中文摘要：

许多抗癌药物通过引起癌细胞的凋亡来达到治疗目的,因此开发能诱导癌细胞凋亡的药物一直是癌症研究的热点.以153个结构各异的具有caspase-3激活作用的细胞凋亡诱导剂为研究对象,通过三维定量构效关系（3D-QSAR）分析,得到了一个基于位阻场、静电场、疏水场、氢键供体场和受体场参数的最优比较分子相似性指数法（CoMSIA）模型.该模型（Q^2=0.51、R^2ncv=0.89和R^2pred=0.82）具有良好的内部一致性和预测能力,通过对模型的等值线图分析发现：（1）R2取代基提高诱导剂活性的因素包括位阻大、负电性大、有亲水性和具有氢键供体作用;（2）位阻适中和/或具有氢键供体作用的R4取代基,以及位阻小和/或亲水的R1取代基对提高分子的活性是有利的;（3）N-甲基-N-苯基-1-萘胺类细胞凋亡诱导剂具有正电性的A环3号位或C环7号位取代基,以及具有负电性的B环1号位取代基有利于提高诱导剂的生物活性.对该模型的分析更有利于认识细胞凋亡诱导剂的分子特征,并为设计和开发新型细胞凋亡诱导剂提供理论指导.

英文摘要：

A large number of anti-cancer agents exert their therapeutic effects through inducing apoptosis in malignant cells.Therefore,developing apoptosis-inducing drugs is always one of the hotspots in the field of cancer research.153 structurally diverse apoptosis inducers with caspase-3activation are studied by three-dimensional quantitative structure-activity relationships（3D-QSAR）analysis,resulting in an optimal CoMSIA（comparative molecular similarity indices analysis）model which is constructed based on the parameters of steric,electrostatic,hydrophobic,hydrogen-bond donor and receptor fields.The experimental results show that this CoMSIA model（Q^2=0.51,R^2ncv=0.89 and R^2pred=0.82）displays excellent inter-consistency and predictive abilities.Meanwhile,from analyzing CoMSIA contour maps,it can be concluded that（1）the R2 substituent with one or more features of bulk,electronegativity,hydrophilicity and H-bond donor is beneficial to the activity;（2）medium-sized and/or H-bond donor substitution of R4,as well as the R1 substituent with small and/or hydrophilic group can improve the activity;（3）the apoptosis inducers N-methyl-N-phenyl naphthalen-1-amines with electropositive groups in 3-position of ring-A or 7-position of ring-C,and 1-position of ring-B possessing the electronegative groups will benefit the apoptosis-inducing bio-activity.These conclusions may be helpful to understanding the molecular characteristics of apoptosis inducers,as well as providing theoretical guidance for the design and development of novel apoptosis inducers.