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Chemical Compound Review

Epothilones     (1R,5S,6S,7R,10S,14S,16S)- 6,10-dihydroxy-5...

Synonyms: Epoa, Epothilone-A, Epothilone A, Epothilon A, Epo A, ...
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Disease relevance of Epothilones


High impact information on Epothilones

  • Epothilones A and B, two compounds that have been recently isolated from myxobacterium Sorangium cellulosum strain 90, have generated intense interest among chemists, biologists and clinicians owing to the structural complexity, unusual mechanism of interaction with microtubules and anticancer potential of these molecules [6].
  • Doxorubicin treatment prevented mitotic arrest, Bcl-2 phosphorylation, and cell death caused by paclitaxel, epothilones, and vinblastine [7].
  • Several structurally diverse antimitotic compounds, including the epothilones, compete with Taxol for binding to mammalian microtubules, suggesting that Taxol and these compounds share an overlapping binding site [8].
  • In these cells, epothilones can principally be recognized and exported by Verapamil-sensitive efflux pumps, which are not identical to MDR1 [9].
  • In addition, the structure-activity relationships of multiple taxanes and epothilones in the tubulin mutant cells can be fully explained by the model presented here, verifying its predictive value [10].

Chemical compound and disease context of Epothilones

  • Phase I studies have shown that dose-limiting toxicities of epothilones are generally neurotoxicity and neutropoenia although initial studies with patupilone indicated that diarrhoea was dose limiting [11].

Biological context of Epothilones


Anatomical context of Epothilones

  • The epothilones differ in their ability to retain activity against multidrug-resistant (MDR) cell lines and tumors where paclitaxel fails [15].
  • Epothilones have effects on the cytoskeleton similar to those of the antineoplastic drug Taxol [16].
  • These metabolites include several compounds of biotechnological importance such as the epothilones and chivosazols, which, respectively, stabilize the tubulin and actin skeletons of eukaryotic cells [17].
  • The epothilones represent a new class of bacterial natural products with broad spectrum of antiproliferative activity against various types of human tumors and tumor cell lines [18].
  • In this work, a series of Epo-resistant A549 and HeLa cell lines have been selected and analyzed [19].

Associations of Epothilones with other chemical compounds


Gene context of Epothilones

  • This strategy also allowed a selective killing of HL60/TX cells which express MDR-1, with the only difference being that the second drug, paclitaxel, was substituted for epothilones, non-Pgp substrates [24].
  • Our results further provide a strong rationale for testing taxanes and epothilones in clinical trials targeting HIF-1 in cancer patients [25].
  • The epoxidation of epothilones C and D to A and B, respectively, is mediated by EpoK, a cytochrome P450 enzyme encoded in the epothilone gene cluster [20].
  • Enzymatic assembly of epothilones: the EpoC subunit and reconstitution of the EpoA-ACP/B/C polyketide and nonribosomal peptide interfaces [26].
  • Laulimalide was active against cell lines resistant to paclitaxel or epothilones A and B on the basis of mutations in the M40 human beta-tubulin gene [27].

