Abstract
Epothilones (Epo’s) are bacterial natural products which are potent inhibitors of human cancer cell proliferation in vitro and in vivo. Tumor growth inhibition is based on the stabilization of cellular microtubules and at least seven epothilone-derived agents are presently undergoing clinical evaluation in humans. While all of these compounds are closely related structurally to the natural product leads Epo A and B, our own work involves the design, synthesis, and biological evaluation of analogs with significantly altered structural features. The ultimate goal of these efforts is the stepwise creation of new (and simplified) scaffolds for microtubule inhibition, bearing little or no obvious resemblance with the original epothilone structure. Such compounds would constitute new lead structures for anticancer drug discovery. In this paper we discuss the synthesis and biological properties of such hypermodified epothilone analogs, whose biological activity is within the same potency range as that of Epo A or B.
Highlights
Epothilones are 16-membered cytotoxic macrolides produced by the myxobacterium Sorangium cellulosum Sc 90, which were first reported by Reichenbach and Höfle in 19931
Trans-Epo A was reported by Nicolaou et al to be virtually equipotent with Epo A on an ovarian (1A9) and a breast cancer (MCF-7) cell line[11] the absolute stereochemistry of the active epoxide isomer was not reported and the trans isomers were obtained as minor components during the synthesis of the natural cis isomers rather than being the result of a directed synthetic effort
In view of the interesting biological features of trans(deoxy)epothilones we embarked on a project directed at the stereoselective synthesis of transepothilones A, the determination of the absolute stereochemistry of the bioactive isomer, and a more exhaustive biological characterization of this compound.[13]
Summary
Epothilones are 16-membered cytotoxic macrolides produced by the myxobacterium Sorangium cellulosum Sc 90, which were first reported by Reichenbach and Höfle in 19931. The activity-enhancing effect was pronounced for the deoxy derivative 12a, which is > 10-fold more potent against the human epidermoid carcinoma cell line KB-31 than Epo D.19 We have recently demonstrated that the beneficial effects of this side chain modification are not limited to analogs of the Epo B series, but are observed for the corresponding Epo A derivatives.[20]
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