Total synthesis and evaluation of C25-benzyloxyepothilone C for tubulin assembly and cytotoxicity against MCF-7 breast cancer cells

The total synthesis of C25-benzyloxy epothilone C is described. A sequential Suzuki-Aldol-Yamaguchi macrolactonization strategy was utilized employing a novel derivatized C8-C12 fragment. The C25-benzyloxy analog exhibited significantly reduced biological activity in microtubule assembly and cytotoxicity assays. Molecular modeling simulations indicated that excessive steric bulk in the C25 position may reduce activity by disrupting key hydrogen bonds that are crucial for epothilone binding to β-tubulin.

 

Oliver E. Hutt, Bollu S. Reddy, Sajiv K. Nair, Emily A. Reiff, John T. Henri, Jack F. Greiner, Ting-Lan Chiu, David G. VanderVelde, Elizabeth A. Amin, Richard H. Himes, Gunda I. Georg
September 1, 2008
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