喜树碱药效构象及分子内氢键对抗肿瘤活性的影响  

Bioactive Conformation of Camptothecin and the Influence of Intramolecular HydrogenBond on Antitumor Activity

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

机构地区：[1]第二军医大学药学院药物化学教研室,上海200433

出　　处：《中国药物化学杂志》2001年第6期311-315,共5页Chinese Journal of Medicinal Chemistry

基　　金："973"国家重点基础研究项目子项目 (No .G19980 5 110 4 ) ;国家自然科学基金项目 (No .39970 874 )

摘　　要：喜树碱类抗肿瘤药物是临床广泛使用的DNA拓扑异构酶Ⅰ (topoisomeraseⅠ ,TopoⅠ )的特异性抑制剂。为从原子水平阐明喜树碱的作用模式 ,设计结构新颖、活性更高、毒性更低的TopoⅠ抑制剂 ,本研究采用abinitio方法RHF/ 3 2 1G对喜树碱分子构象空间进行了系统研究 ,并与半经验量化AM1、PM 3方法比较 ,所得构象均采用密度泛函方法B3LYP/ 6 31G(d)计算单点能 ,并进行频率检查验证。结果发现 ,A型构象可形成分子内氢键 ,较B型构象能量更低 ,为喜树碱药效构象。喜树碱E环形成分子内氢键 ,能量约为 2 9 31kJ/mol,这是该分子发挥药效的结构基础 ,同时使得它易于受溶剂水影响而裂解 ,生成无活性的羧酸盐形式。本研究还表明 ,喜树碱与TopoⅠ DNA复合物作用 ,需破坏分子内氢键 ,能量补偿较大 。Camptothecin(CPT)compounds are specific inhibitors of DNA topoisomerase Ⅰ(TopoⅠ)which have been widely used in the clinic.To elucidate the mode of action of CPT from the atomic level and design novel highly potent and less toxic inhibitors acting on TopoⅠ,based on previous systematic quantum chemical studies on the conformation similar to the CPT crystal structure,the conformational space of CPT was explored by ab initio calculations at the restricted Hartree Fock level(HF/3 21G)as well as by semi empirical AM1,PM3 calculations in this study.All the resulting conformations were checked by frequency calculations and single point energy was calculated by using B3LYP/6 31G(d).It was found that type A conformations that may be the bioactive conformations of CPT,were much more stable than type B conformations.The conformation obtained by ab initio study similar to that obtained by X ray crystallographic studies was found to be the global minimum.Intramolecular hydrogen bond existed in the hydroxyl lactone in the type A conformations,and its contribution to the energy was as much as 29 31 kJ/mol,which is the structural basis of CPT interaction with TopoⅠ DNA,and also makes CPT more susceptible to hydrolysis by solvent effects of water.It was indicated that during the interaction of CPT with TopoⅠ DNA,it needed considerable energy to break the intramolecular hydrogen bond,which prompted us that it was likely to design new highly potent inhibitors acting on TopoⅠ.It was also shown that the molecular mechanics MM2 method was unable to reflect the energetic contribution of intramolecular hydrogen bond,which suggested molecular mechanics methods would obtain incorrect results in some cases due to their intrinsic limitations.

关 键 词：喜树碱 拓扑异构酶Ⅰab INITIO 分子构象 分子内氢键 抗肿瘤活性 

分 类 号：R914[医药卫生—药物化学]