMID: 22941284

Abstract

This review describes the major discoveries of structurally diverse and/or biologically significant compounds from plant resources in China, mainly from the traditional Chinese medicines (TCMs) since the establishment of our research group in 1999. In the past decade, a large array of biologically significant and novel structures has been identified from plant resources (or TCM) in our laboratory. The structural modification of several biologically important compounds led to more than 400 derivatives, some of which exhibited significantly improved activities and provided opportunities to elucidate the structure-activity relationship of the related compound class. These findings are important for drug discovery and help us understand the biological basis for the traditional applications of these plants in TCM.

Keywords: natural products, plant resources, traditional Chinese medicine, bioactive compounds, structural modification, structure-activity relationship

Introduction

Natural products have long been used by humans, especially in the healthcare industry, providing us products from food supplements to chemical therapeutics to biological probes and beyond. Natural products from both plants and microbes have had great success in past drug discovery programs1,2. Structural novelty and biological significance are the two major innovative elements of natural products chemistry and are also key issues for drug development. The identification of natural compounds with novel structures and important biological activities, especially those possessing new carbon skeletons, has been the main challenge in the fields of natural products, organic synthesis and pharmacology. Traditional Chinese medicines (TCM) medications are proven reservoirs of novel lead structures, including the well-known examples of artemisinin (an antimalarial)3 and huperzine A (for AD treatment)4,5. China has rich medicinal plant resources, and approximately 11 000 species have been documented, only approximately 30% of which have been chemically studied. We therefore view TCM plants as a promising resource for lead structures that deserve further investigation. In depth chemical and pharmacological studies of TCM plants will also provide starting points for TCM development and standardization.

In the past decade, chemical studies conducted in our research group have led to the isolation more than 2700 structurally diverse compounds from 125 plants (most with applications in TCM or folk medicine), of which 650 compounds were new structures, and 63 compounds featured unprecedented carbon skeletons or possessed unique structural motifs. The biosynthetic origins of most of these compounds with new carbon skeletons or unique structural motifs were proposed. Biological tests on these isolates via collaboration with the pharmacological research groups both in our institute and in outside organizations revealed that 182 compounds were active in the tested assays, and a number of them showed significant bioactivities associated with fatal human diseases. The structural modification of a few of the most promising bioactive compounds or drug leads produced more than 400 derivatives, 58 of which showed obviously improved activity. These studies also demonstrated the structure-activity relationship of the related compound classes. The major research findings are summarized here.

Structurally diverse and novel alkaloids

Daphniphyllum alkaloids (Figure 1): The genus Daphniphyllum is mainly distributed in the southern Asia, with 10 species growing in China. Some of these species have long been used in TCM for the treatment of various disorders. Daphniphyllum alkaloids possessing highly complex and polycyclic features have been a challenging topic in natural products and organic synthesis. Since we published the first chemical studies on D subverticillatum in 2003, a total of 194 structurally complex alkaloids have been isolated from 9 species of Daphniphyllum in our research group, 72 of which were novel structures. Among the novel compounds, 14 of them had new skeletons or possessed rearranged carbon frameworks6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21. Some alkaloids showed strong cytotoxic activity16.

Figure 1.

Figure 1

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Alkaloids isolated from Daphniphyllum genus.

Daphnipaxinin (1)8, the first diamino Daphniphyllum alkaloid, was isolated from D paxianum. The structure of 1 was determined by spectroscopic methods, and its absolute configuration was assigned by CD spectrum. A series of structurally related Daphniphyllum alkaloids with an unusual degraded skeleton of C-22-noryuzurimine-type (2–5)15,16 were identified from D longeracemosum and D yunnanense. Compound 4 showed strong cytotoxic activities, with IC50 values of 3.0 and 0.6 μmol/L against the tumor cell lines P388 and A549, respectively16. The discovery of daphnilongeranin A (6)15, the first seco-10,17-longistylumphlline alkaloid from D longeracemosum, suggested that the hypothetical biosynthetic route proposed for daphnicyclidine A should be reconsidered. The chemical investigation of D yunnanense also afforded the first C22-nor,10,17-seco-yuzurimine-type alkaloid, daphniyunnine B (7)16, which represents the most degraded compound in the Daphniphyllum alkaloid class.

