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Design, Synthesis, and Biological Evaluation of Isoquinoline-1,3,4-trione Derivatives as Potent Caspase-3 Inhibitors

2006; American Chemical Society; Volume: 49; Issue: 5 Linguagem: Inglês

10.1021/jm050896o

1520-4804

Yihua Chen, Yahui Zhang, Hua-jie Zhang, Dazhi Liu, Min Gu, Jing-Ya Li, Fang Wu, Xing-Zu Zhu, Li Jia, Fa-Jun Nan,

Autophagy in Disease and Therapy

A series of isoquinoline-1,3,4-trione derivatives were identified as novel and potent inhibitors of caspase-3 through structural modification of the original compound from high-throughput screening. Various analogues (2, 6, 9, 13, and 14) were synthesized and identified as caspase inhibitors, and the introduction of a 6-N-acyl group (compound 13) greatly improved their activity. Some of them showed low nanomolar potency against caspase-3 in vitro (for example, for 6k, IC50 = 40 nM) and significant protection against apoptosis in a model cell system. Additionally, compound 13f demonstrated a dose-dependent decrease in infarct volume in the transient MCA occlusion stroke model. 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.