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| Epothilones | |
|---|---|
Epothilones A (R = H) and B (R = CH3) |
|
| Chemical formulae |
A: C26H39NO6S |
| Molecular masses |
A: 493.66 g/mol |
| CAS numbers |
A: 152044-53-6 |
| PubChem |
A: 448799 |
Epothilones C (R = H) and D (R = CH3) |
|
| Chemical formulae |
C: C26H39NO5S |
| Molecular masses |
C: 477.66 g/mol |
| CAS numbers |
D: 189453-10-9 |
| PubChem |
C: 9891226 |
Epothilones E (R = H) and F (R = CH3) |
|
| Chemical formulae |
E: C26H39NO7S |
| Molecular masses |
E: 509.66 g/mol |
| Disclaimer and references | |
The epothilones are a new class of cytotoxic molecules identified as potential chemotherapeutic drugs.[1] As of September 2008[update], epothilones A to F have been identified and characterised.[2] Early studies in cancer cell lines and in human cancer patients indicate superior efficacy to the taxanes. Their mechanism of action is similar, but their chemical structure is simpler. Due to their better water solubility, cremophors (solubilizing agents used for paclitaxel which can affect cardiac function and cause severe hypersensitivity) are not needed.[3] Endotoxin-like properties known from paclitaxel, like activation of macrophages synthesizing inflammatory cytokines and nitric oxide, are not observed for epothilone B.[4]
Epothilones were originally identified as metabolites produced by the myxobacterium Sorangium cellulosum.
Contents |
History
The structure of epothilone A was determined in 1996 using x-ray crystallography.[5]
Mechanism of action
The principal mechanism of the epothilone class is inhibition of microtubule function.[6] 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 because 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.[7]
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.[8] In November 2008, the EMEA has refused a marketing authorisation for Ixabepilone.[9]
Epothilone B has proven to contain potent in vivo anticancer activities at tolerate dose levels in several human xenograft models.[10] As a result, epothilone B and its various analogues are currently undergoing various clinical phases (patupilone [EPO906] and sagopilone [SH-Y03757A, ZK-EPO, chemical structure] are in phase II trials; BMS-310705 and BMS-247550 in phase I trials). Results of a phase III trial with ixabepilone in combination with capecitabine in metastatic breast cancer have been announced.[11]
Organic synthesis
Due to the high potency and clinical need for cancer treatments, epothilones have been the target of many total syntheses.[12] The first group to publish the total synthesis of epothilones was S. J. Danishefsky et al. in 1996.[7][13] This total synthesis of epothilone A was achieved via an intramolecular ester enolate-aldehyde condensation. Other syntheses of epothilones have been published by Nicolaou[14], Schinzer[15], Mulzer[16], and Carreira[17]. 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[18], 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, macrolactonization, and epoxidation to give the various epothilone B as seen in Figure 3.
Biosynthesis
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.[19]
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.[19]
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.[19]
References
- ^ Rosenberg, Steven; DeVita, Vincent T.; Hellman, Samuel (2005). Cancer: Principles & Practice of Oncology (7th ed.). Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-4450-4.
- ^ H. Spreitzer (September 15, 2008). "Neue Wirkstoffe - Sagobepilon - eine synthetische Variation von Epothilon B als Hoffnungsträger gegen Krebs" (in German). Österreichische Apothekerzeitung (19/2008): 978.
- ^ Julien, B.; Shah, S. (2002). "Heterologous expression of epothilone biosynthetic genes in Myxococcus xanthus.". Antimicrob. Agents Chemother. 46 (9): 2772. doi:. PMID 12183227.
- ^ Muhlradt, P.F.; Sasse, F. (1997). "Epothilone B stabilizes microtubuli of macrophages like taxol without showing taxol-like endotoxin activity.". Cancer Research 57 (16): 3344. PMID 9269992.
- ^ Hofle, G.; Bedorf, N.; Steinmertz, H.; Schomburg, D.; Gerth, K.; Reichenach, H. (1996). "Epothilone A and B—Novel 16-Membered Macrolides with Cytotoxic Activity: Isolation, Crystal Structure, and Conformation in Solution". Angew. Chem. 35: 1567. doi:.
- ^ Goodin S, Kane MP, Rubin EH (May 2004). "Epothilones: mechanism of action and biologic activity". J. Clin. Oncol. 22 (10): 2015–25. doi:. PMID 15143095. http://www.jco.org/cgi/content/full/22/10/2015/.
- ^ a b Balog, D. M.; Meng, D.; Kamanecka, T.; Bertinato, P.; Su, D.-S.; Sorensen, E. J.; Danishefsky, S. J. (1996). "Totalsynthese von (—)-Epothilon A". Angew. Chem. 108: 2976. doi:.
- ^ Medical News Today: FDA Approves IXEMPRA(TM) (ixabepilone), A Semi-Synthetic Analog Of Epothilone B, For The Treatment Of Advanced Breast Cancer
- ^ London, 20 November 2008 Doc. Ref. EMEA/602569/2008
- ^ Ojima, I.; Vite, G.D.; Altmann, K.H.; 2001 Anticancer Agents: Frontiers in Cancer Chemotherapy. American Chemical Society, Washington, DC.
- ^ News Today.
- ^ Luduvico, I.; Hyaric, M. L.; Almeida, M. V.; Da Silva, A. D. (2006). "Synthetic Methodologies for the Preparation of Epothilones and Analogs" (Review). Mini-Reviews in Organic Chemistry 3: 49–75. doi:.
- ^ 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. (1997). "Total Synthesis of(–)-Epothilone B: An Extension of the Suzuki Coupling Method and Insights into Structure–Activity Relationships of the Epothilones". Angew. Chem. Int. Ed. Engl. 36: 757. doi:.
- ^ Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou, K. C. (1997). "Total Synthesis of Epothilone A: The Olefin Metathesis Approach". Angew. Chem. Int. Ed. Engl. 36: 166. doi:.
- ^ Schinzer, D.; Limberg, A.; Bauer, A.; Böhm, O. M.; Cordes, M. (1997). "Total Synthesis of(−)-Epothilone A". Angew. Chem. Int. Ed. Engl. 36: 523. doi:.
- ^ Mulzer, J.; Mantoulidis, A.; Öhler, E. (2000). "Total syntheses of epothilones B and D.". J. Org. Chem. 65 (22): 7456–67. doi:. PMID 11076603.
- ^ Bode, J. W.; Carreira, E. M. (2001). "Stereoselective syntheses of epothilones A and B via directed nitrile oxide cycloaddition.". J. Am. Chem. Soc. 123 (15): 3611–2. doi:. PMID 11472140.
- ^ a b c d Nicolaou, K.C.; Ninkovic, S.; Sarabia, F.; Vourloumis, D.; He, Y.; Vallberg, H.; Finlay, M.R.V.; Yang, Z.; (1997). "Total Syntheses of Epothilones A and B via a Macrolactonization-Based Strategy". J. Am. Chem. Soc. 119: 7974. doi:.
- ^ 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.; (2000). "The biosynthetic gene cluster for the microtubule-stabilizing agents epothilones A and B from Sorangium cellulosum So ce90.". Chemistry and Biology 7 (2): 97. doi:. PMID 10662695.
See also
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