Skip to main content
NCBI home page
ACS Medicinal Chemistry Letters logoLink to ACS Medicinal Chemistry Letters
. 2018 Oct 19;9(11):1128–1133. doi: 10.1021/acsmedchemlett.8b00381

Synthesis of Artemisinin–Estrogen Hybrids Highly Active against HCMV, P. falciparum, and Cervical and Breast Cancer

Tony Fröhlich †, Anita Kiss ‡, János Wölfling ‡, Erzsébet Mernyák ‡, Ágnes E Kulmány §, Renáta Minorics §, István Zupkó §, Maria Leidenberger ∥, Oliver Friedrich ∥, Barbara Kappes ∥, Friedrich Hahn ⊥, Manfred Marschall ⊥, Gyula Schneider ‡, Svetlana B Tsogoeva †,*
PMCID: PMC6231177  PMID: 30429957

Abstract

graphic file with name ml-2018-00381a_0005.jpg

Artemisinin–estrogen hybrids were for the first time both synthesized and investigated for their in vitro biological activity against malaria parasites (Plasmodium falciparum 3D7), human cytomegalovirus (HCMV), and a panel of human malignant cells of gynecological origin containing breast (MCF7, MDA-MB-231, MDA-MB-361, T47D) and cervical tumor cell lines (HeLa, SiHa, C33A). In terms of antimalarial efficacy, hybrid 8 (EC50 = 3.8 nM) was about two times more active than its parent compound artesunic acid (7) (EC50 = 8.9 nM) as well as the standard drug chloroquine (EC50 = 9.8 nM) and was, therefore, comparable to the clinically used dihydroartemisinin (6) (EC50 = 2.4 nM). Furthermore, hybrids 9–12 showed a strong antiviral effect with EC50 values in the submicromolar range (0.22–0.38 μM) and thus possess profoundly stronger anti-HCMV activity (approximately factor 25) than the parent compound artesunic acid (7) (EC50 = 5.41 μM). These compounds also exerted a higher in vitro anti-HCMV efficacy than ganciclovir used as the standard of current antiviral treatment. In addition, hybrids 8–12 elicited substantially more pronounced growth inhibiting action on all cancer cell lines than their parent compounds and the reference drug cisplatin. The most potent agent, hybrid 12, exhibited submicromolar EC50 values (0.15–0.93 μM) against breast cancer and C33A cell lines.

Keywords: Artemisinin, estrogen, antimalarial activity, anticancer activity, antiviral activity

Over the last three decades, steroids have become a prime focus of research in the field of medicinal chemistry due to their remarkable and diverse pharmacological properties, such as anticancer,1,2 anti-inflammatory,3,4 antiparasitic,5 and antiviral activities.6,7 In particular, the two steroid hormones estrone (1) and 17β-estradiol (2) (Figure 1) attracted a lot of attention, as these two estrogens are known to be involved in the development of various cancer types such as breast, colorectal, prostate, and ovarian cancer.8 This led to the discovery of many different estradiol derivatives, which revealed to possess promising anticancer activity. In 2003, fulvestrant (3), an estrogen receptor antagonist, was approved in the USA for the treatment of hormone-related breast cancer, and since then it has been used in clinics.9 2-Methoxyestradiol (4), an endogenous metabolite of 17β-estradiol (2), turned out to effectively inhibit cancer cell proliferation both in vitro and in vivo and is currently investigated in advanced phases of clinical trials.10−15 One of the main advantages of 2-methoxyestradiol (4) over other biologically active estrogens is that it does not act as an estrogen receptor agonist and consequently is free of the typical hormone-related side effects.16,17 Furthermore, no serious toxicity was observed in clinical trials when 2-methoxyestradiol (4) was applied in pharmacological effective doses, and therefore, it can be regarded as a promising anticancer agent.16,18

Figure 1.

Figure 1

Open in a new tab

Structures of estrone (1), 17β-estradiol (2), fulvestrant (3), 2-methoxyestradiol (4), artemisinin (5), dihydroartemisinin (6), and artesunic acid (7).

As of now, no artemisinin-estrogen hybrids were reported in the literature, and our working group already could obtain remarkable results applying the hybridization concept;19−22 where two different biologically active substances are linked via a covalent bond,23,24 we planned to use estrogen derivatives as precursors for the synthesis of novel artemisinin hybrid molecules. Since its isolation in 1972 from the plant Artemisia annua L. by Youyou Tu, for which she received the Nobel Prize in 2015, artemisinin (5) was intensively investigated for its pharmacological activities.25,26 Artemisinin (5) exhibits not only antimalarial activity, for what it was mainly used in traditional Chinese medicine for several centuries,27−29 but it also revealed to possess antiviral30−33 and anticancer efficacy.34−38 These promising properties are also reflected in its semisynthetic derivatives dihydroartemisinin (6)39−41 and artesunic acid (7),42−45 bearing an alcohol or a carboxylic acid functionality and for that reason appear to be well-suited for hybridization purposes. Recently, it could be even demonstrated in a phase I clinical trial, which was performed in patients with metastatic breast cancer, that higher cumulative doses of artesunic acid are safe and well tolerated.46

Herein, we present the synthesis of five novel artemisinin-estrogen hybrids 8–12 (Figure 2) and the evaluation of their in vitro biological activity against malaria parasites (Plasmodium falciparum 3D7), human cytomegalovirus (HCMV), and a selection of human breast cancer cell lines (MCF7, MDA-MB-231, MDA-MB-361, T47D) and cervical tumor cell lines (HeLa, SiHa, C33A).

