Epothilones

1.	Introduction and History
2.	Physical Properties
3.	Syntheses
3.1.	Synthesis of Epothilones A and C According to Schinzer
3.2.	Synthesis of Epothilones A and C According to Danishefsky
3.3.	Synthesis of Epothilones B and D According to Nicolaou
3.4.	Synthesis of Epothilone D According to Danishefsky
4.	Occurrence and Biosynthesis
5.	Pharmacological Effects and Uses

Epothilones represent a novel class of anticancer drugs which inhibit the cell cycle by interfering with microtubules. Their chemical and pharmacological properties as well as several synthetic approaches to some of the natural compounds are described.

First results from clinical trials with natural epothilones as well as novel derivatives are promising indicating that epothilones have the potential to become a cornerstone in future cancer therapy.

General References

1 G. Höfle, H. Reichenbach: Epothilone, a Myxobacterial Metabolite with Promising Antitumor Activity, in G. M. Cragg, D. G. I. Kingston, D. J. Newman (ed.): Anticancer Agents From Natural Products, CRC Press Taylor&Francis Group, Boca Raton 2005, pp. 413–450.
Google Scholar
2 E. B. Watkins, A. G. Chittiboyina, Jae-Chul Jung; M. A. Avery: “The epothilones and related analogues — A review of their syntheses and anti-cancer activities”, Curr. Pharm. Design 11 (2005) 1615.
10.2174/1381612053764742
CAS PubMed Web of Science® Google Scholar
3 D. Schinzer: The aldol reaction in natural product synthesis. The epothilone story, in R. Mahrwald (ed.): Modern Aldol Reactions, Vol. 1, Wiley-VCH, Weinheim, Germany 2004, pp. 311–328.
10.1002/9783527619566.ch7
Google Scholar
4 K.-H. Altmann: “The merger of natural product synthesis and medicinal chemistry: on the chemistry and chemical biology of epothilones”, Org. Biomol. Chem. 2 (2004) 2137.
10.1039/b405839a
CAS PubMed Web of Science® Google Scholar
5 R. Zhang, Z. Liu: “Recent progress in the synthesis of epothilones”, Curr. Org. Chem. 8 (2004) 267.
10.2174/1385272043485927
CAS Web of Science® Google Scholar
6 K.-H. Altmann: “Epothilone B and its Analogs — A New Family of Anticancer Agents”, Mini Review in Medicinal Chemistry 3 (2003) 149.
10.2174/1389557033405269
CAS PubMed Web of Science® Google Scholar
7 T. Beckers, S. Mahboobi: “Natural, semisynthetic and synthetic microtubule inhibitors for cancer therapy”, Drugs Future 28 (2003) 767.
10.1358/dof.2003.028.08.744356
CAS Web of Science® Google Scholar
8 R. M. Borzilleri, G. D. Vite: “Epothilones: new tubulin polymerization agents in preclinical and clinical development”, Drugs Future 27 (2002) 1149.
10.1358/dof.2002.027.12.711728
CAS Web of Science® Google Scholar
9 R. Altaha, T. Fojo, E. Reed, J. Abraham: “Epothilones: a novel class of non-taxane microtubule-stabilizing agents”, Curr. Pharm. Design 8 (2002) 1707.
10.2174/1381612023394043
CAS PubMed Web of Science® Google Scholar
10 M. Wartmann, K.-H. Altmann: “The biology and medicinal chemistry of epothilones”, Curr. Med. Chem.: Anti-Cancer Agents 2 (2002) 123.
10.2174/1568011023354489
CAS PubMed Google Scholar
11 M. A. Jordan: “Mechanism of action of antitumor drugs that interact with microtubules and tubulin”, Curr. Med. Chem.: Anti-Cancer Agents 2 (2002) 1.
10.2174/1568011023354290
CAS PubMed Google Scholar
12 U. Klar, W. Skuballa, B. Buchmann, W. Schwede, T. Bunte, J. Hoffmann, R. B. Lichtner: Synthesis and biological activity of epothilones, in I. Ojima, G. D. Vite, K.-H. Altmann (ed.): Anticancer Agents. Frontiers in Cancer Chemotherapy, Oxford University Press, New York 2001, 131–147.
10.1021/bk-2001-0796.ch008
Google Scholar
13 M. Kavallaris, N. M. Verrills, B. T. Hill: “Anticancer therapy with novel tubulin-interacting drugs”, Australia Drug Resistance Updates 4 (2001) 392.
10.1054/drup.2002.0230
CAS PubMed Web of Science® Google Scholar
14 K.-H. Altmann, G. Bold, G. Caravatti, N. End, A. Flörsheimer, V. Guagnano, T. O'Reilly, M. Wartmann: “Epothilones and their analogs — potential new weapons in the fight against cancer”, Chimia 54 (2000) 612.
CAS Web of Science® Google Scholar
15 G. Appendino, G. Casiraghi: “The synthesis of epothilones: highlights from a year’s race”, Chemtracts 11 (1998) 678.
CAS Google Scholar
16 S. B. Buck, S. F. Victory, R. H. Himes, G. I. Georg: “Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action”, Chemtracts 11 (1998) 671.
CAS Google Scholar