A series of Daphniphyllum alkaloids possessing cage-like skeletons were isolated from the seeds of D paxianum11 and D macropodum18. Compounds 8–11 are the representatives of these cage-like Daphniphyllum alkaloids; in particular, paxdaphnine A (11) is the first identified 1,19-bisnor-Daphniphyllum alkaloid with a highly caged skeleton and a constrained Ring-A by the formation of C2–C8 and C1–C9 bonds, whose absolute configuration was determined by X-ray diffraction of its iodide derivative. Two structurally relevant alkaloids, paxdaphnidine A (12), bearing a unique pentacyclic framework, and paxdaphnidine B (13), possessing an uncommon tetracyclic skeleton, were isolated from the twigs and leaves of D paxianum9. Deoxycalyciphylline B (14) and deoxyisocalyciphylline B (15) were the major alkaloids with a unique fused hexacyclic skeleton from the stem of D subverticillatum8. Their structures were assigned based on spectroscopic methods and chemical evidence, and that of 14 was confirmed by a single crystal X-ray diffraction determination.

Recently, angustimine (16), featuring an unprecedented skeleton, and angustifolimine (17), a rare diamino Daphniphyllum alkaloid, were isolated from D angustifolium6. Calycinumines A (18) and B (19) were isolated from D calycinum7. Compound 18 is the first example of C-22-nor yuzurimine-type alkaloid, whose structure was confirmed by a single crystal X-ray diffraction study, and calycinumine B (19) features an unprecedented heteroatom-containing adamantane-like motif.

C,C-linked dimeric indolizidine alkaloids (Figure 2): Flueggea virosa Roxb ex Willd (Euphorbiaceae) is a TCM that has been used to treat rheumatism, pruritus, cephalic eczema, leucorrhea, and injuries. Previous chemical studies on this plant identified a number of indolizidine-type alkaloids known as Securinega alkaloids. In our recent study of this plant, two unprecedented C,C-linked dimeric indolizidine alkaloids, flueggenines A (20) and B (21), along with their precursor (−)-norsecurinine, were isolated from the roots of F virosa22. Their structures and absolute configurations were elucidated by extensive spectroscopic analyses. The biogenetic origin of these two compounds could be traced back to the coexisting major alkaloid (−)-norsecurinine via a self-catalyzed Baylis-Hillman reaction as the key step to achieve the dimerization.

Figure 2.

Figure 2

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Dimeric indolizidine alkaloids and monoterpenoid indole alkaloids.

Other structural classes of alkaloids (Figure 2): Alkaloids are a class of structurally interesting and biologically important natural products. In the past years, we examined the chemical components of eight other plant species in the families Loganiaceae, Apocynaceae, and Lycopodiaceae, and a total of 142 structurally diversified alkaloids were isolated from the genera Gelsemium23,24, Ervatamia25,26, Stephania27,28, Winchia29, and Lycopodium30, of which 42 were new compounds and 5 had novel skeletons. Some alkaloids showed strong cytotoxic activities. For example, gelseganines A–D (22–25), a new class of monoterpenoid indole alkaloids that bear an N4-iridoid unit, together with three new analogs (26–29)23,24 were isolated from the stems and leaves of Gelsemium elegans, a well-known toxic plant in Southeast Asia. The structures of 22–29 were determined by spectroscopic analysis, single-crystal X-ray diffraction, and chemical evidence. A plausible biogenetic pathway for alkaloids 22–25 was also postulated.

