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

Oliver E. Hutt, 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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

The total synthesis of 22-(3-azidobenzoyloxy)methyl epothilone C is described as a potential photoaffinity probe to elucidate the β-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.

Original languageEnglish (US)
Pages (from-to)3293-3296
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume19
Issue number12
DOIs
StatePublished - Jun 15 2009

Keywords

  • Epothilone
  • Microtubules
  • Photoaffinity labels

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