Figure 2.

Figure 2

Open in a new tab

Novel hybrids 8–12 applied for biological tests against P. falciparum 3D7, HCMV, and breast and cervical cancer.

Results and Discussion

Chemistry

Hybrids 8 and 9 were prepared in moderate to good yields (81%/45%) by standard amide coupling between estradiol amine 13 and either artesunic acid (7) or artemisinin-derived carboxylic acid 15 (Scheme 1). The reaction was conducted at room temperature overnight in a 1:1 mixture of CH3CN and CH2Cl2 as solvent, and EDCI was solely used as coupling agent. Surprisingly, under these conditions no ester formation was observed as a side reaction, and the desired amides (8, 9) were the only products. The synthesis of the artemisinin-derived acid 15 was carried out in accordance to an already published protocol starting from dihydroartemisinin (6) (Scheme 2).47 The special feature of this artemisinin derivative is that it is free of the O atom at C-10, and for that reason, it has been referred to a so-called C-10 nonacetal in the previous literature. This derivative has been considered to be more stable compared to the classical C-10-acetals such as artesunic acid (7).48 The other precursor, necessary for the synthesis of hybrids 8 and 9, 3-methoxy-estradiol-derived amine 13 (Scheme 2), was also prepared in analogy to procedures described in the literature.49−51 The stereoselectivity of the metal borohydride-mediated reduction of 16α-azido estrone 3-methyl ether (17) toward 17α- and 17β-estradiol derivatives 18a/b can be achieved by selecting different alkali metals (Li, Na, or K) as countercation. If bigger countercations like potassium are used, the 17β-isomer is predominantly formed (57% yield), whereas smaller countercations such as lithium lead almost exclusively to the formation of the 17α-isomer (59% yield). 16α-Azido 17β-estradiol 3-methyl ether (18b) was then converted to the desired amine 13 by hydrazine monohydrate mediated reduction catalyzed by Raney-Ni (95% yield). The synthesis of hybrid 10 containing a 1,2,3-triazole linkage was realized by a copper-catalyzed 1,3-dipolar cycloaddition between 16α-azido estrone 3-methyl ether (17) and artemisinin-derived alkyne 16, which afforded the desired product in 42% yield. Catalytic amounts of copper(II) sulfate and sodium ascorbate served as a source for copper(I), which was generated in situ. Alkyne 16 was prepared according to the literature by etherification of dihydroartemisinin (6) with propargyl alcohol.52 As a final step, 3-benzyloxy-17β-hydroxy-16β-hydroxymethyl-estrone derivative 14 was reacted with either artesunic acid (7) or artemisinin-derived acid 15 in a Steglich esterification in order to yield the desired hybrids 11 and 12 in 95/56%. DCC and DMAP were used as coupling agents and CH2Cl2 as solvent. The ester formation took place only at the primary alcohol group, which is probably attributed to its higher reactivity and less steric hindrance. The stability of target compounds 8–12 was examined by heat exposure at 65 °C for 24 h or 40 °C for 48 h, respectively. After applying these conditions, 1H NMR spectroscopy revealed that all synthesized hybrids remained sufficiently stable, i.e., less than 5% decomposition was detected in the recorded spectra.

Scheme 1. Synthesis Route for Hybrids 8–12.

Scheme 1

Open in a new tab

Scheme 2. Synthesis of Estrogen Precursor 13 and Artemisinin-Derived Acid 15.

Scheme 2

Open in a new tab

The hydroxy group at C-3 of all artemisinin-estrogen hybrids 8–12 was protected via an ether group (benzyloxy or methoxy) to decrease the binding affinities of these novel compounds to the estrogen receptors and consequently reduce eventual hormone-related side effects.

