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Epothilone A (R = H) and B (R = Me)

Chemical formula C26H39NO6S (Epothilone A)

C27H41NO6S (Epothilone B)

Molecular mass 493.66 g/mol (Epothilone A)

507.68 g/mol (Epothilone B)

CAS number 152044-53-6 (Epothilone A)

152044-54-7 (Epothilone B)

Disclaimer and references

The epothilones are a new class of cytotoxic molecules, including epothilone A, epothilone B, and epothilone D, identified as potential chemotherapy drugs.[1] Early studies in cancer cell lines and in human cancer patients indicate superior efficacy to the taxanes. Their mechanism of action is similar to that of the taxanes, but their chemical structure is simpler and they are more soluble in water. Due to improved water solubility, cremophors (solubilizing agents used in paclitaxel which can affect cardiac function and cause severe hypersensitivity) are no longer needed in the formulation of this anticancer drug.[2] Other undesired effects such as endotoxin-like properties where macrophages are activated to synthesize inflammatory cytokines and nitric oxide (paclitaxel)[3] are not observed by epothilone B.

Epothilones were originally identified as metabolites produced by the myxobacterium Sorangium cellulosum.



The structure of epothilone A was determined in 1996 using x-ray crystallography.[4]

Mechanism of action

The principal mechanism of the epothilone class is inhibition of microtubule function.[5] Microtubules are essential to cell division, and epothilones therefore stop cells from properly dividing. Epothilone B possess the same biological effects as taxol both in vitro and in cultured cells. This is due to the fact that they share the same binding site, as well as binding affinity to the microtubule. Like taxol, epothilone B binds to the αβ-tubulin heterodimer subunit. Once bound, the rate of αβ-tubulin dissociation decreases, thus stabilizing the microtubules. Furthermore, epothilone B has also been shown to induce tubulin polymerization into microtubules without the presence of GTP. This is caused by formation of microtubule bundles throughout the cytoplasm. Finally, epothilone B also causes cell cycle arrest at the G2-M transition phase, thus leading to cytotoxicity and eventually cell apoptosis.[6]

Clinical trials

Several epothilone analogs are currently undergoing clinical development for treatment of various cancers. One analog, ixabepilone, was approved in October 2007 by the United States Food and Drug Administration for use in the treatment of aggressive metastatic or locally advanced breast cancer no longer responding to currently available chemotherapies [7].

Epothilone B has proven to contain potent in vivo anticancer activities at tolerate dose levels in several human xenograft models.[8] As a result, epothilone B and its various analogues are currently undergoing various clinical phases (patupilone (EPO906) - phase II trials; BMS-310704 and BMS-247550 - phase I trials). Results of a phase III trial with Ixabepilone in combination with capecitabine in metastatic breast cancer have been announced.[9]

Organic synthesis

Due to the high potency and clinical need for cancer treatments, epothilones have been the target of many total syntheses.[10] The first group to publish the total synthesis of epothilones was S. J. Danishefsky et al. in 1996.[6][11] This total synthesis of epothilone A was achieved via an intramolecular ester enolate-aldehyde condensation. Other syntheses of epothilones have been published by Nicolaou[12], Schinzer[13], Mulzer[14], and Carreira[15]. In this approach, key building blocks aldehyde, glycidols, and ketoacid were constructed and coupled to olefin metathesis precursor via an aldol reaction and then an esterification coupling. Grubbs' catalyst was employed to close the bis terminal olefin of the precursor compound. The resulting compounds were cis- and tran-macrocyclic isomers with distinct stereocenters. Epoxidation of cis- and trans-olefins yield epothilone A and its analogues.

The particular synthetic method determined by the laboratories of K.C Nicolaou[16], described the synthesis of appropriate building blocks 9, 11, and 12, derived from the retrosynthetic analysis of epothilone B (Figure 1), both diastereoisomers and the geometrical isomers at C6-C7 and C12-C13, can be obtained to give a diverse molecular product. The synthesis of required building blocks 9, 11 and 12, were obtained in a maximum of 4 steps for each building block as seen in Figure 2. With fragments 9, 11 and 12 in hand, these intermediates can then react with one another via Wittig olefination, aldol reaction, macrolactionization, and epoxidation to give the various epothilone B as seen in Figure 3.




