Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors

Yi Hua Chen, Ya Hui Zhang, Hua Jie Zhang, Da Liu, Min Gu, Jing Ya Li, Fang Wu, Xing Zu Zhu, Jia Li, Fa Jun Nan

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

Abstract

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, IG50 = 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.

Original languageEnglish (US)
Pages (from-to)1613-1623
Number of pages11
JournalJournal of Medicinal Chemistry
Volume49
Issue number5
DOIs
StatePublished - Mar 5 2006
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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