Complex and novel terpenoids

Triterpenoids (limonoids) from Meliaceae plants (Figure 3): China has a rich diversity of Meliaceae. To date, 62 species and 12 varieties of 15 genera in the Meliaceae family have been documented, and these are mainly distributed in the provinces south of the Yangtze River. Plants of this family are known to metabolize abundant nortriterpenoids (limonoids) with diverse and complex structures that have been demonstrated to have a variety of important biological activities, such as antifeeding, antibacterial, anticancer and antimalarial activities.

Figure 3.

Figure 3

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Triterpenoids (limonoids) isolated from Meliaceae plants.

In the past several years, our research group made tremendous efforts to explore biologically significant chemical components from the plants in the Meliaceae family, which has led to the isolation of more than 600 structurally diverse compounds from 30 plant species. Among these, 406 were new structures, and 32 possessed previously unknown skeletons. A variety of assays revealed that 50 additional compounds had important biological activities31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71. Our research results supported the traditional medical applications of several plants in the Meliaceae family. This is by far the most systematic and leading chemical study on the plants of the Meliaceae family worldwide. Several representative examples are summarized below.

Walsuronoid A (30)39, a limonoid featuring an unprecedented 3,4-peroxide-bridged A-seco skeleton, together with walsuronoids B (31) and C (32), possessing a rare 18(13→14)-abeo-limonoid skeleton, was isolated from Walsura robusta. Their structures were elucidated by spectroscopic analysis and chemical correlation, and that of 30 was confirmed by single-crystal X-ray diffraction. Compounds 31 and 32 showed antimalarial activities, which well matched the traditional application of this plant as a treatment for malaria.

Compounds 33–38 are 9,10-seco-tetranortriterpenoids that were discovered in the seeds of the Chinese marine mangrove plant Xylocarpus granatum42,63. Xylogranatin A (33) featured a unique 1,9-oxygen bridge, whose structure was confirmed by single-crystal X-ray diffraction, and xylogranatin D (38) furnished a novel skeleton via C-30–C-9 linkage that was postulated to arise from 36 via an γ-hydroxyl ketone rearrangement, and this pathway was chemically mimicked. Compounds 33–38 were cytotoxic to the tumor cell lines P388 and A549, with IC50 values ranging from 6.3 to 15.7 μmol/L.

Turrapubesins A (39) and B (40)41, two tetranortriterpenoids representing the first examples of halogenated and maleimide-bearing limonoids, respectively, were isolated from the twigs and leaves of Turraea pubescens. Their absolute configurations were determined by X-ray crystallography (39) and by CD analysis of a dihydrogenated derivative (40).

Four 16-norphragmalin-type limonoids, chuktabularins A-D (41–44)40, featuring unprecedented carbon skeletons of a biosynthetically extended C2 or C3 unit at C-15 forming a unique 2,7-dioxabicyclo[2.2.1]heptane moiety, and two limonoids, chuktabrin A (45), with the unique 1,3-dioxolan-2-one and 3,4-dihydro-2H-pyran motifs, and chuktabrin B (46)37 possessing an unprecedented polycyclic skeleton, were isolated from Chukrasia tabularis. Their structures were elucidated by spectroscopic analyses and single crystal X-ray diffraction.

The chemical investigations of Dysoxylum hainanense revealed a series of ring A modified triterpenoids among which dysoxyhainanin A (47)38 possessed a unique 1,3-cyclo-2,3-seco A ring with a formamido-containing appendage, dysoxyhainanin B (48)38 featured an unprecedented 1,2-dinor-3,10:9,10-bisseco skeleton, and dysoxyhainic acid A (49)52 had an unprecedented 2-nor-1,3-cyclotirucallane skeleton. Four compounds, dysoxyhainanin A (47) and dysoxyhainic acids B–C, showed significant activities against four gram-positive bacteria, Staphylococcus aureusATCC 25923, S epidermidisATCC 12228, Micrococcus luteusATCC 9341, and Bacillus subtilisCMCC 63501, with MICs in the range of 6.25–50 μg/mL.

