Cytotoxic natural products that affect microtubule dynamics have been an important class of cancer chemotherapeutic agents for several decades. Recently, specific microtubule stabilizing polyketides have received considerable attention from the synthetic, biological, and medicinal communities due to their improved pharmacological properties and potent activities against multi-drug resistant cancers. Our lab has contributed to the study of a number of these agents, including the epothilones, the pelorusides, and most recently, zampanolide. (-)-Zampanolide is a 20-membered polyketide that exhibits nanomolar cytotoxicity against multiple cancer cell lines and induces apoptosis through microtubule bundle formation. Preliminary studies by Field and co-workers have reported that zampanolide binds �-tubulin through a unique covalent interaction with amino acid residues within the paclitaxel-binding site. Despite isolation from two marine organisms and several total syntheses, zampanolide remains in scarce supply and only a few analogues have been reported to date. As a part of our long-standing program that correlates ligand conformation to biological activity, we embarked on a synthetic preparation of this unique polyketide to further investigate its bioactive conformation and characterize its interaction with tubulin at the molecular level. Herein, we describe an efficient synthetic route for the preparation of (-)-zampanolide utilizing our electrophile-induced ether transfer methodology. With zampanolide, in hand, we have performed high-field NMR and molecular modeling experiments to help elucidate the functional role of the hemiaminal side chain and the conformational preferences of the macrolide core.

Synthesis, conformational analysis, and biological evalulation of the potent microtubule stabilizing agents, (-)-dactylolide and (-)-zampanolide

246th National Meeting (2013)

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