新型噻唑基衍生物的设计、合成及作为人 Pin1 抑制剂的生物学评价。
Design, synthesis and biological evaluation of novel thiazole-based derivatives as human Pin1 inhibitors.
机构信息
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
出版信息
Bioorg Med Chem. 2021 Jan 1;29:115878. doi: 10.1016/j.bmc.2020.115878. Epub 2020 Nov 18.
Pin1 is a peptidyl prolyl cis-trans isomerase (PPIase) and inhibiting Pin1 is a potential way for discovering anti-tumor agents. With an aim to find potent Pin1 inhibitors with a novel scaffold, a series of thiazole derivatives with an alicyclic heterocycles on the 2-position were designed, synthesized and tested against human Pin1. Compound 9p bearing a 2-oxa-6-azaspiro [3,3] heptane moiety on the thiazole scaffold was identified as the most potent Pin1 inhibitor of this series with an IC value of 0.95 μM. The structure-activity relationship (SAR) and molecular modeling study indicated that introducing an alicyclic ring with an H-bond acceptor would be a viable way to improve the binding affinity.
Pin1 是一种肽基脯氨酰顺反异构酶（PPIase），抑制 Pin1 是发现抗肿瘤药物的一种潜在方法。为了找到具有新型骨架的有效 Pin1 抑制剂，设计、合成了一系列噻唑衍生物，并在 2 位带有脂环杂环，对人 Pin1 进行了测试。噻唑骨架上带有 2-氧代-6-氮杂螺[3.3]庚烷部分的化合物 9p 被鉴定为该系列中对 Pin1 抑制活性最强的化合物，IC 值为 0.95 μM。构效关系（SAR）和分子模拟研究表明，引入具有氢键受体的脂环是提高结合亲和力的可行方法。
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