苯并异噻唑酮类caspase-3抑制剂结构优化与生物活性评价

项目名称： 苯并异噻唑酮类caspase-3抑制剂结构优化与生物活性评价

项目编号： No.21302139

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 数理科学和化学

项目作者： 刘伟

作者单位： 天津科技大学

项目金额： 25万元

中文摘要： 细胞凋亡紊乱将导致多种人类疾病，包括神经退行性疾病、缺血性损伤、自身免疫性疾病和各种癌症。大量caspase家族成员与各种疾病的作用机制研究被报道，证明其与细胞凋亡紊乱有密切关系。在依赖半胱天冬酶进行细胞凋亡模式中，caspase-3是主要执行凋亡蛋白之一，其在各种细胞凋亡模式中的不同信号通路中均被激活，它可被看作一个非常有前景的治疗靶点，开发针对caspase-3的激活剂及抑制剂已成为研究热点。本课题是围绕开发caspase-3非肽类小分子抑制剂展开的，用于治疗caspase-3过表达相关疾病。目前，我们基于高通量药物筛选方法已发现一个结构新颖小分子母核（hit）具有很好的体外酶抑制活性，以该母核为基础，通过结构生物学、合成化学及计算化学等跨学科共同努力，进一步修饰与改变活性化合物的分子结构，争取找到具有更高活性、更低毒性的先导化合物，并阐明构效关系。

中文关键词： 抑制剂；苯并异噻唑酮；高通量筛选；半胱氨酸-天冬氨酸蛋白酶；细胞凋亡

英文摘要： Deregulation of the apoptotic process can contribute to many human diseases, including neurodegenerative diseases (such as Alzheimer disease and Huntington disease), ischemic damage, autoimmune disorders, and several forms of cancer. Caspase-3 is one of executioners in caspase-dependent apoptosis, and is activated in nearly every model of apoptosis, including those with different signaling pathways. Furthermore, Caspase-3 is expressed in almost all tissues at relatively high levels and has high catalytic activity compared with other executioner caspases, so it has been seen as a promising therapeutic target, which received particular attention in finding its inhibitors. One hit was identified as novel and potent inhibitors of caspase-3 from high-throughput screening. Various analogues will be designed and synthesized as caspase inhibitors through structural modification of the original compound. The aim of optimizing the structure of hit is in order to increase their potency and effciency, and to find the lead compound or candidate compound. Meanwhile, the structure-activity relationship will be clarified. The present small-molecule caspase-3 inhibitor with novel structures different from structures of known caspase inhibitors will reveal a new direction for therapeutic strategies directed against diseases invol

英文关键词： inhibitor；1;2-benzisothiazol-3-one；high-throughput screening；caspase-3；apoptosis