Biological Activity of the Hybrids

Antimalarial Activity

All synthesized hybrids 8–12 as well as their precursors, dihydroartemisinin (6), artesunic acid (7), estrone diol 14, and estrone azide 17 were investigated for their antimalarial activity against chloroquine-sensitive Plasmodium falciparum 3D7 parasites (Table 1). Hybrids 8–12 exhibited excellent to moderate antimalarial efficacy with EC50 values ranging from 3.8 to 128.8 nM, while their estrogen precursors 14 and 17 showed no activity (EC50 > 16,000 nM). The best performing hybrid 8 was roughly two times more active than its parent compound artesunic acid (7) (EC50 = 8.9 nM) as well as the standard drug chloroquine (9.8 nM) and was therefore in terms of antimalarial efficacy comparable to the clinically used dihydroartemisinin (6) (EC50 = 2.4 nM). Hybrids 9 and 12 containing a C-10 nonacetal artemisinin moiety were found to be two and four times, correspondingly, less active (EC50 values of 7.7 and 128.8 nM) than their C-10 acetal counterparts (EC50(8) = 3.8 nM; EC50(11) = 34.2 nM). The same behavior was also observed in connection with artemisinin-quinazoline hybrids,53 which is in contrast to that of artemisinin-derived dimers.54 This indicates that different mechanisms might be involved for artemisinin-derived hybrids than for artemisinin-based dimeric structures. In addition, these EC50 values also demonstrate that a benzyloxy subunit at C-3 of the estrogen moiety (hybrids 11 and 12) seems to be unbeneficial for antimalarial activity of artemisinin-estrogen hybrids, as compounds 8 and 9 with a methoxy group were much more active. This result might be explained by the fact that hybrids 11 and 12 are more lipophilic than compounds 8 and 9, and as a result, their cellular uptake into compartments of the malaria parasite in which they unfold their effect may be more limited.

Table 1. EC50 Values for Hybrids 8–12 and Selected Reference Compounds Tested against P. falciparum 3D7 Parasites, HCMV, and Various Human Breast and Cervical Cancer Cell Lines.
        EC50 (μM)e
compound MW (g/mol) EC50 (nM) P.f. 3D7 EC50 (μM) HCMV MCF7 MDA-MB-231 MDA-MB-361 T47D HeLa SiHa C33A
chloroquine 319.87 9.8 ± 2.8a                
ganciclovir 579.98   2.60 ± 0.50b              
cisplatin 300.05     5.78 19.13 3.76 9.78 12.43 7.87 3.69
artemisinin (5) 282.14   >10c - - - - - - -
DHA (6) 284.35 2.4 ± 0.4a >10c 8.24 10.69 1.71 4.60 10.46 29.80 1.71
artesunic acid (7) 384.42 8.9 ± 1.9 5.41 ± 0.60d 4.21 10.04 2.27 2.22 12.03 >30 1.83
estrone amine 13 301.43 - - 11.90 15.95 4.58 5.56 13.30 17.35 13.25
estrone diol 14 392.54 17,250 ± 586 - 12.89 12.75 2.77 8.32 12.80 7.75 12.20
estrone azide 17 325.41 >50,000 - >30 >30 >30 >30 >30 >30 >30
8 667.84 3.8 ± 0.8 2.44 ± 0.13 4.69 6.89 0.64 0.74 11.45 26.00 0.87
9 609.80 7.7 ± 2.4 0.23 ± 0.20 1.02 1.85 0.69 1.17 1.65 6.21 0.57
10 647.81 13.1 ± 1.8 0.24 ± 0.01 1.77 1.78 0.17 0.16 15.40 28.90 2.05
11 758.95 34.2 ± 3.2 0.38 ± 0.10 0.76 2.30 0.20 0.22 >30 28.43 1.73
12 700.91 128.8 ± 13.0 0.22 ± 0.00 0.45 0.86 0.18 0.93 14.22 16.12 0.15
Open in a new tab
a

EC50 values have been previously reported.19

b

EC50 value has been previously reported.43

c

EC50 values have been previously reported.21

d

EC50 value has been previously reported.58

e

Mean values from two independent determinations with five parallel wells.

Anticytomegaloviral Activity

Furthermore, hybrids 8–12 were analyzed for their antiviral activity, focusing on human cytomegalovirus (recombinant HCMV AD169-GFP) used for the infection of cultured primary human foreskin fibroblasts (HFFs). Experimental determination of EC50 values was carried out in accordance to a previously established protocol,55−58 and the results thereof are summarized in Table 1. Hybrids 9–12 exerted a high antiviral efficacy with EC50 values in the submicromolar range (0.22–0.38 μM) and thus possessed a profoundly stronger anti-HCMV activity (approximately factor 25) than the parent compound artesunic acid (7). These compounds were also more effective than ganciclovir used as the gold standard of current antiviral treatment. In contrast to the determined antimalarial activities, C-10 nonacetal-linked artemisinin-derived hybrids 9 and 12 were more potent in anti-HCMV activity than their C-10 acetal-linked counterparts (hybrids 8 and 11). This difference was most pronounced between compounds 8 and 9. In this case, hybrid 8 (EC50 = 2.44 μM) was approximately ten times less active than hybrid 9 (EC50 = 0.23 μM). Cell morphology, growth behavior, and signs of cytotoxicity were routinely monitored by microscopic inspection under compound treatment along the period of infection (7 days, referring to a situation of multiround viral replication), and no cytotoxicity was observed within the range of all concentrations tested.

