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 journalArticle

106 Citations (Scopus)

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

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Caspase Inhibitors
Caspase 3
Apoptosis
Stroke
isoquinoline-1,3,4-trione
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors. / Chen, Yi Hua; Zhang, Ya Hui; Zhang, Hua Jie; Liu, Da; Gu, Min; Li, Jing Ya; Wu, Fang; Zhu, Xing Zu; Li, Jia; Nan, Fa Jun.

In: Journal of Medicinal Chemistry, Vol. 49, No. 5, 05.03.2006, p. 1613-1623.

Research output: Contribution to journalArticle

Chen, Yi Hua ; Zhang, Ya Hui ; Zhang, Hua Jie ; Liu, Da ; Gu, Min ; Li, Jing Ya ; Wu, Fang ; Zhu, Xing Zu ; Li, Jia ; Nan, Fa Jun. / Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors. In: Journal of Medicinal Chemistry. 2006 ; Vol. 49, No. 5. pp. 1613-1623.
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AU - Gu, Min

AU - Li, Jing Ya

AU - Wu, Fang

AU - Zhu, Xing Zu

AU - Li, Jia

AU - Nan, Fa Jun

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