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3D-QSAR Study of 7,8-Dialkyl-1,3-diaminopyrrolo-[3,2-f] Quinazolines with Anticancer Activity as DHFR Inhibitors
Jin-can Chen,Lan-mei Chen,Si-yan Liao,Li Qian,Kang-cheng Zheng*
Author NameAffiliationE-mail
Jin-can Chen Analysis Centre of Guangdong Medical College, Zhanjiang 524023, ChinaMOE Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China  
Lan-mei Chen School of Pharmacy, Guangdong Medical College, Zhanjiang 524023, China  
Si-yan Liao MOE Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China  
Li Qian MOE Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China  
Kang-cheng Zheng* MOE Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China ceszkc@mail.sysu.edu.cn 
Abstract:
A three-dimensional quantitative structure-activity relationship (3D-QSAR) study of a series of 7,8-dialkyl-1,3-diaminopyrrolo-[3,2-f] quinazolines with anticancer activity as dihydrofolate reductase (DHFR) inhibitors was carried out by using the comparative molecular field analysis (CoMFA), on the basis of our reported 2D-QSAR of these compounds. The established 3D-QSAR model has good quality of statistics and good prediction ability; the non cross-validation correlation coefficient and the cross-validation value of this model are 0.993 and 0.619, respectively, the F value is 193.4, and the standard deviation SD is 0.208.This model indicates that the steric field factor plays a much more important role than the electrostatic one, in satisfying agreement with the published 2D-QSAR model. However,the 3D-QSAR model offers visual images of the steric field and the electrostatic field. The 3D-QSAR study further suggests the following: to improve the activity, the substituent R’ should be selected to be a group with an adaptive bulk like Et or i-Pr, and the substituent R should be selected to be a larger alkyl. In particular, based on our present 3D-QSAR as well as the published 2D-QSAR, the experimentally-proposed hydrophobic binding mechanism on the receptor-binding site of the DHFR can be further explained in theory. Therefore, the QSAR studies help to further understand the “hydrophobic binding”action mechanism of this kind of compounds, and to direct the molecular design of new drugs with higher activity.
Key words:  Dihydrofolate reductase, Quinazoline, 3D-QSAR, Comparative molecular field Analysis
FundProject:
3D-QSAR Study of 7,8-Dialkyl-1,3-diaminopyrrolo-[3,2-f] Quinazolines with Anticancer Activity as DHFR Inhibitors
陈锦灿,陈兰美,廖思燕,钱力,郑康成*
摘要:
在对一系列抗癌性7,8-二烃基-1,3-二氨基吡咯-[3,2-f]喹唑啉类二氢叶酸还原酶抑制剂的二维定量构效关系(2D-QSAR)研究基础上,应用比较分子场分析法对该类配合物进行了三维定量构效关系(3D-QSAR)研究. 建立了具有良好的统计学性能及预报能力的3D-QSAR模型,非交叉验证相关系数为0.993,交叉验证相关系数为0.619,估算的标准误差0.208, 统计方差比193.4. 该模型表明立体场因素的影响比静电场因素大很多,此结果与我们已经报道的2D-QSAR模型结果相一致. 然而,3D-QS
关键词:  二氢叶酸还原酶,喹唑啉,3D-QSAR, 比较分子力场分析
DOI:10.1088/1674-0068/22/03/285-289
分类号: