系列异构配合物Ru(azpy)2Cl)2的结构与抗癌活性

用量子化学密度泛函(DFT)方法, 在B3LYP/LanL2DZ的水平上, 研究了一系列异构配合物α-, β-, γ-, δ-, ε-[Ru(azpy)2Cl2](azpy = 2-phenylazopyridine)(1～5)的电子结构与几何构型, 并着重研究了已报道具有优良抗癌活性的1～3的构效关系(SAR). 计算结果表明, 配合物3的两个共轭配体(azpy)的主体部分几乎处于同一平面上, 有利于插入到DNA碱基对之间. 而配合物1和2的两个共轭配体(azpy)的主体部分几乎相互垂直, 对配合物的DNA插入键合空间位阻较大. 计算结果还进一步显示了该系列异构体配合物的电子结构特征及相关性质. 作为配合物在亲电反应中起主要作用的最低未占据分子轨道(LUMO)的能量顺序为εL(2)＞εL(1)＞εL(3); 与反应活性密切相关的LUMO与最高占据分子轨道(HOMO)之间的能量差(ΔεL-H)顺序为ΔεL-H(3)＜ΔεL-H(1)＜ΔεL-H(2); 反映配合物疏水性的偶极矩顺序为µ(2)＞µ(1)＞µ(3); 此外, 与亲电反应有关的配合物共轭配体azpy上正电荷(QL)顺序为QL(3)＞QL(1)＞QL(2). 同时, 对迄今尚未见抗癌活性报道的同系列其它两个异构配合物(4和5)进行了活性预测.     

13位取代苦参碱衍生物抗癌活性的定量构效关系研究

采用密度泛函理论B3LYP方法计算了13个13位取代苦参碱衍生物的电子结构,研究了化合物结构与抑制人肝癌细胞HepG2抗癌活性的定量构效关系(QSAR).结果表明:(1)13位取代的苦参碱类衍生物的最低空轨道能ELUMO越低,最低空轨道与最高占据轨道的能隙ΔE越小,化合物抗癌活性越高;(2)分子的能量Etotal、面积S以及体积V越大,其极化度P越大,活性越大;(3)分子的油水分配系数logP越大,活性越大,即分子的疏水性增大活性增强.综合得到了显著性较好的QSAR方程:-lgIC50=97.008-11.759ΔE+818.602QC2-2.132×10-4Etotal,可用于预测该类衍生物抑制人肝癌细胞HepG2的活性并进行分子设计.     

一类新型N型钙通道阻滞剂的比较定量构效关系研究

使用结构和量子化学参数对一系列N取代N-甲基二肽衍生物的N型钙通道阻滞活性进行了定量构效关系研究, 并使用SOMFA方法建立了三维定量构效关系模型. 结果表明分子的范德华体积和最低未占据轨道能量是影响化合物生物活性的主要因素. N原子上取代基的溶剂可及面积也对化合物的钙通道阻滞活性有重要影响. 三维定量构效关系模型进一步支持了以上结果. 这些研究结果可为设计更高活性的N型钙通道阻滞剂提供有价值的参考信息.     

基于人工神经网络研究芳胺喹唑啉衍生物的抗胃癌活性

基于分子电性距离矢量(M1)表征21个芳胺喹唑啉衍生物的分子结构,并与其对人胃癌细胞的抗癌活性(pI)关联.通过最佳变量子集回归方法建立上述化合物抗胃癌活性的三参数(M15、M18、M82)定量构效关系模型.其交叉验证系数(R2cv)、非交叉验证系数(R2)依次为0.386和0.737.通过R、R2cv.、VIF等检验...     

靛玉红及其异构体构效关系的密度泛函理论研究

采用密度泛函理论(DFT)方法计算了靛玉红及其异构体分子的几何构型、电子结构以及前线分子轨道等,研究了结构与抗癌活性之间的关系,探讨了其构效关系上的差异.结果表明,分子是否具有平面构型和广泛共轭体系、3′位C原子的净电荷、分子偶极矩等参数的差异是影响各异构体药效的主要因素.提高3′位C原子的负电荷和增大分子偶极矩将有助于提高化合物的抗癌活性.     