Walsucochins A (50) and B (51), with a novel carbon skeleton, were isolated from Walsura cochinchinensis36. Their structures, including absolute configuration, were elucidated by spectral methods. Both compounds significantly attenuated H2O2-induced damage in PC12 cells in a dose-dependent manner at dosages of 1, 5, and 10 μmol/L.

A chemical study of the stems of Khaya senegalensis led to the isolation of two limonoids, namely khayalenoids A (52) and B (53)35, with an unprecedented 8-oxa-tricyclo[4.3.2.02.7]undecane motif in the nortriterpenoid core. Their structures, with absolute configuration, were determined by spectroscopy, X-ray crystallography, and CD analysis. Recently, another limonoid with an unprecedented carbon skeleton, grandifotane A (54), was isolated from the stem bark of K grandifoliola34. The absolute configuration of 54 was determined by spectroscopy, X-ray crystallography, and ECD calculations. A biogenetic route for grandifotane A (54) synthesis from a mexicanolide-type limonoid precursor, involving an enzymatic Baeyer-Villiger oxidation as the key step, was proposed.

Aphanamolide A (55)33, featuring an unprecedented carbon skeleton with a C-3–C-6 bond, was isolated from the seeds of Aphanamixis polystachya. Its structure was established using spectroscopic methods.

Walsucochinoids A (56) and B (57)32, two rearranged limonoids possessing an unprecedented carbon framework, were isolated from Walsura cochinchinensis. Their absolute configurations were assigned based on a detailed examination of spectroscopic data, single crystal X-ray diffraction analysis, and CD experiments.

Diterpenoids (Figure 4): Diterpenoids are a class of structurally interesting and biologically important natural products that are found in many TCM plants, and some were even proven to be the active ingredients in their respective plants. More than 260 diterpenoids were obtained by our research group in the past years from the Euphorbia72, Trigonostemon73,74,75,76,77,78,79, Daphne80, Pseudolarix81,82, Siegesbeckia83, Sapium84, and Larix85 genera. Among them, 122 were new compounds, and 4 possessed novel carbon scaffolds. Biological tests demonstrated that 49 compounds exhibited important biological activities in a variety of bioassays, some of which demonstrated the biological basis of the traditional applications of those plants in TCM medication.

Figure 4.

Figure 4

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Structurally interesting and biologically important diterpenoids.

Diterpenoids from the Euphorbiaceae family: Lathyranoic acid A (58)72, the first seco-lathyrane diterpenoid with a new skeleton was isolated from the seeds of Euphorbia lathyris. Its structure was elucidated by spectroscopic analysis and chemical transformation. Lathyranoic acid A was proposed to be biosynthetically produced from the co-existing diterpenoid Euphorbia factor L11 with an enzymatic Baeyer-Villiger oxidation as the key and the committed step, and its chemical synthesis was achieved (Scheme 1).

Scheme 1.

Scheme 1

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Chemical transformations from Euphorbia factor L11 to 58.

Two highly modified daphnane-type diterpenoids, trigochilides A (59) and B (60), together with six highly oxygenated diterpenes, trigochinins A-I (61–66)73,74,75, were isolated from the twigs and leaves of Trigonostemon chinensis Merr collected from Yunnan Province. Trigochilides A (59) and B (60) contain 12-carbon-containing polyketide appendages, which are linked to the diterpenoid core at C-16 by a C-bond and form a macrolactone between C-1′ and C-3, while trigochinins A–I (61–66) share a rare 4,6-oxetane moiety. Their structures were elucidated by spectroscopic analysis, X-ray crystallography, and CD analysis. Compounds 64 and 65 showed potent cytotoxic activities against HL-60 tumor cell lines with IC50 values of 8.1 and 6.4 μmol/L, respectively. Compound 66 significantly inhibited MET tyrosine kinase activity (IC50=1.95 μmol/L). Trigonochinenes A–E (66–71)79, five antibacterial diterpenoids, were isolated from the aerial parts of this plant collected from Hainan Province. Compounds 67–70 possess a rare 3,4-secocleistanthanic skeleton, and compound 71 is a highly aromatized tetranorditerpene. Compounds 67–71 were tested for antimicrobial activity against 11 microorganisms in vitro. All compounds tested were active against Helicobacter pylori-SS1, with MICs of 12.5–25 μg/mL, and compounds 67–70 also significantly inhibited the growth of the drug (metronidazole)-resistant strain H pylori-ATCC 43504, with MICs of ca 50 μg/mL. Compounds 69 and 71 also exhibited selective activities against the gram-positive bacteria Staphylococcus aureusATCC 25923, Staphylococcus epidermidisATCC 12228, and Micrococcus luteusATCC 9341 with MICs in the range of 6.25–50 μg/mL.