Anticancer Activity

In a next step, hybrids 8–12 as well as their artemisinin and estrone precursors were investigated for their anticancer potential by means of MTT assay against a panel of human breast (MCF7, MDA-MB-231, MDA-MB-361, T47D) and cervical (HeLa, SiHa, C33A) cancer cell lines (Table 1). Estrone derivatives 13 and 14 exhibited antiproliferative action similar to that of reference agent cisplatin in terms of potency, while estrone azide 17 proved to be ineffective. Both artemisinin-derived compounds 6 and 7 elicited growth inhibitory effects comparable to cisplatin with exception for SiHa cell line, which was not sensitive toward them. All of the synthesized hybrids 8–12 exhibited substantially pronounced antiproliferative action on breast cancer cells. The most potent hybrid 12 displayed submicromolar EC50 values (0.18–0.93 μM) indicating an outstanding increase in the efficacy when compared with the actions of the building elements of the molecule. In the case of cervical cell lines, the actions of the precursors were modest and the increase in the anticancer potency were less dynamic, though compound 9 was remarkable on all utilized cells, and hybrid 12 exhibited promising action on C33A cell line.

Conclusion

In conclusion, several estradiol/estrone derivatives could be coupled to artemisinin for the first time, thereby forming five novel artemisinin-estrogen hybrids 8–12. These were investigated for their in vitro biological activity against malaria parasites (Plasmodium falciparum 3D7), human cytomegalovirus (HCMV), and a selection of human breast and cervical cancer cell lines. All synthesized hybrids exhibited a strong antimalarial effect with EC50 values in the nanomolar range (3.8–128.8 nM). The most active hybrid in terms of antimalarial efficacy, compound 8, was about two times more active than its parent compound artesunic acid (7) (EC50 = 8.9 nM) as well as the standard drug chloroquine (9.8 nM) and was therefore comparable to the clinically used dihydroartemisinin (6) (EC50 = 2.4 nM). Furthermore, hybrids 9–12 exhibited high antiviral activity (EC50 = 0.22–0.38 μM) and thus represent a group of very attractive, novel chemical structures exerting a pronounced anti-HCMV activity mostly in the submicromolar range, which appears even superior to the in vitro efficacy of reference drug ganciclovir. Besides the antimicrobial properties of the prepared agents, they exhibited a pronounced growth inhibitory action against a panel of human cancer cells. EC50 values of the hybrids were lower by orders of magnitude when compared with those of the building blocks. Based on the results of the presented antiproliferative assays, hybrid molecules designed and synthesized from artemisinin and estrone elements can be regarded as potential lead molecules for development of innovative anticancer agents. All in all, a relatively low level of effort in chemical synthesis was sufficient to generate very promising pharmacological candidate compounds, which once again highlights the attractiveness of the hybridization concept. We like to stress that this concept possesses a broad translational potential and might be useful for a number of future drug and biomedical developments.

Acknowledgments

S.B.T. and M.M. are grateful to the Deutsche Forschungsgemeinschaft (DFG) for generous funding by grants TS 87/16-3; MA 1289/7-3 and to the Interdisciplinary Center for Molecular Materials (ICMM), the Graduate School Molecular Science (GSMS), as well as Emerging Fields Initiative (EFI) “Chemistry in Live Cells” supported by Friedrich-Alexander-Universität Erlangen-Nürnberg for research funding. Financial support by the National Research, Development and Innovation Office-NKFIH through project GINOP-2.3.2.-15-2016-00038 (Hungary) is gratefully acknowledged. Furthermore, the authors are grateful for financial support from OTKA K113150 and K109293. The work of A.K. was supported by a Ph.D. Fellowship of the Talentum Fund of Richter Gedeon Plc. R.M. was supported by a János Bolyai Research Scholarship of the Hungarian Academy of Sciences.

Glossary

ABBREVIATIONS

DCC

N,N′-dicyclohexylcarbodiimide

DCE

1,2-dichloroethane

DHA

dihydroartemisinin

DMAP

4-(dimethylamino)pyridine

EDCI

N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide

GFP

green fluorescent protein

HCMV

human cytomegalovirus

HFFs

human foreskin fibroblasts.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.8b00381.

  • Experimental conditions and procedures as well as spectral data for precursors 13, 15, 16, 18a/b, 19, and 20 and target compounds 8–12; recorded spectra of target compounds; details of cell lines and reagents as well as cell viability assay for biological evaluation (PDF); SMILES data (XLSX)

The authors declare no competing financial interest.

Dedication

This paper is dedicated to Professor Youyou Tu.

Supplementary Material

ml8b00381_si_001.pdf (1.7MB, pdf)
ml8b00381_si_002.xlsx (13.1KB, xlsx)

