黄酮-多胺衍生物的合成及活性评价

Synthesis and Biological Evaluation of Flavonoid-Polyamine Derivatives

目的设计合成黄酮-多胺衍生物,并对其体外胆碱酯酶抑制活性和细胞毒性进行研究。方法以间二酚为起始原料,经5步合成了目标化合物,采用Ellman法测试了化合物对乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BChE)的抑制活性,用酶动力学和分子对接研究了化合物与AChE的作用模式,用溴化噻唑蓝四氮唑(MTT)法研究了化合物对人肝癌细胞(HepG2)和神经细胞(PC12)的体外毒性。结果合成了7个新化合物,结构经1H-NMR,ESI-MS和元素分析确认。活性结果表明,化合物对AChE的抑制活性均强于对照药物卡巴拉汀,其中化合物6g活性最强,IC50值为0.65μmol·L^-1。酶动力学和分子对接结果显示化合物6g对AChE的作用类型是混合型抑制。另外,细胞结果表明,这些化合物在100μmol·L^-1浓度下细胞毒性较低。结论该系列化合物具有较强的胆碱酯酶抑制活性,具有进一步研究的意义。

OBJECTIVE To design and synthesize flavonoid-polyamine derivatives and investigate their cholinesterase inhibitory activity and cytotoxicity in vitro. METHODS The target compounds were synthesized in five steps from the starting material resorcinol. Their inhibitory activity of acetylcholinesterase(AChE), and butyrylcholinesterase(BChE) were screened by Ellman method. The interaction mode with AChE was studied by enzyme kinetics and molecular docking method. The in vitro toxicity against human hepatocarcinoma(HepG2) and rat pheochromocytoma(PC12) was evaluated by MTT assay. RESULTS Seven novel compounds were obtained, and their structures were confirmed by 1H-NMR, ESI-MS and elemental analysis. In vitro bioassay indicated that these compounds had stronger AChE inhibitory activity than the commercial drug rivastigmine, and compound 6 g showed strongest activity on AChE with the IC50 value 0.65 μmol·L-1. Enzyme kinetics and molecular modeling results showed that the interaction type of compound 6 g with AChE was mixed-type inhibition. Besides, these compounds did not show obvious toxicity against HepG2 and PC12 cell lines at the concentration of 100 μmol·L-1. CONCLUSION These series of compounds show preferable inhibition for cholinesterases, which are worthy of further study.