Design, Synthesis, and Interaction Study of Quinazoline-2(1H)-thione Derivatives as Novel Potential Bcl-xL Inhibitors
Design, Synthesis, and Interaction Study of Quinazoline-2(1H)-thione Derivatives as Novel Potential Bcl-xL Inhibitors
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DOI：
10.1021/jm901004c
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发表时间：
2010-05-13
影响因子：
7.3
通讯作者：
Liu, Dongxiang
中科院分区：
文献类型：
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作者：
Feng, Yu;Ding, Xiao;Liu, Dongxiang
开发拮抗抗凋亡Bcl-2家族蛋白活性的抑制剂在癌症化疗中特别令人感兴趣。我们通过虚拟数据库筛选发现了一个新的Bcl-x（L）、Bcl-2和Mcl-1抑制剂喹唑啉-2（1H）-吲哚衍生物（DCBL 55）。我们通过化学合成对化合物1进行了系统的结构修饰。通过分子模拟预测了化合物与Bcl-x（L）的相互作用，并通过构效关系分析和蛋白质突变研究证实了预测结果。发现Bcl-x（L）疏水沟中的三个位置（称为P2、P4和P5）有助于配体相互作用。虽然这些化合物诱导线粒体电位降低、半胱天冬酶激活和ROS产生，但细胞毒性和线粒体外膜的超微结构变化表明，这些化合物可能靶向Bcl-2家族以外的其他蛋白。总之，本研究提供了新的先导化合物和重要的结构信息，为进一步开发更有效和更特异的抗凋亡Bcl-2家族蛋白的抑制剂。
Development of inhibitors to antagonize the activities of antiapoptotic Bcl-2 family proteins is of particular interest in cancer chemotherapy. We discovered a quinazoline-2(1H)-thione derivative (DCBL55) as a new Bcl-x(L), Bcl-2, and Mcl-1 inhibitor by virtual database screening. We systematically modified the structure of compound 1 by chemical synthesis. The interactions of the compounds with Bcl-x(L), were predicted by molecular modeling simulations, which were confirmed by structure activity relationship analysis and protein mutation studies. Three locations at the hydrophobic groove of Bcl-x(L), referred to as P2, P4, and P5, were found to contribute to the ligand interactions. Although the compounds induced mitochondrial potential reduction, caspase activation, and ROS generation, the cytotoxicities and the ultrastructural changes of outer mitochondrial membrane suggested that the compounds may target additional proteins outside the Bcl-2 family. Altogether, the present study provides new lead compounds and critical structural information for further development of more potent and specific inhibitors of antiapoptotic Bcl-2 family proteins.