具有抗癌活性的喜树碱类化合物的构效关系研究

Study on the relationships between the structureand antitumor activity of camptothecin analogues

目的探寻喜树碱类似物的电子结构与抗癌活性的关系。方法应用分子力学MM+ 法、量子化学从头算法和AM 1法对 18个喜树碱类似物进行几何优化 ,计算了化合物的电子结构 ,并应用逐步回归方法探寻化合物量子化学指数和抗癌活性的关系。结果 (1)喜树碱类似物的logP与活性参数间呈抛物线关系 ;(2 )分子的logP及 2 0位碳原子电荷是影响化合物抗癌活性的重要因素 ;7位取代基的疏水参数logP2 对分子的logP影响很大 ;(3 )得到较显著的QSAR方程 :pIC50 =3 8 12 3 + 8 0 90 7logP -0 814 2 5 (logP) 2 -682 3 79QC2 0 。结论疏水性对喜树碱类似物的活性影响较大 ;D环及相连的羰基氧O2 3可能是与受体作用的活性中心 ;

Purpose To analyze the QSAR of CPTs.Methods To calculate the electronic structure of camptothecin analogues(CPTs)by the MM + molecular mechanics method,the semi empirical AM1 method and the ab initio at 6 31G * level,the method of stepwise regression had also been performed.Result 1)The relationship between log P values of CPTs and activity is a parabola model.2)Molecular log P and the net charge of C 20 affect antitumor activity of CPTs remarkably,and log P 2 of substitutent in position 7 of CPT has important effect on log P .3)A significant QSAR is also obtained:pIC 50 =38 123+8 0907log P -0 81425(log P ) 2-682 379QC 20 .Conclusion Log P has important influence on the CPTs activity,the plots of frontier molecular orbit of CPTs indicate that the area of ring D and the O 23 of carbonyl binding to ring D may be the active center that influences acceptor,and the obtained QSAR is significative to estimate the CPTs′activity.