References

  1. Arenas-González A.; Mendez-Delgado L. A.; Merino-Montiel P.; Padrón J. M.; Montiel-Smith S.; Vega-Báez J. L.; Meza- Reyes S. Synthesis of monomeric and dimeric steroids containing [1,2,4]triazolo[1,5-a]pyrimidines. Steroids 2016, 116, 13. 10.1016/j.steroids.2016.09.014. [DOI] [PubMed] [Google Scholar]
  2. Alsayari A.; Kopel L.; Ahmed M. S.; Pay A.; Carlson T.; Halaweish F. T. Design, synthesis, and biological evaluation of steroidal analogs as estrogenic/anti-estrogenic agents. Steroids 2017, 118, 32. 10.1016/j.steroids.2016.11.005. [DOI] [PubMed] [Google Scholar]
  3. Khan M. O. F.; Lee H. J. Synthesis and Pharmacology of Anti-inflammatory Steroidal Antedrugs. Chem. Rev. 2008, 108, 5131. 10.1021/cr068203e. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Biju P.; Bitar R.; Lim Y.-H.; Wang Y.; Berlin M.; Aslanian R.; McCormick K. Synthesis of novel anti-inflammatory steroidal macrocycles using ring closing metathesis reaction. Tetrahedron Lett. 2015, 56, 636. 10.1016/j.tetlet.2014.12.048. [DOI] [Google Scholar]
  5. Krieg R.; Jortzik E.; Goetz A. A.; Blandin S.; Wittlin S.; Elhabiri M.; Rahbari M.; Nuryyeva S.; Voigt K.; Dahse H. M.; Brakhage A.; Beckmann S.; Quack T.; Grevelding C. G.; Pinkerton A. B.; Schonecker B.; Burrows J.; Davioud-Charvet E.; Rahlfs S.; Becker K. Arylmethylamino steroids as antiparasitic agents. Nat. Commun. 2017, 8, 14478. 10.1038/ncomms14478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Nadaraia N. S.; Onashvili E. O.; Kakhabrishvili M. L.; Barbakadze N. N.; Sylla B.; Pichette A. Synthesis and Antiviral Activity of Several N-Containing 5α-STEROIDS. Chem. Nat. Compd. 2016, 52, 853. 10.1007/s10600-016-1795-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Zhao J. L.; Zhang M.; Liu J. M.; Tan Z.; Chen R. D.; Xie K. B.; Dai J. G. Bioactive steroids and sorbicillinoids isolated from the endophytic fungus Trichoderma sp. Xy24. J. Asian Nat. Prod. Res. 2017, 19, 1028. 10.1080/10286020.2017.1285908. [DOI] [PubMed] [Google Scholar]
  8. Deroo B. J.; Korach K. S. Estrogen receptors and human disease. J. Clin. Invest. 2006, 116, 561. 10.1172/JCI27987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Jones S. E. Fulvestrant: an estrogen receptor antagonist that downregulates the estrogen receptor. Semin. Oncol. 2003, 30, 14. 10.1053/j.seminoncol.2003.08.003. [DOI] [PubMed] [Google Scholar]
  10. Fotsis T.; Zhang Y.; Pepper M. S.; Adlercreutz H.; Montesano R.; Nawroth P. P.; Schweigerer L. The endogenous oestrogen metabolite 2-methoxyoestradiol inhibits angiogenesis and suppresses tumour growth. Nature 1994, 368, 237. 10.1038/368237a0. [DOI] [PubMed] [Google Scholar]
  11. Tevaarwerk A. J.; Holen K. D.; Alberti D. B.; Sidor C.; Arnott J.; Quon C.; Wilding G.; Liu G. Phase I Trial of 2-Methoxyestradiol (2ME2, Panzem®) NanoCrystal® Dispersion (NCD®) in Advanced Solid Malignancies. Clin. Cancer Res. 2009, 15, 1460. 10.1158/1078-0432.CCR-08-1599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fukui M.; Zhu B. T. Mechanism of 2-methoxyestradiol-induced apoptosis and growth arrest in human breast cancer cells. Mol. Carcinog. 2009, 48, 66. 10.1002/mc.20458. [DOI] [PubMed] [Google Scholar]
  13. Kulke M. H.; Chan J. A.; Meyerhardt J. A.; Zhu A. X.; Abrams T. A.; Blaszkowsky L. S.; Regan E.; Sidor C.; Fuchs C. S. A prospective phase II study of 2-methoxyestradiol administered in combination with bevacizumab in patients with metastatic carcinoid tumors. Cancer Chemother. Pharmacol. 2011, 68, 293. 10.1007/s00280-010-1478-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Bruce J. Y.; Eickhoff J.; Pili R.; Logan T.; Carducci M.; Arnott J.; Treston A.; Wilding G.; Liu G. A phase II study of 2-methoxyestradiol nanocrystal colloidal dispersion alone and in combination with sunitinib malate in patients with metastatic renal cell carcinoma progressing on sunitinib malate. Invest. New Drugs 2012, 30, 794. 10.1007/s10637-010-9618-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gorska M.; Kuban-Jankowska A.; Slawek J.; Wozniak M. New Insight into 2-Methoxyestradiol- a Possible Physiological Link between Neurodegeneration and Cancer Cell Death. Curr. Med. Chem. 2016, 23, 1513. 10.2174/0929867323666160316123443. [DOI] [PubMed] [Google Scholar]
