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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:19

Article

Hutt, Oliver E.^2,4  Inagaki, Jun²  Reddy, Bollu S.²  Nair, Sajiv K.²  Reiff, Emily A.²  Henri, John T.²  Greiner, Jack F.²  VanderVelde, David G.²  Chiu, Ting-Lan⁴  Amin, Elizabeth A.⁴  Himes, Richard H.³  Georg, Gunda I.^1,2,4 

[1] Univ Minnesota, Coll Pharm, Inst Therapeut Discovery & Dev, Minneapolis, MN 55414 USA

[2] Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA

[3] Univ Kansas, Dept Mol Biosci, Lawrence, KS 66045 USA

[4] Univ Minnesota, Dept Med Chem, Minneapolis, MN 55414 USA

关键词: Epothilone;    Photoaffinity labels;    Microtubules;   

DOI  :  10.1016/j.bmcl.2009.04.077

来源: Elsevier

【 摘 要 】

The total synthesis of 22-(3-azidobenzoyloxy)methyl epothilone C is described as a potential photoaffinity probe to elucidate the beta-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. (C) 2009 Elsevier Ltd. All rights reserved.

【 授权许可】

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