Specific References

17 Gesellschaft für Biotechnologische Forschung mbH, DE 4138042 C2, 1991 (G. Hoefle, N. Bedorf, K. Gerth, H. Reichenbach)
Google Scholar
18 D. M. Bollag et al.: “Epothilones, a New Class of Microtubule-Stabilizing Agents with a Taxol-like Mechanism of Action”, Cancer Res. 55 (1995) 2325.
CAS PubMed Web of Science® Google Scholar
19 D. M. Bollag: “Epothilones: Novel Microtubule-Stabilizing Agents”, Expert Opin. Invest. Drugs 6 (1997) 867.
10.1517/13543784.6.7.867
CAS PubMed Google Scholar
20 O. A. O'Connor et al.: “ Stability and toxicity of 12,13-Desoxyepothilone B (DEPOB) in dogs with spontaneous tumors”, poster presentation 92th AACR Meeting, New Orleans, March 24-28 (2001).
Google Scholar
21 G. Höfle et al.: “Epothilon A und B — neuartige, 16gliedrige Makrolide mit cytotoxischer Wirkung: Isolierung, Struktur im Kristall und Konformation in Lösung”, Angew. Chem. 108 (1996) 1671,
10.1002/ange.19961081342
Google Scholar
Angew. Chem., Int. Ed. 35 (1996) 1567.
10.1002/anie.199615671
CAS Web of Science® Google Scholar
22 R. E. Taylor; Y. Chen, A. Beatty, D. C. Myles, Y. Zhou: “Conformation–Activity Relationships in Polyketide Natural Products: A New Perspective on the Rational Design of Epothilone Analogues”, J. Am. Chem. Soc. 125 (2003) 26.
10.1021/ja028196l
CAS PubMed Web of Science® Google Scholar
23 D. Schinzer, A. Limberg, A. Bauer, O. M. Böhm, M. Cordes: “Totalsynthese von (−)-Epothilon A”, Angew. Chem. 109 (1997) 543;
10.1002/ange.19971090525
Google Scholar
Angew. Chem., Int. Ed. 36 (1997) 523.
10.1002/anie.199705231
CAS Web of Science® Google Scholar
24 D. Schinzer, A. Limberg, O. M. Böhm: “Studies Towards the Total Synthesis of Epothilones: Asymmetric Synthesis of the Key Fragments”, Chem. Eur. J. 2 (1996) 1477.
10.1002/chem.19960021121
CAS Web of Science® Google Scholar
25 A. Balog et al.: “Totalsynthese von (−)-Epothilon A”, Angew. Chem. 108 (1996) 2976,
10.1002/ange.19961082318
Google Scholar
Angew. Chem., Int. Ed. 35 (1996) 2801.
10.1002/anie.199628011
CAS Web of Science® Google Scholar
26 P. Bertinato, E. J. Sorensen, D. Meng, S. J. Danishefsky: “Studies towards a Synthesis of Epothilone A: Stereocontrolled Assembly of the Acyl Region and Models for Macrocyclization”, J. Org. Chem. 61 (1996) 8000.
10.1021/jo961674o
CAS PubMed Web of Science® Google Scholar
27 K. C. Nicolaou et al.: “Total Syntheses of Epothilones A and B via a Macrolactonization-Based Strategy”, J. Am. Chem. Soc. 119 (1997) 7974.
10.1021/ja971110h
CAS Web of Science® Google Scholar
28 D. Meng et al.: “Remote Effects in Macrolide Formation through Ring-Forming Olefin Metathesis: An application to the Synthesis of Fully Active Epothilone Congeners”, J. Am. Chem. Soc. 119 (1997) 2733.
10.1021/ja964275j
CAS Web of Science® Google Scholar
29 L. Tang et al.: “Cloning and heterologous expression of the epothilone gene clust”, Science 287 (2000) 640.
10.1126/science.287.5453.640
CAS ADS PubMed Web of Science® Google Scholar
30 I. Molnar et al.: “The biosynthetic gene cluster for the microtubule-stabilizing agents epothilones A and B from Sorangium cellulosum So ce90”, Chem. Biol. 7 (2000) 97.
10.1016/S1074-5521(00)00075-2
CAS PubMed Web of Science® Google Scholar
31 B. Julien et al.: “Isolation and characterization of the epothilone biosynthetic gene cluster from Sorangium cellulosum”, Gene 249 (2000) 153.
10.1016/S0378-1119(00)00149-9
