Synthesis and biological evaluation of novel hydrogen sulfide releasing nicotinic acid derivatives.
Twelve novel hybrids of slowly releasing hydrogen sulfide donor ADT-OH combined with nicotinic acid were synthesized. All of their structures had been confirmed by1H NMR,13C NMR and MS spectra. The target compounds were evaluated for their neuroprotective effects on hippocampal neuron HT22 cells against glutamate-induced injury at the concentrations of 1-100μM with MTT assay, and their toxicity on HT22 cells untreated by glutamine at the concentration of 100μM. The active compound was further investigated for its effect on ischemic infarct volume by intraperitoneal injection at 3h after ischemia in mice models of permanent middle cerebral artery occlusion (pMCAO). The results showed that all the compounds significantly protected HT22 cells from glutamate-induced damage at most of the experimental concentrations, and had no or little neurotoxicity on normal HT22 cells at the high concentration. More importantly, compound A6 significantly reduced infarct volume in the pMCAO model. These results suggested that compound A6 may be promising for further evaluation for the intervention of cerebral ischemic injury.
Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, 199 Renai Road, Suzhou, Jiangsu Province 215123, China.
Yinxing
Y
Sun
Institute of Neuroscience, Soochow University, Suzhou, China.
Yusuo
Y
Zhang
Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, 199 Renai Road, Suzhou, Jiangsu Province 215123, China.
Yuyao
Y
Li
Institute of Neuroscience, Soochow University, Suzhou, China.
Jian
J
Cheng
Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, 199 Renai Road, Suzhou, Jiangsu Province 215123, China.
Shiyu
S
Chen
Institute of Neuroscience, Soochow University, Suzhou, China.
Yunqi
Y
Xiao
Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, 199 Renai Road, Suzhou, Jiangsu Province 215123, China. Electronic address: aoguizhen@suda.edu.cn.
Guizhen
G
Ao
D000818:Animals; D002545:Brain Ischemia / Q000139:chemically induced / Q000188:drug therapy*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid; D006862:Hydrogen Sulfide / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D051379:Mice; D015394:Molecular Structure; D009539:Nicotinic Acids / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D009539:Nicotinic Acids; D018698:Glutamic Acid; D006862:Hydrogen Sulfide
Hybrid; Hydrogen sulfide donor; Ischemic stroke; Neuroprotection; Nicotinic acid