  16. Lakhani N. J.; Sarkar M. A.; Venitz J.; Figg W. D. 2-Methoxyestradiol, a promising anticancer agent. Pharmacotherapy 2003, 23, 165. 10.1592/phco.23.2.165.32088. [DOI] [PubMed] [Google Scholar]
  17. Luc J. G. Y.; Paulin R.; Zhao J. Y.; Freed D. H.; Michelakis E. D.; Nagendran J. 2-Methoxyestradiol: A Hormonal Metabolite Modulates Stimulated T-Cells Function and proliferation. Transplant. Proc. 2015, 47, 2057. 10.1016/j.transproceed.2015.05.021. [DOI] [PubMed] [Google Scholar]
  18. Perez-Sepulveda A.; España-Perrot P. P.; Norwitz E. R.; Illanes S. E. Metabolic Pathways Involved in 2-Methoxyestradiol Synthesis and Their Role in Preeclampsia. Reprod. Sci. 2013, 20, 1020. 10.1177/1933719113477483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Reiter C.; Fröhlich T.; Zeino M.; Marschall M.; Bahsi H.; Leidenberger M.; Friedrich O.; Kappes B.; Hampel F.; Efferth T.; Tsogoeva S. B. New efficient artemisinin derived agents against human leukemia cells, human cytomegalovirus and Plasmodium falciparum: 2nd generation 1,2,4-trioxane-ferrocene hybrids. Eur. J. Med. Chem. 2015, 97, 164. 10.1016/j.ejmech.2015.04.053. [DOI] [PubMed] [Google Scholar]
  20. Fröhlich T.; Ndreshkjana B.; Muenzner J. K.; Reiter C.; Hofmeister E.; Mederer S.; Fatfat M.; El-Baba C.; Gali-Muhtasib H.; Schneider-Stock R.; Tsogoeva S. B. Synthesis of Novel Hybrids of Thymoquinone and Artemisinin with High Activity and Selectivity Against Colon Cancer. ChemMedChem 2017, 12, 226. 10.1002/cmdc.201600594. [DOI] [PubMed] [Google Scholar]
  21. Held F. E.; Guryev A. A.; Fröhlich T.; Hampel F.; Kahnt A.; Hutterer C.; Steingruber M.; Bahsi H.; von Bojničić-Kninski C.; Mattes D. S.; Foertsch T. C.; Nesterov-Mueller A.; Marschall M.; Tsogoeva S. B. Facile access to potent antiviral quinazoline heterocycles with fluorescence properties via merging metal-free domino reactions. Nat. Commun. 2017, 8, 15071. 10.1038/ncomms15071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Fröhlich T.; Reiter C.; Saeed M. E. M.; Hutterer C.; Hahn F.; Leidenberger M.; Friedrich O.; Kappes B.; Marschall M.; Efferth T.; Tsogoeva S. B. Synthesis of Thymoquinone-Artemisinin Hybrids: New Potent Antileukemia, Antiviral and Antimalarial Agents. ACS Med. Chem. Lett. 2018, 9, 534. 10.1021/acsmedchemlett.7b00412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mehta G.; Singh V. Hybrid systems through natural product leads: An approach towards new molecular entities. Chem. Soc. Rev. 2002, 31, 324. 10.1039/b204748a. [DOI] [PubMed] [Google Scholar]
  24. Tietze L. F.; Bell H. P.; Chandrasekhar S. Natural Product Hybrids as New Leads for Drug Discovery. Angew. Chem., Int. Ed. 2003, 42, 3996. 10.1002/anie.200200553. [DOI] [PubMed] [Google Scholar]
  25. Tu Y. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat. Med. 2011, 17, 1217. 10.1038/nm.2471. [DOI] [PubMed] [Google Scholar]
  26. Su X.-z.; Miller L. H. The discovery of artemisinin and Nobel Prize in Physiology or Medicine. Sci. China: Life Sci. 2015, 58, 1175. 10.1007/s11427-015-4948-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Qinghaosu Antimalarial Coordinating Research Group. Antimalaria studies on Qinghaosu. Chin. Med. J. (Engl. Ed.) 1979, 12, 811–816. [PubMed] [Google Scholar]
  28. Klayman D. Qinghaosu (artemisinin): an antimalarial drug from China. Science 1985, 228, 1049. 10.1126/science.3887571. [DOI] [PubMed] [Google Scholar]
  29. Miller L. H.; Su X. Artemisinin: Discovery from the Chinese Herbal Garden. Cell 2011, 146, 855. 10.1016/j.cell.2011.08.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Romero M. R.; Serrano M. A.; Vallejo M.; Efferth T.; Alvarez M.; Marin J. J. Antiviral effect of artemisinin from Artemisia annua against a model member of the Flaviviridae family, the bovine viral diarrhoea virus (BVDV). Planta Med. 2006, 72, 1169. 10.1055/s-2006-947198. [DOI] [PubMed] [Google Scholar]