CAS PubMed Web of Science® Google Scholar
32 E. B. Watkins, A. G. Chittiboyina, J.-C. Jung, M. A. Avery: “The epothilones and related analogues-A review of their syntheses and anti-cancer activities”, Curr. Pharm. Design 11 (2005) 1615.
10.2174/1381612053764742
CAS PubMed Web of Science® Google Scholar
33 B. Julien, S. Shah: “Heterologous expression of epothilone biosynthetic genes in Myxococcus xanthus”, Antimicrob. Agents Chemother. 46 (2002) 2772.
10.1128/AAC.46.9.2772-2778.2002
CAS PubMed Web of Science® Google Scholar
34 R. L. Arslanian et al.: “Large-Scale Ilaon and Crystallizaon of Epothilone D From Myxococcus xanthus Cultures”, J. Nat. Prod. 64 (2002) 570.
10.1021/np010438s
CAS Web of Science® Google Scholar
35 J. Lau, S. Frykman, R. Regentin, S. Ou, H. Tsuruta, P. Licari: “Optimizing the heterologous production of epothilone D in Myxococcus xanthus”, Biotechnol. Bioeng. 78 (2002) 280.
10.1002/bit.10202
CAS PubMed Web of Science® Google Scholar
36 L. Melton: “Cellular pump changes prospect of disease resistance”, Lancet 357 (2001) 1186.
10.1016/S0140-6736(00)04394-4
CAS PubMed Web of Science® Google Scholar
37 D. M. Bollag et al.: “Epothilones, a New Class of Microtubule-Stabilizing Agents with a Taxol-like Mechanism of Action”, Cancer Res. 55 (1995) 2325.
CAS PubMed Web of Science® Google Scholar
38 R. J. Kowalski, P. Giannakakou, E. Hamel: “Activities of Mictotubule-stabilizing Agents Epothilones A and B with Purified Tubulin and in Cells Resistant to Paclitaxel (Taxol^®)”, J. Biol. Chem. 272 (1997) 2534.
10.1074/jbc.272.4.2534
CAS PubMed Web of Science® Google Scholar
39 J. H. Nettles et al.: “The Binding Mode of Epothilone A on α, β-Tubulin by Electron Crystallography”, Science 305 (2004) 866.
10.1126/science.1099190
CAS ADS PubMed Web of Science® Google Scholar
40 E. Nogales, S. G. Wolf, K. H. Downing: “Structure of the α, β-Tubulin dimer by electron crystallography”, Nature 391 (1998) 199.
10.1038/34465
CAS ADS PubMed Web of Science® Google Scholar
41 G. Vite: Synthesis and biological activity of epothilones, In: New Prospects in Anticancer Agents for the 21st Century, American Chemical Society, 2001, pp. 131–147.
Google Scholar
42 U. Klar et al.: “A new potent epothilone derivative superior to Epothilone B”, Proc. Am. Assoc. Cancer Res. 43 (2002) 791, abs 3924.
Google Scholar
43 R. B. Lichtner et al.: “Subcellular distribution of epothilones in human tumor cells”, J. Proc. Natl. Acad. Sci. USA 98 (2001) 11743.
10.1073/pnas.171023398
CAS ADS PubMed Web of Science® Google Scholar
44 K.-H. Altmann, M. Wartmann, T. O'Reilly: “Epothilones and related structures — a new class of microtubule inhibitors with potent in vivo antitumor activity”, Biochim. Biophys. Acta 1470 (2000) M79.
10.1016/S0304-419X(00)00009-3
CAS PubMed Web of Science® Google Scholar
45 S. Mani et al.: “Phase I Clinical and Pharmacokinetic Study of BMS-247550, a Novel Derivative of Epothilone B, in Solid Tumors”, Clin. Cancer Res. 10 (2004), 1289.
10.1158/1078-0432.CCR-0919-03
CAS PubMed Web of Science® Google Scholar

Epothilones

View previous versions

Epothilones

Abstract

General References

Specific References

Further Reading

References

Information

About Wiley Online Library

Help & Support

Opportunities

Connect with Wiley

Epothilones

View previous versions

Epothilones

Abstract

General References

Specific References

Further Reading

References

Related

Information