抑制人乳腺癌细胞MCF-7生长的查尔酮类化合物的三维定量构效关系研究

摘要

目的：通过研究抑制人乳腺癌细胞MCF-7生长的查尔酮类化合物的三维定量构效关系（3D-QSAR），为查尔酮类抗肿瘤药物的研发提供理论基础。方法：分析55个查尔酮类化合物的结构和活性（pIC50）值，进行分子叠合后，采用比较分子力场分析（CoMFA）模型考察化合物的立体场和静电场，比较分子相似性指数分析（CoMSIA）模型考察化合物的立体场、静电场、疏水场、氢键供体场和氢键受体场，确立最优取代基团并进行预测。结果：CoMFA模型显示立体场、静电场对化合物活性有影响，CoMSIA模型显示疏水场、静电场、立体场对化合物活性影响显著。分子叠合后，在公共骨架上的R1、R2取代基附近引入亲水性基团，R1、R4取代基区域引入具有一定负电荷的基团，减少R2取代基上的位阻并在R2、R4引入正电荷基团，可明显增加查尔酮类化合物的活性。按此结果设计了2种新的化合物，其pIC50分别达到了5.538、5.589（CoMFA法）和5.552、5.628（CoMSIA法）。结论：3D-QSAR可准确分析查尔酮类化合物抑制人乳腺癌细胞MCF-7生长活性的结构特征，可为新药的开发研究提供理论指导。%OBJECTIVE:To provide theoretical basis for R&D of chalcone anti-tumor drugs by studying 3D-QSAR of chalcone compounds inhibiting the growth of human breast tumor cell MCF-7. METHODS:The structure and activity value (pIC50) of 55 chalcone compounds were analyzed. After molecular alignment,comparative molecular field analysis(CoMFA)was used to investi-gate three dimensional field and electrostatic field,and comparative molecular similarity indices analysis(CoMSIA)was used to in-vestigate steric field,electrostatic field,hydrophobic field,hydrogen bond donor field and hydrogen bond receptor field of chemi-cal compound. Finally,optimal substituent group was confirmed and predicted. RESULTS:CoMFA model showed the effects of ste-ric field and electrostatic field of the compound on its activity;CoMSIA model showed the effects of hydrophobic field,electrostat-ic field and hydrogen bond acceptor field of the compound on its activity. After molecular alignment,hydrophilic group introduced around R1,R2 substituent group of public frame,and the group with negative charge introduced in R1,R4 substituent group,steric hindrance of R2 substituent group reduced and positive charge introduced in R2 and R4,can significantly increase the activity of chal-cone compounds. 2 new compounds were designed according to above results,pIC50 of them were 5.538,5.589 (CoMFA model) and 5.552,5.628(CoMSIA method). CONCLUSIONS:3D-QSAR can accurately analyze the structural character of chalcone com-pounds inhibiting the growth activity of MCF-7 cells and provide theoretic direction for new drug R&D.