Twelve new highly oxygenated daphnane-type diterpenoids, genkwanines A–L (72–83)80, were isolated from the bud of Daphne genkwa, a well-known TCM. These compounds showed very potent cytotoxic activities against two tumor cell lines, P388 and A549, with IC50 levels of 0.15–8.40 μmol/L. Most interestingly, three of the compounds, 75, 78, and 81, and two known compounds, yuanhuacine and yuanhuadine, strongly inhibited the endothelial cell line HMEC at the IC50 levels of 2.90–15.0 μmol/L.

Sesquiterpenoids: Sesquiterpenoids are the major components of many TCM plants, and they have a broad spectrum of biological activities including antiinflammatory, antiparasitic, antitumor, and anti-HIV properties. More than 18 TCM plants in the families of Chloranthaceae (four genera, Chloranthus, Sarcandra, and Hedyosmum)86,87,88,89,90,91,92,93,94,95 and Compositae (five genera, Eupatorium96,97, Vernonia98, Siegesbeckia, Saussurea, and Parasenecio)96,97,98,99,100,101, and a fungus (Lactarius piperatus)102, have been investigated in our laboratory, which led to the identification more than 280 compounds. Among them, 126 were new compounds, and 8 possessed new carbon skeletons. Biological activity screening revealed that 28 isolates showed important biological activities in a number of tested bioassays, and some of the results were consistent with the traditional applications of these plants in TCM.

Mono- and dimeric sesquiterpenoids (Figure 5): The Chloranthaceae family has 16 species and 5 variants belonging to three genera, Chloranthus, Sarcandra and Hedyosmum, in China. Most plants in this family have been applied in TCM and/or Chinese folk medicine for a variety of indications. Chemical studies of seven species in the Chloranthaceae family conducted in our research group identified 42 new mono- and dimeric sesquiterpenoids, of which the sesquiterpenoid dimers are particularly interesting, especially 4 of these dimers, which possessed unprecedented carbon skeletons.

Figure 5.

Figure 5

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Structurally complex sesquiterpenoids.

Chlorahololides A–F (84–89)87,88, six highly complex sesquiterpenoid dimers, were isolated from whole C holostegius. Their structures and absolute configurations were established by spectroscopy, X-ray crystallography and CD analysis. Chlorahololides A–F (84–89) exhibited potent and selective inhibition of the delayed rectifier (IK) K+ current, with IC50 values of 10.9±12.3, 18.6±2.5, 3.6±10.1, 2.7±0.3, 27.5±5.1, and 57.5±6.1 μmol/L, respectively. It is noteworthy that the activities of chlorahololides A–F (84–89) are 18- to 388-fold more potent than the positive control tetraethylammonium chloride (IC50=1.05±0.21 mmol/L), a classical blocker of the delayed rectifier K+ current. Three more sesquiterpenoid dimers, multistalides A–B and chloramultilide A (90–92), were isolated from whole C multistachys90,91. Serratustones A (93) and B (94), which share an unprecedented carbon skeleton representing a novel dimerization of an elemane and a eudesmane sesquiterpenoid, were isolated from C serratus86. Two novel lindenane-type sesquiterpenoid dimers, sarcanolides A (95) and B (96), featuring an unprecedented carbon framework via the formation of C-11–C-7′ bond, were isolated from whole S hainanensis92. The structures of compounds 93–96, including the absolute configuration were fully determined by spectroscopy, X-ray crystallography, and CD analysis in combination with ECD calculation. A number of novel sesquiterpenoids were also isolated from plants in the Chloranthaceae family; eg, hlorantene A (97) isolated from C serratus possessed a unique C-4 to C-10 linkage89.