Analytical, diagnostic and therapeutic context of Epothilones


  1. Cloning and heterologous expression of the epothilone gene cluster. Tang, L., Shah, S., Chung, L., Carney, J., Katz, L., Khosla, C., Julien, B. Science (2000) [Pubmed]
  2. Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Bollag, D.M., McQueney, P.A., Zhu, J., Hensens, O., Koupal, L., Liesch, J., Goetz, M., Lazarides, E., Woods, C.M. Cancer Res. (1995) [Pubmed]
  3. Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol(R)). Kowalski, R.J., Giannakakou, P., Hamel, E. J. Biol. Chem. (1997) [Pubmed]
  4. Heterologous expression of epothilone biosynthetic genes in Myxococcus xanthus. Julien, B., Shah, S. Antimicrob. Agents Chemother. (2002) [Pubmed]
  5. Epothilone induced cytotoxicity is dependent on p53 status in prostate cells. Ioffe, M.L., White, E., Nelson, D.A., Dvorzhinski, D., DiPaola, R.S. Prostate (2004) [Pubmed]
  6. Synthesis of epothilones A and B in solid and solution phase. Nicolaou, K.C., Winssinger, N., Pastor, J., Ninkovic, S., Sarabia, F., He, Y., Vourloumis, D., Yang, Z., Li, T., Giannakakou, P., Hamel, E. Nature (1997) [Pubmed]
  7. Pretreatment with DNA-damaging agents permits selective killing of checkpoint-deficient cells by microtubule-active drugs. Blagosklonny, M.V., Robey, R., Bates, S., Fojo, T. J. Clin. Invest. (2000) [Pubmed]
  8. Understanding tubulin-Taxol interactions: mutations that impart Taxol binding to yeast tubulin. Gupta, M.L., Bode, C.J., Georg, G.I., Himes, R.H. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  9. Subcellular distribution of epothilones in human tumor cells. Lichtner, R.B., Rotgeri, A., Bunte, T., Buchmann, B., Hoffmann, J., Schwede, W., Skuballa, W., Klar, U. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  10. A common pharmacophore for epothilone and taxanes: molecular basis for drug resistance conferred by tubulin mutations in human cancer cells. Giannakakou, P., Gussio, R., Nogales, E., Downing, K.H., Zaharevitz, D., Bollbuck, B., Poy, G., Sackett, D., Nicolaou, K.C., Fojo, T. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  11. Epothilones in the treatment of cancer. Larkin, J.M., Kaye, S.B. Expert opinion on investigational drugs. (2006) [Pubmed]
  12. Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones. Moasser, M.M., Sepp-Lorenzino, L., Kohl, N.E., Oliff, A., Balog, A., Su, D.S., Danishefsky, S.J., Rosen, N. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  13. A common pharmacophore for cytotoxic natural products that stabilize microtubules. Ojima, I., Chakravarty, S., Inoue, T., Lin, S., He, L., Horwitz, S.B., Kuduk, S.D., Danishefsky, S.J. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  14. Crystal structures of epothilone D-bound, epothilone B-bound, and substrate-free forms of cytochrome P450epoK. Nagano, S., Li, H., Shimizu, H., Nishida, C., Ogura, H., Ortiz de Montellano, P.R., Poulos, T.L. J. Biol. Chem. (2003) [Pubmed]
  15. Desoxyepothilone B is curative against human tumor xenografts that are refractory to paclitaxel. Chou, T.C., Zhang, X.G., Harris, C.R., Kuduk, S.D., Balog, A., Savin, K.A., Bertino, J.R., Danishefsky, S.J. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  16. Epothilone B stabilizes microtubuli of macrophages like taxol without showing taxol-like endotoxin activity. Muhlradt, P.F., Sasse, F. Cancer Res. (1997) [Pubmed]
  17. Deciphering regulatory mechanisms for secondary metabolite production in the myxobacterium Sorangium cellulosum So ce56. Rachid, S., Gerth, K., Kochems, I., Müller, R. Mol. Microbiol. (2007) [Pubmed]
  18. Generation of novel epothilone analogs with cytotoxic activity by biotransformation. Tang, L., Qiu, R.G., Li, Y., Katz, L. J. Antibiot. (2003) [Pubmed]
  19. Mutations in beta-tubulin map to domains involved in regulation of microtubule stability in epothilone-resistant cell lines. He, L., Yang, C.P., Horwitz, S.B. Mol. Cancer Ther. (2001) [Pubmed]
  20. EpoK, a cytochrome P450 involved in biosynthesis of the anticancer agents epothilones A and B. Substrate-mediated rescue of a P450 enzyme. Ogura, H., Nishida, C.R., Hoch, U.R., Perera, R., Dawson, J.H., Ortiz de Montellano, P.R. Biochemistry (2004) [Pubmed]
  21. Recent developments in the chemical biology of epothilones. Altmann, K.H. Curr. Pharm. Des. (2005) [Pubmed]
  22. Total synthesis and antitumor activity of 12,13-desoxyepothilone F: an unexpected solvolysis problem at C15, mediated by remote substitution at C21. Lee, C.B., Chou, T.C., Zhang, X.G., Wang, Z.G., Kuduk, S.D., Chappell, M.D., Stachel, S.J., Danishefsky, S.J. J. Org. Chem. (2000) [Pubmed]
  23. Studies on the biosynthesis of epothilones: hydroxylation of Epo A and B to epothilones E and F. Gerth, K., Steinmetz, H., Höflel, G., Reichenbach, H. J. Antibiot. (2002) [Pubmed]
  24. Drug-resistance enables selective killing of resistant leukemia cells: exploiting of drug resistance instead of reversal. Blagosklonny, M.V. Leukemia (1999) [Pubmed]
  25. Both microtubule-stabilizing and microtubule-destabilizing drugs inhibit hypoxia-inducible factor-1alpha accumulation and activity by disrupting microtubule function. Escuin, D., Kline, E.R., Giannakakou, P. Cancer Res. (2005) [Pubmed]
  26. Enzymatic assembly of epothilones: the EpoC subunit and reconstitution of the EpoA-ACP/B/C polyketide and nonribosomal peptide interfaces. O'Connor, S.E., Chen, H., Walsh, C.T. Biochemistry (2002) [Pubmed]
  27. The microtubule stabilizing agent laulimalide does not bind in the taxoid site, kills cells resistant to paclitaxel and epothilones, and may not require its epoxide moiety for activity. Pryor, D.E., O'Brate, A., Bilcer, G., Díaz, J.F., Wang, Y., Wang, Y., Kabaki, M., Jung, M.K., Andreu, J.M., Ghosh, A.K., Giannakakou, P., Hamel, E. Biochemistry (2002) [Pubmed]
  28. Generation of new epothilones by genetic engineering of a polyketide synthase in Myxococcus xanthus. Tang, L., Chung, L., Carney, J.R., Starks, C.M., Licari, P., Katz, L. J. Antibiot. (2005) [Pubmed]
  29. Activity of epothilones. Kolman, A. Current opinion in investigational drugs (London, England : 2000) (2005) [Pubmed]
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