Design, synthesis and evaluation of 1,2-benzisothiazol-3-one derivatives as potent caspase-3 inhibitors
Design, synthesis and evaluation of 1,2-benzisothiazol-3-one derivatives as potent caspase-3 inhibitors
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DOI：
10.1016/j.bmc.2013.03.075
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发表时间：
2013-06-01
影响因子：
3.5
通讯作者：
Yang, Cheng
中科院分区：
文献类型：
--
作者：
Liu, Dazhi;Tian, Zhen;Yang, Cheng
通过高通量筛选，对原化合物进行结构修饰，合成了多个1，2-苯并异噻唑-3-酮类化合物。一些类似物(如6b、6R、6S和6W)被鉴定为新的有效的caspase抑制剂，其IC50为纳米分子。体外评价caspase-3抑制作用的构效关系(SAR)研究。分子模拟研究为这类化合物与活化的caspase-3的相互作用提供了进一步的洞察力。目前的小分子caspase-3抑制剂具有不同于已知caspase抑制剂结构的新结构，为针对涉及异常上调的细胞凋亡的疾病的治疗策略提供了新的方向。(C)2013爱思唯尔有限公司。保留所有权利。
A number of 1,2-benzisothiazol-3-one derivatives were prepared through structural modification of the original compound from high-throughput screening. Some analogues (e. g., 6b, 6r, 6s and 6w) were identified as novel and potent caspase inhibitors with IC50 of nanomolar. Structure-activity relationship (SAR) studies for caspase-3 inhibition were evaluated in vitro. Molecular modeling studies provided further insight into the interaction of this class of compounds with activated caspase-3. The present small molecule caspase-3 inhibitor with novel structures different from structures of known caspase inhibitors revealed a new direction for therapeutic strategies directed against diseases involving abnormally up-regulated apoptosis. (C) 2013 Elsevier Ltd. All rights reserved.