1,2-benzisothiazol-3-one derivatives as a novel class of small-molecule caspase-3 inhibitors

Lixin Wu; Meiqi Lu; Zhihui Yan; Xiaobin Tang; Bo Sun; Wei Liu; Honggang Zhou; Cheng Yang

doi:10.1016/j.bmc.2014.03.002

1,2-benzisothiazol-3-one derivatives as a novel class of small-molecule caspase-3 inhibitors

Bioorg Med Chem. 2014 Apr 15;22(8):2416-26. doi: 10.1016/j.bmc.2014.03.002. Epub 2014 Mar 12.

Authors

Lixin Wu¹, Meiqi Lu², Zhihui Yan¹, Xiaobin Tang¹, Bo Sun³, Wei Liu⁴, Honggang Zhou⁵, Cheng Yang⁶

Affiliations

¹ College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China.
² College of Life Science, NanKai University, Tianjin 300071, China.
³ High Throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology and Medicine, TEDA, Tianjin 300457, China.
⁴ College of Science, Tianjin University of Science and Technology, Tianjin 300457, China. Electronic address: liuwei2006@tust.edu.cn.
⁵ College of Pharmacy, NanKai University, Tianjin 300071, China.
⁶ College of Pharmacy, NanKai University, Tianjin 300071, China; High Throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of Biotechnology and Medicine, TEDA, Tianjin 300457, China.

PMID: 24656804
DOI: 10.1016/j.bmc.2014.03.002

Abstract

A novel series of 1,2-benzisothiazol-3-one derivatives was synthesized and their biological activities were evaluated for inhibiting caspase-3 and -7 activities, in which some of them showed low nanomolar potency against caspase-3 in vitro and significant protection against apoptosis in a camptothecin-induced Jurkat T cells system. Among the tested compounds, compound 5i exhibited the most potent caspase-3 inhibitory activity (IC50=1.15 nM). The molecular docking predicted the interactions and binding modes of the synthesized inhibitor in the caspase-3 active site.

Keywords: 1,2-Benzisothiazol-3-one; Apoptosis; Caspase-3; Inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / drug effects
Benzothiazoles / chemical synthesis
Benzothiazoles / chemistry*
Benzothiazoles / pharmacology
Binding Sites
Camptothecin / toxicity
Caspase 3 / chemistry*
Caspase 3 / metabolism
Caspase Inhibitors / chemical synthesis
Caspase Inhibitors / chemistry*
Caspase Inhibitors / pharmacology
Catalytic Domain
Humans
Jurkat Cells
Molecular Docking Simulation
Morpholines / chemical synthesis
Morpholines / chemistry*
Morpholines / pharmacology
Static Electricity
Thiazoles / chemical synthesis
Thiazoles / chemistry*
Thiazoles / pharmacology

Substances

Benzothiazoles
Caspase Inhibitors
Morpholines
N-(4-morpholinophenyl)-3-oxobenzo(d)isothiazole-2(3H)-carboxamide
Thiazoles
Caspase 3
1,2-benzisothiazoline-3-one
Camptothecin