C(4)取代紫杉醇类似物的定量构效关系研究  

Studies on quantitative structure-activity relationships of C(4) paclitaxel analogs

作　　者：袁传能[1] 许旋[1] 徐志广[1] 

机构地区：[1]华南师范大学化学与环境学院,广东广州510006

出　　处：《分子科学学报》2008年第6期416-421,共6页Journal of Molecular Science

基　　金：广东省自然科学基金资助项目(5005938)

摘　　要：用量子化学B3LYP/6-31G方法计算了23个C(4)取代紫杉醇类似物的结构,用遗传算法(GFA)对能量、电性、拓扑及热力学等类型的278个结构描述符进行筛选,并回归建立其抑制人体结肠癌细胞HCT-116活性的定量构效关系(QSAR).QSAR方程含分子体积Vm、分子分支度指数CHI-0、分子中带正电荷原子的溶剂可积面积与其所带电荷之积的加和值Jurs-PPSA-3以及分子表面积S4个结构描述符.方程的拟合相关系数的平方R2及交叉验证系数Q2分别为0.956和0.913,所得QSAR具有可信的预报能力.由优化后的几何构型知,C(4)取代基、C(13)侧链和2-OBz三基团共同形成疏水腔,C(4)取代基的改变影响C(13)侧链的电子结构.C(13)连接的18号O原子的负电荷越大、3′位连接的NHBz基团的极性越小活性越高;C(4)取代基若为吸电子基对活性不利;适当增大分子体积、表面积和疏水性,保持一定的分支度对活性有利.The geometries of 23 C （4） paclitaxel analogs were optimized by B3 LYP/6-31G method. 278 descriptors, such as the energy, electronic, topological and thermodynamic were calculated. By genetic function approxirnation algorithms （GFA）,four descriptors affecting the activity of anti-human colon carcinoma HCT-116 of these compounds were selected.Then, the equation of quantitative structure-activity relationship （QSAR） was effectively established with four descriptors like the molecular volume （Vm） ,order zero chi index （CHI-O） ,sum of the product of solventaccessible surface area multiplied by partial charge for all positively charged atoms （Jurs-PPSA-3）, and molecular surface area （S） .The QSAR （ R^2 = 0.956, Q^2 = 0.913） shows a strong predictive ability. It was found from the optimized conformations of compounds that the substituents connected with C（13）, C（4）, and C（2） form a hydrophohie cavity. The C（4） substituent affects the electronic structure of C（13） substituent. The inhibitory activity increases with the increase of negative charge of O（18） atom and the decrease of the polarity of NHBz group connected with C-3＇ atom. For these molecules, the electro-withdrawing C（4） substituent is unfavorable for inhibitory activities. Furthermore, appropriate size of volume, surface area and branching of the molecules are favorable for inhibitory activities.

关 键 词：C(4)取代紫杉醇类似物 抑制结肠癌细胞活性 量子化学方法 遗传算法 定量构效关系 

分 类 号：O641[理学—物理化学]