Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.
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.
Chen
Yi-Hua
YH
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.
Zhang
Ya-Hui
YH
Zhang
Hua-Jie
HJ
Liu
Da-Zhi
DZ
Gu
Min
M
Li
Jing-Ya
JY
Wu
Fang
F
Zhu
Xing-Zu
XZ
Li
Jia
J
Nan
Fa-Jun
FJ
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
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