Phloroglucinol-coupled sesquiterpenoids (Figure 5): Eucalyptus globulusLabill, a tall timber tree, grows widely in the southern part of China. Its fruits and leaves have been used as a Chinese folk medicine to treat flu, dysentery, eczema, and scald. A large number of phloroglucinol-coupled sesquiterpenoids and other classes of phloroglucinol-coupled compounds were isolated from E globulus and other species in the Eucalyptus genus. Of these, eucalyptals A–C (98–100)94, with a novel 3,5-diformyl-isopentyl phloroglucinol-coupled cadinane carbon framework, were isolated from the fruits of E globulus. Their structures were elucidated by spectroscopic analysis, and that of 98 was confirmed by single-crystal X-ray diffraction. Compounds 98–100 showed selective activity against HL-60, with IC50 values of 1.7, 6.8, and 17 μmol/L, respectively.

Miscellaneous

In addition to our particular interests in natural alkaloids and terpenoids (tri, di, and sesquiterpenoids), we isolated more than 300 phenolics and prenylated polyketides from approximately 20 TCM or herb plants. Among them, approximately 60 were new compounds, and 6 had new carbon skeletons (Figure 6). In particular, 48 of these compounds showed significant biological activities in a variety of bioassays and provided a scientific foundation for the use of a number of traditional Chinese herbs103,104,105,106,107,108,109,110,111,112,113,114.

Figure 6.

Figure 6

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Phenolics and prenylated polyketides.

A series of phenolic compounds were isolated from the ethanolic extract of whole Sarcostemma acidum. Sacidumlignan D (101)108 was found to have an unprecedented rearranged tetrahydrofuran lignan skeleton. Psoracorylifols A–E (102–106)105 represented five novel compounds from buguzhi, a well-known TCM made from the seeds of Psoralea corylifolia. The structure of 102 was confirmed by single-crystal X-ray diffraction. Psoracorylifols D and E (105 and 106) exhibit an unprecedented carbon skeleton. A plausible biogenetic origin of psoracorylifols A–E (102–106) was also postulated. Psoracorylifols A–E (102–106) showed significant inhibition against two strains of H pylori (SS1 and ATCC 43504), with MICs of 12.5–25 μg/mL, respectively. Notably, the activity of psoracorylifols A–E (102–106) are 5–10 times stronger than that of metronidazole against H pylori ATCC 43504, a drug (metronidazole)-resistant strain; metronidazole is a critical ingredient in combination therapies of H pylori infection. The chemical investigation of the seeds of Psoralea corylifolia also revealed a number of prenylflavonoids, among which the two new compounds, corylifols A and B (107 and 108)107, significantly inhibited two hospital pathogenic gram-positive bacteria, S aureus ATCC 25923 (MICs: 0.147 and 0.037 mmol/L) and S epidermidis ATCC 12228 (MICs: 0.147 and 0.037 mmol/L) in vitro. Cinnacassides A–E (109–113)103 are five novel glycosides with a unique geranylphenylacetate aglycone carbon skeleton from a common TCM (Rougui) based on the stem bark of Cinnamomum cassia. Each of the cinnacassides A–D (109–113) possessed one of the four stereoisomers of the aglycone. Their structures were established by extensive spectroscopic analysis and chemical and chiroptical methods. Plausible biosynthetic routes for 109–113 were also proposed.

