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设计、合成及评估 2-甲基-和 2-氨基-N-芳基-4,5-二氢噻唑并[4,5-h]喹唑啉-8-胺作为环状约束的 2-苯胺基-4-(噻唑-5-基)嘧啶细胞周期蛋白依赖性激酶抑制剂。

Design, synthesis, and evaluation of 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines as ring-constrained 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin-dependent kinase inhibitors.

机构信息

School of Chemistry and Biomedical Sciences Research Complex, University of St. Andrews, North Haugh, St Andrews, Fife KY16 9ST, UK.

出版信息

J Med Chem. 2010 Mar 11;53(5):2136-45. doi: 10.1021/jm901660c.

DOI:10.1021/jm901660c
PMID:20146435
Abstract

Following the recent discovery and development of 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin dependent kinase (CDK) inhibitors, a program was initiated to evaluate related ring-constrained analogues, specifically, 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines for inhibition of CDKs. Here we report the rational design, synthesis, structure-activity relationships (SARs), and cellular mode-of-action profile of these second generation CDK inhibitors. Many of the analogues from this chemical series inhibit CDKs with very low nanomolar K(i) values. The most potent compound reported in this study inhibits CDK2 with an IC(50) of 0.7 nM ([ATP] = 100 microM). Furthermore, an X-ray crystal structure of 2-methyl-N-(3-(nitro)phenyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amine (11g), a representative from the chemical series in complex with cyclin A-CDK2, is reported, confirming the design rationale and expected binding mode within the CDK2 ATP binding pocket.

摘要

继最近发现和开发 2-苯胺基-4-(噻唑-5-基)嘧啶细胞周期蛋白依赖性激酶 (CDK) 抑制剂后，启动了一项计划来评估相关的环状约束类似物，特别是 2-甲基-和 2-氨基-N-芳基-4,5-二氢噻唑并[4,5-h]喹唑啉-8-胺，以抑制 CDK。在这里，我们报告了这些第二代 CDK 抑制剂的合理设计、合成、构效关系 (SAR) 和细胞作用模式特征。该化学系列的许多类似物以非常低的纳摩尔 K(i) 值抑制 CDK。本研究报道的最有效化合物对 CDK2 的抑制作用的 IC(50)为 0.7 nM([ATP] = 100 microM)。此外，还报告了一个 X 射线晶体结构，其中包含 2-甲基-N-(3-(硝基)苯基)-4,5-二氢噻唑并[4,5-h]喹唑啉-8-胺（11g），这是化学系列中与细胞周期蛋白 A-CDK2 形成复合物的代表，证实了设计原理和预期的结合模式在 CDK2 ATP 结合口袋内。

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