新型喹啉酮结构的多功能醛糖还原酶抑制剂设计合成与活性评价

Novel 3,4-dihydroquinolin-2(1H)-one derivatives as multifunctional aldose reductase inhibitors for treatment of diabetic complications:design,synthesis and biological evaluation

葡萄糖多元醇通路代谢增强导致的组织细胞中山梨醇的堆积及通路下游氧化应激反应是糖尿病及其并发症的主要成因,是抗糖尿病并发症药物发现两个最重要的药物干预靶点。目前,抗糖尿病并发症药物创制主要以醛糖还原酶活性抑制为主,对多元醇通路下游氧化应激反应关注较少,因而未能形成有效的抗糖尿病并发症药物。本论文研究以3,4-二氢喹啉-2(1H)-酮为母核结构,通过在传统醛糖还原酶抑制剂中引入多酚结构,设计并合成了一系列兼具醛糖还原酶抑制活性及抗氧化活性的新型多功能醛糖还原酶抑制剂。实验结果表明,在喹啉酮母核3,4-二氢喹啉-2(1H)-酮的C6位引入酚羟基结构特征后,保持了羧酸型抑制剂的强ALR2抑制活性,其中目标化合物4b的ALR2抑制活性最强,IC50值可达109 nM,更为重要的是,引入酚羟基所得目标化合物4b和4c均表现出了显著的抗氧化活性,其中目标化合物4c在100μM浓度下对DPPH的清除率达到了94.1%,清除活性氧自由基能力与阳性对照药Trolox相当。本论文研究所得抑制剂分子可以在抑制醛糖还原酶活性的同时,缓解机体内氧化应激反应,实现多靶点协同作用,进而提高药物分子的生物利用度,为抗糖尿病并发症药物发现提供了重要的理论依据。

The accumulation of sorbitol in tissue cells caused by metabolic enhancement of glucose polyol pathway is the main reason for Diabetes Mellitus(DM)and its complications.Aldose Reductase(ALR2)is the key speed limiting enzyme of the polyol pathway,and is the most important drug target for treatment of diabetic complications.In this study,a series of novel 3,4-dihydroquinolin-2(1H)-one derivatives as multifunctional aldose reductase inhibitors were designed and synthesized.Most of these derivatives were found to be potent and selective against ALR2,and compound 4a was the most active with an IC50 value of 0.109μM.Moreover,some prepared derivatives showed strong ability of removing reactive oxygen species(ROS),and among them the phenolic 3,5-dihydroxyl compound 4c was proved to be the most potent,even comparable to that of the well-known antioxidant Trolox at a concentration of 100μM.Thus the results suggested a success on the construction of potent dual inhibitor for the therapeutic intervention target of ALR2/ROS.