DFT法研究阴离子识别剂[Ru（bpy）2L]2+（L=H2biim,H2bbim）去质子后结构变化

配合物[Ru(bpy)2(H2biim)](PF6)2(1)(bpy=2,2′-联吡啶,H2biim=2,2′-联咪唑)和[Ru(bpy)2(H2bbim)](PF6)2(4)(H2bbim=2,2′-苯并联咪唑)是良好的阴离子识别剂.用密度泛函理论方法研究了2种阴离子识别剂脱去质子后的几何结构和电子结构的变化.计算结果表明:脱去质子后配合物HOMO轨道上电子云分布由中心钌原子转移到(苯并)联咪唑上,而LUMO轨道虽然能量增加但电子云仍然分布在bpy配体上;另外,最高占居轨道HOMO与最低空轨道LUMO的能量差ΔεL-H逐渐减小,相对于配合物的吸收波长增大,所以分子的吸收峰发生红移,这与实验现象相吻合。     

抗癌性吲哚喹唑啉衍生物3D-QSAR研究及其分子设计

吲哚喹唑啉衍生物是近年来发现的一类具有良好抗癌活性的化合物. 作者在最近报道的二维定量构效关系(2D-QSAR)的基础上, 采用比较分子力场方法(CoMFA)进一步对该系列化合物进行三维定量构效关系(3D-QSAR)研究, 建立了3D-QSAR的CoMFA模型, 其非交叉验证相关系数r2=0.986, 标准偏差SD=0.084, 统计方差比F=114.6, 交叉验证相关系数q2=0.695, 表明该模型合理、可信, 并具有良好的预测能力. 研究结果表明: (1) 取代基R1的部位上静电效应起主要作用, 并且确保取代基R1的第一个原子具有较大的净正电荷, 对提高化合物的抗癌活性十分重要. 这与2D-QSAR研究结果相一致. (2) 取代基R2的部位上立体效应起主要作用, R2的体积大小要适中. 应用这些规律进行了分子设计, 在理论上获得了一些具有较高抗癌活性的新的吲哚喹唑啉衍生物, 并期待实验证实. 该QSAR的研究结果可为实验工作者合成新药提供理论参考.     

基于分子对接的6-萘甲基取代HEPT类HIV-1逆转录酶抑制剂构效关系研究

采用分子对接方法得到了一系列6-萘甲基取代HEPT类逆转录酶抑制剂分子与HIV-1逆转录酶复合物模型,从中抽取出抑制剂分子的活性构象,进一步应用CoMFA和CoMSIA方法建立了具有较好预测能力的3D-QSAR模型,深入探讨了这些化合物的定量构效关系,为进一步的药物设计奠定了良好的基础.另外,以化合物13及其相应的β异构体24为代表,结合量子化学从头算分子轨道理论方法考察了它们的前线轨道,为阐明α和β系列化合物的活性差异提供了理论依据.     

取代吡唑类化合物对肿瘤抑制活性的QSAR研究与分子设计

采用量子化学中的密度泛函理论(DFT)方法,在B3LYP/6-31++G(d,p)基组水平上系统计算了TβR-I抑制剂吡唑类衍生物(AHSPs)的量子化学结构参数。用逐步线性回归方法(SR)对该类AHSPs化合物进行了定量构效关系研究,筛选出了影响化合物抑制活性的主要因素,得到了最优QSAR方程。研究结果表明,抑制剂分子的偶极矩μ、疏水系数logP、分子中吡啶环的7-N原子的Mulliken电荷是影响AHSPs类化合物的抑制活性的主要因素。偶极矩μ和疏水系数logP越小,吡啶环的7-N原子Mulliken净电荷越正,则化合物的抑制活性越强。所得模型对该类吡唑类化合物针对TβR-Ⅰ的抑制活性有较好的预测结果,据此设计出14个新型AHSPs分子,计算其量子力学参数,利用构效方程预测出新型AHSPs分子的性能,发现其中有3个分子可能有较好的理论抑制活性。     

二芳基三嗪类化合物抗HIV-1活性的理论研究

应用分子力学方法、从头算法优化了28个二芳基三嗪(DATA)类抗野生型HIV-1化合物分子结构,从分子构象模型中提取了多类参数,结合电子类参数、几何类参数、分子物化参数与活性之间建立了QSAR多元线性回归模型.模型显示:分子中连接三嗪环与B环的X位置上净电荷量的增加以及分子中吸电子基团的引入有利于其抗HIV-1活性的增强,同时,前线轨道能级差ΔE的增大和分子体积适当的增大亦有利于其抗HIV-1活性的提高,并且后两者是影响该类化合物抗HIV-1活性的主要因素.     

