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.
Bibliographical noteFunding Information:
This work was supported by the National Institute of Health grants CA79641 and CA105305. E.A.R. and J.F.G. were supported by NIH Training Grant GM 07775. E.A.R. was also supported by DAMD 17-001-0303.
- Photoaffinity labels