Epothilones and their analogs -: Potential new weapons in the fight against cancer

Epothilones are a new class of microtubule depolymerization inhibitors, which inhibit the growth of a broad range of human cancer cell lines in vitro with low nM or sub-nM IC50s. Unlike many other cytotoxic anticancer agents epothilones are also active in vitro against multidrug-resistant cell lines and epothilone B exhibits potent in vivo antitumor activity in multidrug-resistant tumor models. We have prepared various types of synthetic and semi-synthetic analogs of epothilones and we have studied the effect of the corresponding structural modifications on in vitro tubulin polymerization and antiproliferative activity. Epoxide ring opening, replacement of the epoxide moiety by amide groups or a 1,2-disubstituted imidazole ring, or the incorporation of phenylene moieties in the C(9)-C(12) region all lead to a substantial loss in in vitro activity. In contrast, expansion of the 3-membered oxirane ring to a 5-membered 1,3-dioxolane system, either cis- or trans-fused to the 16-membered macrocycle, is reasonably well tolerated. Substitution of a 2-methylbenzothiazole moiety for the natural (2-(2-methyl-thiazol-4-yl)-1-methyl-)ethenyl side-chain results in analogs with more potent antiproliferative activity than natural epothilones.