  31. Paeshuyse J.; Coelmont L.; Vliegen I.; Van hemel J.; Vandenkerckhove J.; Peys E.; Sas B.; De Clercq E.; Neyts J. Hemin potentiates the anti-hepatitis C virus activity of the antimalarial drug artemisinin. Biochem. Biophys. Res. Commun. 2006, 348, 139. 10.1016/j.bbrc.2006.07.014. [DOI] [PubMed] [Google Scholar]
  32. Efferth T.; Romero M. R.; Wolf D. G.; Stamminger T.; Marin J. J.; Marschall M. The antiviral activities of artemisinin and artesunate. Clin. Infect. Dis. 2008, 47, 804. 10.1086/591195. [DOI] [PubMed] [Google Scholar]
  33. Parvez M. K.; Arbab A. H.; Al-Dosari M. S.; Al-Rehaily A. J. Antiviral Natural Products Against Chronic Hepatitis B: Recent Developments. Curr. Pharm. Des. 2016, 22, 286. 10.2174/1381612822666151112152733. [DOI] [PubMed] [Google Scholar]
  34. Woerdenbag H. J.; Moskal T. A.; Pras N.; Malingre T. M.; el-Feraly F. S.; Kampinga H. H.; Konings A. W. Cytotoxicity of artemisinin-related endoperoxides to Ehrlich ascites tumor cells. J. Nat. Prod. 1993, 56, 849. 10.1021/np50096a007. [DOI] [PubMed] [Google Scholar]
  35. Singh N. P.; Lai H. C. Artemisinin induces apoptosis in human cancer cells. Anticancer Res. 2004, 24, 2277–2280. [PubMed] [Google Scholar]
  36. Efferth T. Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells. Curr. Drug Targets 2006, 7, 407. 10.2174/138945006776359412. [DOI] [PubMed] [Google Scholar]
  37. Lai H. C.; Singh N. P.; Sasaki T. Development of artemisinin compounds for cancer treatment. Invest. New Drugs 2013, 31, 230. 10.1007/s10637-012-9873-z. [DOI] [PubMed] [Google Scholar]
  38. Li Z.; Li Q.; Wu J.; Wang M.; Yu J. Artemisinin and Its Derivatives as a Repurposing Anticancer Agent: What Else Do We Need to Do?. Molecules 2016, 21, 1331. 10.3390/molecules21101331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Crespo-Ortiz M. P.; Wei M. Q. Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial Agent to a Potential Anticancer Drug. J. Biomed. Biotechnol. 2012, 2012, 1. 10.1155/2012/247597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sun H.; Meng X.; Han J.; Zhang Z.; Wang B.; Bai X.; Zhang X. Anti-cancer activity of DHA on gastric cancer - An in vitro and in vivo study. Tumor Biol. 2013, 34, 3791. 10.1007/s13277-013-0963-0. [DOI] [PubMed] [Google Scholar]
  41. Xu G.; Zou W.-Q.; Du S.-J.; Wu M.-J.; Xiang T.-X.; Luo Z.-G. Mechanism of dihydroartemisinin-induced apoptosis in prostate cancer PC3 cells: An iTRAQ-based proteomic analysis. Life Sci. 2016, 157, 1. 10.1016/j.lfs.2016.05.033. [DOI] [PubMed] [Google Scholar]
  42. Looareesuwan S.; Wilairatana P.; Vanijanonta S.; Pitisuttithum P.; Ratanapong Y.; Andrial M. Monotherapy with sodium artesunate for uncomplicated falciparum malaria in Thailand: a comparison of 5- and 7-day regimens. Acta Trop. 1997, 67, 197. 10.1016/S0001-706X(97)00063-6. [DOI] [PubMed] [Google Scholar]
  43. Kaptein S. J. F.; Efferth T.; Leis M.; Rechter S.; Auerochs S.; Kalmer M.; Bruggeman C. A.; Vink C.; Stamminger T.; Marschall M. The anti-malaria drug artesunate inhibits replication of cytomegalovirus in vitro and in vivo. Antiviral Res. 2006, 69, 60. 10.1016/j.antiviral.2005.10.003. [DOI] [PubMed] [Google Scholar]
  44. Michaelis M.; Kleinschmidt M. C.; Barth S.; Rothweiler F.; Geiler J.; Breitling R.; Mayer B.; Deubzer H.; Witt O.; Kreuter J.; Doerr H. W.; Cinatl J.; Cinatl J. Jr. Anti-cancer effects of artesunate in a panel of chemoresistant neuroblastoma cell lines. Biochem. Pharmacol. 2010, 79, 130. 10.1016/j.bcp.2009.08.013. [DOI] [PubMed] [Google Scholar]
  45. Zhou X.; Sun W. J.; Wang W. M.; Chen K.; Zheng J. H.; Lu M. D.; Li P. H.; Zheng Z. Q. Artesunate inhibits the growth of gastric cancer cells through the mechanism of promoting oncosis both in vitro and in vivo. Anti-Cancer Drugs 2013, 24, 920. 10.1097/CAD.0b013e328364a109. [DOI] [PubMed] [Google Scholar]
