喜树碱类抗肿瘤药物的量子化学与定量构效关系研究  

Quantitative Structure-Activity Relationships of Antitumor Camptothecin Derivatives Using Quantum Chemical Methods and GA-PLS

作　　者：宋云龙[1] 张万年[1] 季海涛[1] 盛春泉[1] 周有骏[1] 朱驹[1] 吕加国[1] 

机构地区：[1]中国人民解放军第二军医大学药学院,上海200433

出　　处：《计算机与应用化学》2002年第1期4-8,18,共6页Computers and Applied Chemistry

基　　金："973"国家重点基础研究项目子项目(G1998051104);国家自然科学基金资助项目(39970874)

摘　　要：喜树碱类抗肿瘤药物是DNA拓扑异构酶Ⅰ(1bpoisomerase I,TopoI)的特异性抑制剂,目前已广泛应用于临床。为阐明喜树碱类化合物的作用模式,特别是A环取代基对活性的贡献,本研究基于前期喜树碱构象系统研究及其与TopoI-DNA共价复合物对接研究得到的药效构象,依次模建并优化了21个A环取代的喜树碱类化合物。结合偏最小二乘法和遗传算法,系统考察了36个分子描述符对活性的影响,包括半经验AM1方法计算得到的表征电性效应的量化描述符、立体描述符以及得自文献的疏水参数等。得到的A环取代的喜树碱类化合物的定量构效关系方程不仅统计意义显著,而且预测能力较强。本研究发现:以苯环亲电取代反应的邻、对位定位基取代喜树碱A环9、10位,活性大大提高,而且除羟基外,9位取代活性均明显高于10位取代;最高占有分子轨道能量(HOMO)对活性意义显著。这些都提示喜树碱与TopoI-DNA共价复合物可以形成电荷迁移复合物,为下一步合理设计、合成新型高效喜树碱衍生物打下了基础。Camptothecin (CPT) compounds specifically acting on DNA topoisomerase Ⅰ (TopoI) are promising antitumor drugs, and have been widely used in the clinic. In order to elucidate the model of action of camptothecin with TopoI-DNA complex, especially the contribution of A ring to antitumor activity, 21 compounds were built on the basis of the pharmacophoric conformation of camptothecin, which was determined from the previous conformational analysis and docking studies. 36 structural and physico-chemical descriptors consist of quantum chemical parameter calculated by AMI method, hydrophobic parameter (MlogP) and molecular steric descriptors. The descriptors were examined using genetic algorithm (GA) and partial least squares (PIS) analysis , the resulting QSAR models were of not only statistical significance, but also predictive ability. It has been indicated that substitution of electrophlic group on ring A of camptothecin will increase activity, especially on the C9. Our studies have also shown that the energy of highest occupied molecular orbital (HOMO) was important for antitumor activity, which was due to the formation of π - π charge transfer complex between camptothecin and TopoI-DNA complex disclosed by quantum chemical research. The understanding of mechanism of action of CPT with TopoI-DNA complex will benefit future design of novel potent antitumor camptothecin derivatives.

关 键 词：喜树碱 拓扑异构酶Ⅰ 定量构效关系 偏最小二乘法 遗传算法 抗肿瘤药物 量子化学 

分 类 号：R979.1[医药卫生—药品] R914.4[医药卫生—药学]