Clinical development, epothilone analogs

Owing to the clinical importance of several epothilones, and considering the tolerance shown by several modules of the epothilone PKS to substrate modification, several reports appeared on the manipulation of the epothilone PKS to produce potentially superior epothilone analogs. Thus, a system was developed that comprised of modules 6-9 of the epothilone synthetase for the precursor-directed biosynthesis of epothilones in E. coli, and the ability of the crucial first module in this engineered pathway, EpoDM6, to accept, elongate, and process unnatural substrates was... 

Epothilones have been widely pursued targets for total chemical synthesis (for reviews see ref. 34-39) and their structure-activity relationship (SAR) has been broadly evaluated this research has been reviewed extensively (ref. 1, 34, 36, 38 and 40-46). It is not the objective of this chapter to provide yet another all-encompassing collection of SAR and synthetic data. Rather, after a brief summary of the in vitro and in vivo biological properties of Epo B, the discussion will focus on the chemistry of those modifications that have led to clinical development compounds and the most important preclinical features of these analogs. 

Epothilone Analogs in Clinical Development and Related Stractures... 

Early pharmacokinetic studies with epothilones in rodents pointed to a distinct vulnerability of the ester bond in the macrocycle to hydrolysis by (rodent) plasma esterases. Although esterase activity in rodent plasma is known to be substantially higher than in humans, these early findings also raised concerns about the metabolic stability of natural, macrolactone-based epothilones in humans. In response to these concerns the group at BMS conceived the metabolically more stable lactam analog of Epo B (53) as an alternative for future therapeutic applications. This work has resulted in an efficient process for the preparation of the Epo B lactam, a compound that was developed into a clinical anticancer drug and is marketed under the trade name Ixempra (ixabepilone, 53, Figure 3.11). 

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