物理化学学报 >> 2006, Vol. 22 >> Issue (11): 1372 -1376 .doi: 10.1016/S1872-1508(06)60069-7

研究论文 上一篇    下一篇

抗癌性吲哚喹唑啉衍生物3D-QSAR研究及其分子设计

钱力;沈勇;陈锦灿;郑康成   

  1. 中山大学化学与化学工程学院,广州 510275
  • 收稿日期:2006-05-29 修回日期:2006-07-10 发布日期:2006-11-06
  • 通讯作者: 沈勇 E-mail:cessy@mail.sysu.edu.cn

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

QIAN Li;SHEN Yong;CHEN Jin-Can;ZHENG Kang-Cheng   

  1. School of Chemistry and Chemical Engineering, Zhongshan (Sun Yat-Sen) University, Guangzhou 510275, P. R. China
  • Received:2006-05-29 Revised:2006-07-10 Published:2006-11-06
  • Contact: SHEN Yong E-mail:cessy@mail.sysu.edu.cn

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.

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

Abstract: 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 (2D-QSAR) of these compounds, a further study on the three-dimensional quantitative structure-activity relationship (3D-QSAR) 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 R1 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: A electrostatic effect in the substituent R1 part plays a major role,and it is very important to make the first atom of R1 carrying more positive charges in order to improve the anticancer activity of the compounds. B 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.

Key words: Indolo[1,2-b]quinazoline, Antitumor activity, 3D-QSAR, CoMFA, Molecular design