Harrisotones A–E (114–118), five novel prenylated polyketides with a rare spirocyclic hydroperoxypolyketide-derived skeleton, along with the new hydroperoxypolyketide harrisonol A (119), were isolated from Harrisonia perforate104. Their structures were extensively elucidated through spectroscopic analysis and CD spectra. The origins of compounds 114–118 could be traced back to harrisonol A (119). Harrisotone A and C and harrisonol A (114, 116, and 119) exhibited significant cytotoxic activity against P388 tumor cells, with IC50 values of 1.56, 2.35, and 0.27 μmol/L, respectively. Harrisotone A (114) and harrisonol A (119) also showed moderate activity against A549 tumor cells, with IC50 values of 24.5 and 26.6 μmol/L, respectively.

Structural modifications and structure-activity relationship studies

In our search for bioactive natural products13,16,22,24,25,29,33,36,38,39,41,42,44,45,46,51,52,53,58,63,68,70,73,74,75,76,77,78,79,80,81,85,87,88,93,95,96,97,98,103,104,105,106,107,108,109,115,116,117,118,119,120, a large number of compounds were found to exhibit a variety of biological activities, and 11 compounds with particularly promising potential were selected for structure optimization and structure-activity relationship studies. As a result, over 400 new derivatives were obtained. Among these derivatives, 58 showed significantly improved activities, which provided opportunities to explore the structure-activity relationship of the related compound class121,122,123,124,125. As an example, we will discuss the structure optimization and structure-activity relationship study of the antiangiogenesis pseudolaric acid B (PAB)121. PAB is the major active component of a well-known TCM (Tujinpi), the root bark of Pseudolarix kaempferi, which has traditional applications as an antifungal and abortifacient for use in the early stage of pregnancy. PAB also showed strong cytotoxic activity. In our collaboration study, this compound was found for the first time to have strong antiangiogenic activity with a unique mode of antitumor action118,119,120. A structural modification of PAB was thus conducted, and more than 40 derivatives were prepared in the first round. Antitumor assays showed that nine derivatives in the series 120a–120n showed significantly improved activities, while those in the 121a–121d and 122a–122g series were inactive.

Observation of the structures of PAB and its derivatives revealed a clear antitumor structure activity relationship (Scheme 2)121: (1) All of the active PAB compounds tested in our study (120a–120n) have amphipathic properties and possess a hydrophobic domain of a constrained-rings system and a hydrophilic domain consisting of a side chain possessing an conjugated double bond and a terminal carboxylic acid. (2) A hydrophobic group R1 at C-7 and a Δ7 double bond are necessary for the anticancer activity, and the bulk and steric factor of R1 also seem relevant to the activity. (3) The chain length and/or the conjugated double bonds in the side chain are essential for the anticancer activity. (4) Any structural changes in the seven-membered ring, eg, Δ7 double bond migration and oxygenation at C-7 or C-8, will render the analogs inactive. (5) The C-4 acetoxyl group is crucial for the activity and its removal or replacement with a bulk acyloxy group significantly attenuated the activity. (6) The free carboxylic acid group in the terminus of the side chain is necessary for the anticancer activity, while acylation or amidation of this group with either a hydrophilic or a hydrophobic group is detrimental to the activity.

Scheme 2.

Scheme 2

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Preparation of PAB derivatives and structure activity relationship study.

PAB is also a strong antifungal agent. The anticancer SAR of the aforementioned PAB analogs is very similar to the antifungal SAR reported by our group81, except for the difference in the modification of the R1 group. The modification of the R1 group of PAB showed a particularly exciting result with respect to anticancer activity. Meanwhile, in an antifungal assay, all of the structurally modified PAB analogs showed attenuated activities or were completely inactive81. Our studies suggest that PAB is very promising as an anticancer drug lead but limited as an antifungal lead due to its loss of activity upon modification and strong cytotoxic side effects.

Acknowledgments

This work was supported by the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program” (Grant No 2011ZX09307-002-03), the foundation of the Ministry of Science and Technology (2012CB721105) of China, and the National Natural Science Foundation (Grant No 30025044, 30630072, and 21072203) of China.

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