title: Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.
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, 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.
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, 201203, PRC.
authors.forename: Yi-Hua
authors.initials: YH
authors.lastname: Chen
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Zhang
authors.forename: Hua-Jie
authors.initials: HJ
authors.lastname: Zhang
authors.forename: Da-Zhi
authors.initials: DZ
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Gu
authors.forename: Jing-Ya
authors.initials: JY
authors.lastname: Li
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
authors.forename: Xing-Zu
authors.initials: XZ
authors.lastname: Zhu
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Fa-Jun
authors.initials: FJ
authors.lastname: Nan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001157:Arterial Occlusive Diseases / Q000150:complications; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019169:Jurkat Cells; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013386:Succinates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D061945:Caspase Inhibitors; D007546:Isoquinolines; C509707:N-(2-methoxyphenyl)-N'-(1,3,4-trioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)succinamide; D013386:Succinates; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases