Total synthesis and evaluation of 22-(3-azidobenzoyloxy)methyl epothilone C for photoaffinity labeling of beta-tubulin

Bioorg Med Chem Lett. 2009 Jun 15;19(12):3293-6. doi: 10.1016/j.bmcl.2009.04.077.

Oliver E Hutt ¹, Jun Inagaki, Bollu S Reddy, Sajiv K Nair, Emily A Reiff, John T Henri, Jack F Greiner, David G VanderVelde, Ting-Lan Chiu, Elizabeth A Amin, Richard H Himes, Gunda I Georg

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Affiliation

1 Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA.

PMID: 19428248 DOI: 10.1016/j.bmcl.2009.04.077

Abstract

The total synthesis of 22-(3-azidobenzoyloxy)methyl epothilone C is described as a potential photoaffinity probe to elucidate the beta-tubulin binding site. A sequential Suzuki-aldol-Yamaguchi macrolactonization strategy was utilized employing a novel derivatized C1-C6 fragment. The C22-functionalized analog exhibited good activity in microtubule assembly assays, but cytotoxicity was significantly reduced. Molecular modeling simulations indicated that excessive steric bulk in the C22 position is accommodated by the large hydrophobic pocket of the binding site. Photoaffinity labeling studies were inconclusive suggesting non-specific labeling.

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