Epothilones epoxide modifications

A large part of the early SAR work on epothilones has focused on modifications of the epoxide moiety at positions 12/13 of the macrolactone ring. These studies have demonstrateded that the presence of the epoxide ring is not an indispensible prerequisite for efficient microtubule stabilization and potent antiproliferative activity. Thus, Epo C (10) and D (11) (Figure 1-1) are virtually equipotent inducers of tubulin polymerization as Epo A and B, respectively. They are also potent inhibitors... 

All these data revealed the multiple interactions that epothilones make with (3-tubulin. They also explain why modification of the epoxide at the C12-C13 position to form the N12-ferf-Boc-C13 unit and the introduction of a polycyclic benzimidiazole ring at C15 in 12-aza-epothilone 1 have contributed so much to the improvement of biological activity. Development of 12-aza-epothilones is one of the most impressive successes of the combined structural and molecular biological approach to the design of new lead molecules. 

Formally, the N-atom of azithromycin is inserted into the macrolide ring of erythromycin, and the carbonyl group is reduced to methylene. In contrast, in 12-aza-epothilones, the C12 atom in natural epothilones is replaced by an N-atom, and epoxide oxygen is reduced. While the first substantial alteration of the macrolactone ring was achieved in a few steps firom erythromycin, the second epothilone modification cannot be made with compoxmds from the natural pool, and required total synthesis of the target stmctures. 

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