喹啉环取代喜树碱抗癌活性的定量构效关系研究

利用量子化学密度泛函理论(DFT)中的杂化泛函B3LYP对三个系列60个喹啉环取代的喜树碱衍生物(CPTs)进行了构型优化,在6-311+G(d,p)基组下计算出相应的电子结构参数;采用逐步多元回归方法对各组化合物建立了几个新的分子描述符与抗癌活性之间的定量结构-活性关系(QSAR)模型,探讨了影响化合物抗癌活性的主要结构因素及其作用机理.结果表明,所得QSAR模型具有良好的预测能力,影响药物活性的主要因素有分子极化率和原子净电荷以及及最高占据分子轨道能量.根据所建最佳QSAR可以较准确地预测喜树碱类衍生物的抗癌活性,这有助于未来设计合成新型高效抗癌喜树碱类似物以及改进和完善其作用机理.

Quantitative Structure-Antitumor Activity Relationships of Camptothecin Derivatives Substituted at Quinoline Ring

The geometrical structures of three types of 60 camptothecin derivatives with substitutions within the quinoline(A/B) ring were optimized and the corresponding electronic structural descriptors were calculated using DFT/B3LYP procedure at 6-311+G(d,p) level.Several novel quantitative structure-activity relationships(QSARs) between the biological activity and the molecular descriptors of those compounds were obtained with stepwise multiple regression.The results show that not only those QSAR models have good predictive ability,but also molecular polarizability and net charges of key atoms and the energy of the highest occupied molecular orbital are the main factors affecting the antitumor activity of the camptothecin derivatives.That will be of great benefit to our future design and synthesis of novel highly potent antitumor camptothecin analogues and be helpful for proving or improving the action mechanism supposed.