Epothilones antitumor activity

Altmann KH, Wartmann M, O Reilly T. Epothilones and related structures—anew class of microtubule inhibitors with potent in vivo antitumor activity. Biochim Biophys Acta 2000 1470(3) M79-91. 

Epothilones are naturally occurring cytotoxic macrolides, which were initially isolated from a mycobacterium. Their antitumor activity is similar to that of the clinically established taxoids (Taxol, Taxotere), by interrupting the dynamic mechanism of microtubule assembly/disassembly via microtubule stabilization. In contrast to taxoids, epothilones are remarkably efficient against multidrug resistant cells. 

Manzamine A and epothilone A are two natural products with promising antitumor activities. Manzamine A is isolated from marine sponges, whereas epothilone A is isolated from myxo-bacteria. 

Lactam-based analogs of epothilones were conceived by the BMS group as metabolically more stable alternatives to the lactone-based natural products (which exhibit limited metabolic stability in rodent plasma). It is worth noting, however, that despite its short plasma half-life in rodent species, Epo B shows potent antitumor activity in a variety of nude mouse human tumor models,and the same is tme for Epo D (vide infra). In addition, Epo D has subsequently been demonstrated to... 

Frykman S, Tsuruta H, Lau J, Regentin R, Ou S, Reeves C, Carney J, Santi D, Licari P. Modulation of epothilone analog production through media design. J. Ind. Microbiol. Biotech. 2002 28 17-20. Klar U, Buchmann B, Schwede W, Skuballa W, Hoffmann J, Lichtner RB. Total synthesis and antitumor activity of ZK-EPO the first fully synthetic epothilone in chnical development. Angew Chem Int. Ed. 2006 45 7942-7948. 

The epothilones 6 (and Fig. la), which are produced by So-rangium cellulosum, are mixed NRPS-polyketide derived natural products that possess potent antitumor activity. Interestingly,... 

G. Hotle H. Reichenbach, Epothilone, a Myxobacterial Metabolite with Promising Antitumor Activity. In Anticancer Agents from Natural Products G. M. Cragg, D. G. Kingston, D. J. Newman, Eds. Taylor Francis Boca Raton, FL, 2005 pp 413-450. 

Epothilones A and B [82] In 1997, Nicolaou and coworkers reported the total synthesis of epothilones A (90) and B (91), two natural products isolated from myxobacteria Sorangium cellulosum [82]. These molecules exhibit impressive antitumor activities due to important microtubule binding affinities. Their retrosynthetic analysis relied on a late-stage epoxidation and a macrolactonization (Scheme 2.60). The synthesis of the two macrolactone... 

The clinical success of Paclitaxel has stimulated research into compounds with similar modes of action with antineoplastic efficacy while minimizing its less desirable properties, such as water insolubility, difficult synthesis, and emerging resistance. The epothilones are a novel class of natural product cytotoxic compounds derived from the fermentation of the Sorangium cellulosum, which are non-taxane microtubule-stabilizing compounds that trigger apoptosis [182-189]. The natural product epothilone B 144 (Figure 4.39) has demonstrated broad-spectrum antitumor activity... 

As indicated above, the antitumor activity of Epo B is based on its ability to bind to microtubules and to alter their intrinsic stability and dynamic properties. (For excellent reviews on microtubule structure and function see ref. 6 and 47-49.) Epothilones prevent the Ca or cold-induced depolymerization of pre-existing microtubule polymers in cell-free systems at the same time, they promote the polymerization of soluble tubulin into microtubule-like polymers under conditions that would normally destabilize microtubules.As demonstrated by kinetic experiments, epothilones inhibit the binding of taxol to microtubules in a competitive manner and they bind to the taxol binding site on p-tubulin with affinities that exceed (Epo B) or are comparable (Epo A) to taxol affinity likewise Epo B is a more potent tubulin-polymerizing agent than taxol or Epo Structural studies on... 

The basics and the synthetic potential of olefin metathesis has been recently presented in a comprehensive handbook and several reviews [58]. Thus, this chapter will be restricted to demonstrate the scope and flexibility of this type of reaction in the total synthesis of a complex natural product skeleton such as epothilone. The first total syntheses of these antitumor-active 16-membered macrolactones were based on a ringclosing metathesis (RCM) strategy (Scheme 11.36) [73]. Grubbs catalyst 143 has been used for the construction of the endocydic 1,2-disubstituted C12-C13 double bond in epothilone C 148 that, after epoxidation, affords epothilone A 150 [74]. In this approach, ruthenium carbene 143 is more efiident than Schrock molybdenum catalyst 142b [75a[. However, the RCM-route to epothilone D 149, the desoxy precursor of epothilone B 151 bearing a trisubstituted C=C bond, requires the molybdenum carbene catalyst 142b attempts to initiate ring-closure with 143 failed [75]. 

Polyketide and non-ribosomal peptides produced by bacteria and fungi often attain the conformations that establish biological activity by cychzation constraints introduced by tailoring enzymes. This includes heterocychzation of cysteines, serines and threonines in non-ribosomal peptides. The second cychzation constraint is macrocychzation in polyketides, such as the above-mentioned antibiotic erythromycin and the antitumor epothilones. Regio- and stereospecific macrocychzation usuaUy occurs at the end of the polyketide and non-ribosomal peptide assembly hnes during chain release by thioesterase domains [49]. However, in the case of antibiotics of the ansamycin class, like the antitubercular drug rifamycin, the final... 

Petersen, F., Schinzer, D., Altmann, K.-H., Griesinger, C.,The high-resolution solution structure of epothilone a bound to tubulin An understanding of the structure-activity relationships for a powerful class of antitumor agents, Angew. Chem. Int. Ed. 2003, 42, 2511-2515. 

Thiazoles have been often discovered as key components of novel and structurally diverse natural products exhibiting a range of biological activities. Their antitumor, antiviral, and antibiotic activities their ubiquitous occurrence in peptides and their ability to bind to proteins, DNA and RNA have all led to several synthetic studies and their inclusion in drug discovery. Perhaps the best-known example of such a complex natural product featuring a thiazole substructure is the epothilones, which have demonstrated activity against taxol resistant tumor cell lines. ... 

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