Sun Yinxing, Zhang Yusuo, Li Yuyao, Cheng Jian, Chen Shiyu, Xiao Yunqi, Ao Guizhen
Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, 199 Renai Road, Suzhou, Jiangsu Province 215123, China.
Institute of Neuroscience, Soochow University, Suzhou, China.
Bioorg Med Chem. 2016 Nov 1;24(21):5368-5373. doi: 10.1016/j.bmc.2016.08.060. Epub 2016 Aug 30.
Twelve novel hybrids of slowly releasing hydrogen sulfide donor ADT-OH combined with nicotinic acid were synthesized. All of their structures had been confirmed by H NMR, C 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.
合成了十二种新型的缓慢释放硫化氢供体ADT-OH与烟酸的杂合物。它们的所有结构均已通过氢核磁共振、碳核磁共振和质谱光谱得到证实。采用MTT法，在1-100μM浓度下评估目标化合物对海马神经元HT22细胞谷氨酸诱导损伤的神经保护作用，以及在100μM浓度下对未用谷氨酰胺处理的HT22细胞的毒性。在永久性大脑中动脉闭塞（pMCAO）小鼠模型中，于缺血后3小时通过腹腔注射进一步研究活性化合物对缺血梗死体积的影响。结果表明，在大多数实验浓度下，所有化合物均能显著保护HT22细胞免受谷氨酸诱导的损伤，且在高浓度下对正常HT22细胞无神经毒性或神经毒性很小。更重要的是，化合物A6在pMCAO模型中显著降低了梗死体积。这些结果表明，化合物A6在进一步评估其对脑缺血损伤的干预作用方面可能具有前景。
