噻唑并[5,4-f]喹唑啉-9-酮，糖原合酶激酶-3抑制剂

Thiazolo[5,4-f]quinazolin-9-ones, inhibitors of glycogen synthase kinase-3.

作者信息

Testard Alexandra, Logé Cédric, Léger Benoît, Robert Jean-Michel, Lozach Olivier, Blairvacq Mélina, Meijer Laurent, Thiéry Valérie, Besson Thierry

机构信息

Laboratoire de Biotechnologies et de Chimie Bio-organique, FRE CNRS 2766, UFR Sciences Fondamentales et Sciences pour l'Ingénieur, Université de La Rochelle, Bâtiment Marie Curie, 17042 La Rochelle, France.

出版信息

Bioorg Med Chem Lett. 2006 Jul 1;16(13):3419-23. doi: 10.1016/j.bmcl.2006.04.006. Epub 2006 Apr 27.

DOI:10.1016/j.bmcl.2006.04.006

PMID:16644220

Abstract

In an effort to identify new protein kinase inhibitors with increased potency and selectivity, we have developed the microwave-assisted synthesis of thiazolo[5,4-f]quinazolin-9-ones. The effects of eighteen derivatives on CDK1/cyclin B, CDK5/p25, and GSK-3 were investigated. Several turned out to inhibit GSK-3 in the micromolar range. Molecular modeling studies suggest that the most selective GSK-3 inhibitors 7a-d bind into the ATP-binding site through a key hydrogen bond interaction with Val135 and target the specific hydrophobic backpocket of the enzyme.

摘要

为了鉴定具有更高效力和选择性的新型蛋白激酶抑制剂，我们开发了微波辅助合成噻唑并[5,4-f]喹唑啉-9-酮的方法。研究了十八种衍生物对CDK1/细胞周期蛋白B、CDK5/p25和GSK-3的影响。结果发现有几种在微摩尔范围内抑制GSK-3。分子模拟研究表明，最具选择性的GSK-3抑制剂7a-d通过与Val135的关键氢键相互作用结合到ATP结合位点，并靶向该酶特定的疏水后袋。