Epothilone B is a 16-membered polyketide macrolactone with a methylthiazole group connected to the macrocycle by an olefinic bond. The polyketide backbone was synthesized by type I polyketide synthase (PKS) and the thiazole ring was derived from a cysteine incorporated by a nonribosomal peptide synthetase (NRPS). In this biosythesis, both PKS and NRPS use carrier proteins, which have been post-translationally modified by phosphopantheteine groups, to join the growing chain. PKS uses coenzyme-A thioester to catalyze the reaction and modify the substrates by selectively reducing the β carbonyl to the hydroxyl (Ketoreductase, KR), the alkene (Dehydratase, DH), and the alkane (Enoyl Reductase, ER). PKS-I can also methylate the α carbon of the substrate. NRPS, on the other hand, uses amino acids activated on the enzyme as aminoacyl adenylates. Unlike PKS, epimerization, N-methylation, and heterocycle formation occurs in NRPS enzyme.[17]

Epothilone B starts with a 2-methyl-4-carboxythiazole starter unit, which was formed through the translational coupling between PKS, EPOS A (epoA) module, and NRPS, EPOS P(epoP) module. The EPOS A contains a modified β-ketoacyl-synthase (malonyl-ACP decarboxylase, KSQ), an acyltransferase (AT), an enoyl reductase (ER), and an acyl carrier protein domain (ACP). The EPOS P however, contains a heterocylization, an adenylation, an oxidase, and a thiolation domain. These domains are important because they are involved in the formation of the five-membered heterocyclic ring of the thiazole. As seen in Figure 4, the EPOS P activates the cysteine and binds the activated cysteine as an aminoacyl-S-PCP. Once the cysteine has been bound, EPOS A loads an acetate unit onto the EPOS P complex, thus initiating the formation of the thiazoline ring by intramolecular cyclodehydration.[17]

Once the 2-methylthiazole ring has been made, it is then transferred to the PKS EPOS B (epoB), EPOS C (epoC), EPOS D (epoD), EPOS E (epoE), and EPOS F (epoF) for subsequent elongation and modification to generate the olefinic bond, the 16-membered ring, and the epoxide, as seen in Figure 5. One important thing to note is the synthesis of the gem-dimethyl unit in module 7. These two dimethyls were not synthesized by two successive C-methylations. Instead one of the methyl group was derived from the propionate extender unit, while the second methyl group was integrated by a C-methyl-transferase domain.[17]



  1. ^ Vincent T. DeVita, Jr., MD; Samuel Hellman, MD; and Steven A. Rosenberg, MD, PhD (2004) Cancer: Principles And Practice Of Oncology (7th Edition) Lippincott Williams & Wilkins ISBN 0-7817-4450-4
  2. ^ Julien, B.; Shah, S. Antimicrob. Agents Chemother. 2002, 46, 2772.
  3. ^ Muhlradt, P.F.; Sasse, F. [Cancer Research]] 1997, 57,3344.
  4. ^ Hofle, G.; Bedorf, N.; Steinmertz, H.; Schomburg, D.; Gerth, K.; Reichenach, H. Angew. Chem. 1996, 35, 1567.
  5. ^ Epothilones: Mechanism of Action and Biologic Activity, Susan Goodin, Michael P. Kane, Eric H. Rubin, Journal of Clinical Oncology, Vol 22, No 10 (May 15), 2004: pp. 2015-2025. (Article)
  6. ^ a b Balog, D. M.; Meng, D.; Kamanecka, T.; Bertinato, P.; Su, D.-S.; Sorensen, E. J.; Danishefsky, S. J. Angew. Chem. 1996, 108, 2976.
  7. ^
  8. ^ Ojima, I.; Vite, G.D.; Altmann, K.H.; 2001 Anticancer Agents: Frontiers in Cancer Chemotherapy. American Chemical Society, Washington, DC.
  9. ^ News Today.
  10. ^ Luduvico, I.; Hyaric, M. L.; Almeida, M. V.; Da Silva, A. D. Mini-Reviews in Organic Chemistry 2006, 3, 49-75. (Review)
  11. ^ Su, D.-S.; Meng, D.; Bertinato, P.; Balog, D. M.; Sorensen, E. J.; Danishefsky, S. J.; Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S. B. Angew. Chem. Int. Ed. Engl. 1997, 36, 757.
  12. ^ Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou, K. C. Angew. Chem. Int. Ed. Engl. 1997, 36, 166.
  13. ^ Schinzer, D.; Limberg, A.; Bauer, A.; Böhm, O. M.; Cordes, M. Angew. Chem. Int. Ed. Engl. 1997, 36, 523.
  14. ^ Mulzer, J.; Mantoulidis, A.; Öhler, E. J. Org. Chem. 2000, 65, 7456-7467. (doi:10.1021/jo0007480)
  15. ^ Bode, J. W.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 3611-3612. (doi:10.1021/ja0155635)
  16. ^ a b c d Nicolaou, K.C.; Ninkovic, S.; Sarabia, F.; Vourloumis, D.; He, Y.; Vallberg, H.; Finlay, M.R.V.; Yang, Z.; J. Am. Chem. Soc. 1997, 119, 7974.
  17. ^ a b c Molnar, I.; Schupp, T.; Ono, M.; Zirkle, RE.; Milnamow, M.; Nowak-Thompson, B.; Engel, N.; Toupet, C.; Stratmann, A.; Cyr, DD.; Gorlach, J.; Mayo, JM.; Hu, A.; Goff, S.; Schmid, J.; Ligon, JM.; Chemistry and Biology. 2000, 7, 97.

See also

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Epothilone". A list of authors is available in Wikipedia.
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