  46. von Hagens C.; Walter-Sack I.; Goeckenjan M.; Osburg J.; Storch-Hagenlocher B.; Sertel S.; Elsässer M.; Remppis B. A.; Edler L.; Munzinger J.; Efferth T.; Schneeweiss A.; Strowitzki T. Prospective open uncontrolled phase I study to define a well-tolerated dose of oral artesunate as add-on therapy in patients with metastatic breast cancer (ARTIC M33/2). Breast Cancer Res. Treat. 2017, 164, 359. 10.1007/s10549-017-4261-1. [DOI] [PubMed] [Google Scholar]
  47. Stocks P. A.; Bray P. G.; Barton V. E.; Al-Helal M.; Jones M.; Araujo N. C.; Gibbons P.; Ward S. A.; Hughes R. H.; Biagini G. A.; Davies J.; Amewu R.; Mercer A. E.; Ellis G.; O’Neill P. M. Evidence for a Common Non-Heme Chelatable-Iron-Dependent Activation Mechanism for Semisynthetic and Synthetic Endoperoxide Antimalarial Drugs. Angew. Chem., Int. Ed. 2007, 46, 6278. 10.1002/anie.200604697. [DOI] [PubMed] [Google Scholar]
  48. Posner G. H.; Ploypradith P.; Parker M. H.; O’Dowd H.; Wou S.-H.; Northrop J.; Krasavin M.; Dolan P.; Kensler T. W.; Xie S.; Shapiro T. A. Antimalarial, antiproliferative, and antitumor activities of artemisinin-derived, chemically robust, trioxane dimers. J. Med. Chem. 1999, 42, 4275. 10.1021/jm990363d. [DOI] [PubMed] [Google Scholar]
  49. Schönecker B.; Ponsold K. Steroide. XXX. Synthesen vicinaler Steroid-Azidoketone. J. Prakt. Chem. 1971, 313, 817. 10.1002/prac.19713130506. [DOI] [Google Scholar]
  50. Schönecker B.; Ponsold K. Steroide—XL. Tetrahedron 1975, 31, 1113. 10.1016/0040-4020(75)80134-7. [DOI] [Google Scholar]
  51. Becker K.; Krieg R.; Schönecker B. Derivate von steroidbenzylaminen mit antiparasitärer, antibakterieller, antimykotischer und/oder antiviraler wirkung. DE 102010047714 A1, 2012.
  52. Bora P. P.; Baruah N.; Bez G.; Barua N. C. New Method for the Synthesis of Ether Derivatives of Artemisinin. Synth. Commun. 2012, 42, 1218. 10.1080/00397911.2010.538887. [DOI] [Google Scholar]
  53. Fröhlich T.; Reiter C.; Ibrahim M. M.; Beutel J.; Hutterer C.; Zeitträger I.; Bahsi H.; Leidenberger M.; Friedrich O.; Kappes B.; Efferth T.; Marschall M.; Tsogoeva S. B. Synthesis of Novel Hybrids of Quinazoline and Artemisinin with High Activities against Plasmodium falciparum, Human Cytomegalovirus, and Leukemia Cells. ACS Omega 2017, 2, 2422. 10.1021/acsomega.7b00310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Fröhlich T.; Çapcı Karagöz A.; Reiter C.; Tsogoeva S. B. Artemisinin-Derived Dimers: Potent Antimalarial and Anticancer Agents. J. Med. Chem. 2016, 59, 7360–7388. 10.1021/acs.jmedchem.5b01380. [DOI] [PubMed] [Google Scholar]
  55. Marschall M.; Freitag M.; Weiler S.; Sorg G.; Stamminger T. Recombinant Green Fluorescent Protein-Expressing Human Cytomegalovirus as a Tool for Screening Antiviral Agents. Antimicrob. Agents Chemother. 2000, 44, 1588–1597. 10.1128/AAC.44.6.1588-1597.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Marschall M.; Niemann I.; Kosulin K.; Bootz A.; Wagner S.; Dobner T.; Herz T.; Kramer B.; Leban J.; Vitt D.; Stamminger T.; Hutterer C.; Strobl S. Assessment of drug candidates for broad-spectrum antiviral therapy targeting cellular pyrimidine biosynthesis. Antiviral Res. 2013, 100, 640. 10.1016/j.antiviral.2013.10.003. [DOI] [PubMed] [Google Scholar]
  57. Hutterer C.; Eickhoff J.; Milbradt J.; Korn K.; Zeitträger I.; Bahsi H.; Wagner S.; Zischinsky G.; Wolf A.; Degenhart C.; Unger A.; Baumann M.; Klebl B.; Marschall M. A novel CDK7 inhibitor of the Pyrazolotriazine class exerts broad-spectrum antiviral activity at nanomolar concentrations. Antimicrob. Agents Chemother. 2015, 59, 2062. 10.1128/AAC.04534-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Hutterer C.; Niemann I.; Milbradt J.; Fröhlich T.; Reiter C.; Kadioglu O.; Bahsi H.; Zeitträger I.; Wagner S.; Einsiedel J.; Gmeiner P.; Vogel N.; Wandinger S.; Godl K.; Stamminger T.; Efferth T.; Tsogoeva S. B.; Marschall M. The broad-spectrum antiinfective drug artesunate interferes with the canonical nuclear factor kappa B (NF-kappaB) pathway by targeting RelA/p65. Antiviral Res. 2015, 124, 101. 10.1016/j.antiviral.2015.10.003. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ml8b00381_si_001.pdf (1.7MB, pdf)
ml8b00381_si_002.xlsx (13.1KB, xlsx)

Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society

RESOURCES