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(3 D-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(Q2=0.51、R2ncv=0.89和R2pred=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.%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.1 5 3 structurally diverse apoptosis inducers with caspase-3 activation 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 (Q2=0.51,R2ncv=0.89 and R2pred=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.
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