新型醛糖还原酶抑制剂的设计合成及活性评价

Design,synthesis and activity evaluation of novel aldose reductase inhibitors

目的设计合成一系列靛红衍生物,研究其对醛糖还原酶的抑制活性和选择性。方法以5-溴靛红为起始原料合成5′-溴螺[[1,3]二氧戊环-2,3′-吲哚啉]-2′-酮的三环骨架,然后经N烷基化反应、Suzuki或Heck偶联、水解合成了目标化合物。测定目标化合物对醛糖还原酶的抑制活性和选择性,通过计算机辅助药物设计软件在分子水平上研究化合物与醛糖还原酶活性位点的相互作用模式。结果设计合成了14个目标化合物,其结构经^(1)H-NMR、^(13)C-NMR与MS谱确证。化合物6a~6g,8a~8f对醛糖还原酶具有良好的抑制活性和选择性。其中,化合物8d的活性最强,IC_(50)为0.090μmol·L^(-1),与阳性对照药依帕司他相当。分子对接结果显示,化合物7、6b、8a和8d能与醛糖还原酶的活性位点较好结合。结论构效关系和分子对接研究表明三环结构上N-1位的羧酸基团与C-5侧链上的苯乙烯结构是提高醛糖还原酶抑制活性的关键。甲氧基或者酚羟基的引入可显著改善化合物对醛糖还原酶的抑制活性和选择性。

Objective To design and synthesize a series of isatin derivatives,and to further study their inhibitory activity and selectivity towards aldose reductase(ALR2).Methods The tricyclic skeleton of 5′-bromospiro[[1,3]dioxolane-2,3′-indoline]-2′-one was synthesized with 5-bromoisatin as the starting material.Then the target compounds were synthesized through the procedure of N-alkylation,Suzuki or Heck coupling and hydrolysis.The target compounds were tested for the inhibitory activity and selectivity towards ALR2,and computer-aided drug design software was used to study the interaction mode of compounds with the active site of ALR2 at the molecular level.Results Fourteen target compounds were designed and synthesized,and their structures were confirmed by ^(1)H-NMR,^(13)C-NMR and MS.Compounds 6a-6g,8a-8f demonstrated well inhibitory activity and selectivity towards ALR2.Among them,compound 8d displayed the highest ALR2 inhibitory activity with an IC_(50)value of 0.090μmol·L,which was equivalent to the positive control drug epalrestat.The results of molecular docking showed that compounds 7,6b,8a and 8d could bind to the active site of ALR2 in a good way.Conclusion Structure-activity relationship and molecular docking studies show that the acetic acid group at N-1 and styryl side chain at C-5 of the tricyclic skeleton are the key structures to increase the ALR2 inhibitory activity.The introduction of methoxy group or phenolic hydroxyl group significantly improves the inhibitory activity and selectivity of compounds toward ALR2.