【摘要】 目的：探讨鬼臼毒素衍生物的三维定量构效关系 (three- dimensional quantitative structure- activity relationship,3D- QSAR)及活性部位。方法：用比较分子力场分析 (comparative molecular field analysis, CoMFA)方法对鬼臼毒素 23个衍生物进行了三维定量构效关系研究，然后用 AM1(Austin model 1)方法进行计算，讨论它们的 3D- QSAR及活性部位。结果：以 CoMFA方法建立了一个有较强预测能力的 QSAR模型。在对体外 L1210白血病细胞生长的抑制活性上， C4位为改变活性的有效修饰位点；其 B环是药物分子接受电子部分，对保持此类药物的生物活性有重要作用； E环及其含氧取代基是分子的负电中心。结论：所得 CoMFA模型可预测该类化合物的活性，化合物 B环及 E环是重要的活性部位。更多还原

【Abstract】 Objective： This study was designed to investigate the three- dimensional quantitative structure- activity relationship (3D- QSAR) and the active sites of podophyllotoxin derivatives. Methods： Twenty- three podophyllotoxin derivatives had been designed to investigate 3D- QSAR against L1210 cells by comparative molecular field analysis (CoMFA), then they were studied by Austin model 1 (AM1) method of quantum chemical calculation. The 3D- QSAR and the active sites were discussed according to their stereo structure and electronic structure. Results： A CoMFA model with considerable predictive ability was established. The results showed that the C4 position was an effective modified point. The steric effect and the electrostatic effect of 4- substituted group were the dominant factor for the activity. The replacement of the“- NH-” bridge at C4 with the“- O-” bridge resulted in lowering of the anticancer activity. The results revealed that there was a large electropositive region around the B ring moiety and it could easily combine with an acceptor of the drug. The B ring was essential for the activity. The E ring and its C4′ hydroxyl group also have strong influence on the activity and is an important center of negative electricity within the molecule. Conclusions： The inhibitory activities of the compounds can be predicated by the CoMFA mode. The B ring and E ring are important active sites of the molecule.更多还原