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.
Bibliographical noteFunding Information:
The authors gratefully acknowledge financial support from the National Institutes of Health: National Cancer Institute CA79641.
- C-25 epothilone analogue
- Total synthesis
- Tubulin assembly