抗癌性吲哚喹唑啉衍生物3D-QSAR研究及其分子设计  

3D-QSAR Study of a Series of Indolo[1,2-b]quinazoline Derivatives with Antitumor Activity and their Molecular Design

作　　者：钱力[1] 沈勇[1] 陈锦灿[1] 郑康成[1] 

机构地区：[1]中山大学化学与化学工程学院,广州510275

出　　处：《物理化学学报》2006年第11期1372-1376,共5页Acta Physico-Chimica Sinica

基　　金：教育部留学回国人员科研启动基金;广东省自然科学基金(05003264)资助项目

摘　　要：吲哚喹唑啉衍生物是近年来发现的一类具有良好抗癌活性的化合物．作者在最近报道的二维定量构效关系(2D-QSAR)的基础上,采用比较分子力场方法(CoMFA)进一步对该系列化合物进行三维定量构效关系(3D- QSAR)研究,建立了3D-QSAR的CoMFA模型,其非交叉验证相关系数r2=0．986,标准偏差SD=0．084,统计方差比F=114．6,交叉验证相关系数q2=0．695,表明该模型合理、可信,并具有良好的预测能力．研究结果表明:(1)取代基R1的部位上静电效应起主要作用,并且确保取代基R1的第一个原子具有较大的净正电荷,对提高化合物的抗癌活性十分重要．这与2D-QSAR研究结果相一致．(2)取代基R2的部位上立体效应起主要作用,R2的体积大小要适中．应用这些规律进行了分子设计,在理论上获得了一些具有较高抗癌活性的新的吲哚喹唑啉衍生物,并期待实验证实．该QSAR的研究结果可为实验工作者合成新药提供理论参考．Indolo [1,2-b]quinazoline derivatives have recently been reported as a type of compound with potential anticancer activity. On the basis of our the published two-dimensional quantitative structure-activity relationship （2DQSAR） of these compounds, a further study on the three-dimensional quantitative structure-activity relationship （3DQSAR） was carried out using the method of comparative molecular field analysis （CoMFA）. A reasonable, receivable, and an effective 3D-QSAR model has been established, in which the correlation coefficient （r2） and cross-validation coefficient （q2） values are 0.986 and 0.695, respectively, the statistical squared deviation ratio （F） is 114.6, and the standard deviation （SD） is 0.084. The results suggest that the electrostatic effect of substituent Rt and steric effect of substituent R2 play a very important roles in the improvement of the anticancer activity of these compounds. In this article, some significant conclusions were drawn, which are in good agreement with the conclusions obtained using 2D-QSAR, which are as follows： （1） The electrostatic effect in the substituent R, part plays a major role, and it is very important to make the first atom of R~ carrying more positive charges in order to improve the anticancer activity of the compounds. （2） The steric effect plays a major role in the substituent R2 part, and the volume of R2 should be moderate. Based on the above conclusions, three new molecules of Indolo [1,2-b]quinazoline derivatives with higher anticancer activity have been theoretically designed and are waiting for support from experiment. The QSAR results can offer a theoretical reference for the pharmaceutical synthesis.

关 键 词：吲哚喹唑啉 抗癌活性 3D-QSAR 比较分子力场分析 分子设计 

分 类 号：R914[医药卫生—药物化学]