(−)-Zampanolide (1) is a complex marine macrolide that was first isolated from the sponge Fasciospongia rimosa in 1996 by Tanaka & Higa. and found to exhibit nanomolar in vitro antiproliferative activity against a range of human cancer cell lines. The compound was subsequently shown to be a microtubule-stabilizing agent which, as the only potent microtubule stabilizer known, binds to b-tubulin in a covalent fashion. (−)-Zampanolide has been the target of several total synthesis campaigns, including a synthesis developed in our own laboratory that is based on macrocycle formation by intramolecular HWE reaction. We have recently reported the total synthesis of C(13)-desmethylene-(−)-zampanolide (2), including the first stereoselective construction of the C(20) stereocenter. C(13)-Desmethylene-(−)-zampanolide (2) was found to be at least equipotent with natural 1 and has thus served as the template for SAR studies that have addressed the relevance of the double bonds in the macrocycle, either alone or in combination, and of the C(5) and C(17) methyl groups. This contribution describes the synthesis of these different analogs and their microtubule-binding affinity, effects on the cellular microtubule network and in vitro antiproliferative activity. While all analogs were found to be less potent than 2, in some cases the drop in antiproliferative activity was less than 10-fold.

Synthesis of analogs of C(13)-desmethylene-(−)-zampanolide and structure-activity relationship studies

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