Total synthesis and evaluation of 22-(3-azidobenzoyloxy)methyl epothilone C for photoaffinity labeling of β-tubulin
详细信息 查看全文
- 作者：Oliver E. Hutt ; Jun Inagaki ; Bollu S. Reddy ; Sajiv K. Nair ; Emily A. Reiff ; John T. Henri ; Jack F. Greiner ; David G. V ; erVelde ; Ting-Lan Chiu ; Elizabeth A. Amin ; Richard H. Himes ; Gunda I. Georg
- 关键词：Epothilone ; Photoaffinity labels ; Microtubules
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2009
- 出版时间：15 June 2009
- 年：2009
- 卷：19
- 期：12
- 页码：3293-3296
- 全文大小：306 K
文摘
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.