抗癌性吲哚喹唑啉衍生物的定量构效关系

用量子化学密度泛函理论(DFT)、分子力学(MM＋)及回归分析方法,对一系列抗癌性吲哚喹唑啉衍生物进行了定量构效关系(QSAR)的研究.通过回归分析,筛选了影响抗癌活性的主要因素,建立了定量构效关系方程.结果表明,化合物的最低未占据分子轨道(LUMO)与最高占据分子轨道(HOMO)之间的能量差(ΔεL-H)、分子的疏水性(lgP)以及环D上的总电荷(ΣQD)和环D上R1取代基的第一个原子的净电荷(QFR1)是影响化合物抗癌活性的主要因素.所得模型对化合物抗癌活性有较好的预测效果. 同时, 与ΔεL-H密切相关的LUMO轨道能量及共轭平面面积对药物的DNA-结合及其活性起着十分重要的作用,可通过选取具有较强的拉电子性质同时又能与本系列化合物的骨架形成更大共轭体系的取代基R1,设计抗癌活性较高的化合物.

Quantitative Structure-Activity Relationship of Indolo [ 1,2-b] quinazoline Derivatives with Antitumor Activity

The quantitative structure-activity relationship(QSAR) of indolo[1,2-b] quinazoline derivatives, in regard to their antitumor activity, was systematically studied using the density functional theory(DFT), molecular mechanism (MM＋) and regression analysis methods. via a stepwise regression analysis, some main independent factors affecting the activity of the compounds were selected out, and then the QSAR equation was established. It has been found that the energy difference (ΔεL-H) between the lowest unoccupied molecular orbital (LUMO) and the highest occupied molecular orbital (HOMO) of the compound, the hydrophobic parameter (lgP) of the molecule, as well as the total net charge (ΣQD) of the D-ring skeleton and the net charge(QFR1) of the first atom of the substituent R1 on D-ring are the main independent factors contributing to the antitumor activity of the compound. The cross-validation rcv2 and the fitting correlation coefficient r2 for the model established by this study are 0.7364 and 0.8505, respectively. The results suggest that this model has good predictability and further indicate that the LUMO energy closely relative to ΔεL-H and the conjugative planarity area play a very important role in the DNA-binding and the activity of the compounds. Therefore, some higher antitumor active compounds can be designed prior to their synthesis via selecting some substituents (R1), which have stronger electron-withdrawing ability and can form greater conjugative planarity area with the skeletons of the series of the compounds.