核因子κB活性抑制剂定量构效关系

The electronic structures, geometric structures and some molecular properties (generalized structural indexes) of quinazoline derivatives were computed by using density functional theory and molecular mechanism methods to investigate the quantitative structure-activity relationship (QSAR) of the inhibitory activity toward the nuclear factor kappa B. Via a stepwise regression analysis, some main factors affecting the activity of the compounds were factored out, and then the QSAR equation was effectively established. It was found that the hydrophobic parameter of the substituent on ring D is the main factor affecting the inhibitory activity of the compound. The analysis indicated, the larger the hydrophobic parameter, the higher the inhibitory activity of the compound. In addition, the net charge of the first atom and the stereoscopic parameter (MR1) of the substituent R1 on A-ring as well as the net charge of C3 are closely correlated with the inhibitory activity of the compound. In order to test the predicted results of the QSAR equation, we adopted the “leave one out” cross-validation , and found that the calculated coefficient q2 was rather high and the predicted results were both accurate and reliable. Such facts show that the obtained equation has great predictive ability. The above results can offer an important theoretical guide in the search for new quinazoline derivatives with higher inhibitory activity, and in an analysis of their action mechanisms. It is noteworthy that this scheme would be very advantageous in factoring out precursors with excellent inhibitory activity via the computer ADDIT molecule-design, since all parameters in the QSAR equation are computable and controllable.     

A quantitative structure-activity relationship for antitumor activity of long-chain phenols from Ginkgo biloba L

With the aim of obtaining compounds with strong antitumor activity, a quantitative structure-activity relationship (QSAR) of antitumor phenolic compounds (long-chain phenols) was derived using the Hansch-Fujita equation. The ED50 values against Chinese hamster V-79 cells were analyzed in terms of log P as the hydrophobic parameter and the energy of the lowest unoccupied molecular orbital (ELUMO) calculated by using the modified neglect of differential overlap (MNDO) method as the electronic parameter, by means of multiple regression analysis. It was found that the activities mainly depended on log P (an optimum log P of 8.3) and a low-lying ELUMO value. 4-Undecylcatechol, selected on the basis of the above results, exhibited strong antitumor activity against Sarcoma 180 ascites and P-388 lymphocytic leukemia.     

A QSAR study and molecular design of benzothiazole derivatives as potent anticancer agents

A quantitative structure-activity relationship (QSAR) of a series of benzothiazole derivatives showing a potent and selective cytotoxicity against a tumorigenic cell line has been studied by using the density functional theory (DFT), molecular mechanics (MM ) and statistical methods, and the QSAR equation was established via a correlation analysis and a stepwise regression analysis. A new scheme determining outliers by "leave-one-out" (LOO) cross-validation coefficient (q2n-i) was suggested and successfully used. In the established optimal equation (excluding two outliers), the steric parameter (MRR) and the net charge (QFR) of the first atom of the substituent (R), as well as the square of hydrophobic parameter (lgP)2 of the whole molecule, are the main independent factors contributing to the anticancer activities of the compounds. The fitting correlation coefficient (R2) and the cross-validation coefficient (q2) values are 0.883 and 0.797, respectively. It indicates that this model has a significantly statistical quality and an excellent prediction ability. Based on the QSAR studies, 4 new compounds with high predicted anticancer activities have been theoretically designed and they are expected to be confirmed experimentally.     

Electronic structure and hypolipidemic activity of phthalimide and related compounds. A QSAR study

The hypolipidemic activities of phthalimide and seven related compounds are subjected to a QSAR analysis based on results from AM1 molecular orbital calculations. Least-squares fits show a correlation of the activities with LUMO energies and carbonyl polarities and predict enhanced activities for two new phthalimide derivatives.     

Total synthesis of novel D-ring-modified triptolide analogues: structure-cytotoxic activity relationship studies on the D-ring of triptolide

The total synthesis of a trans-position butenolide analogue of triptolide 3 and the semi-synthesis of analogue 4, with a furan ring, and compound 5, without a planar D-ring, are described. Studies into the antitumor activity of these compounds suggest that the five-membered unsaturated lactone ring (D-ring) of triptolide is essential to its potent anticancer activity and the C18 carbonyl group may exert an important influence on the interaction between triptolide and the target molecule(s) responsible for initiating their cytotoxic effects.     

Antitumor Activity and Theoretical Calculation of Evodiamine and Rutaecarpine

The antitumor activities of two alkaloids, evodiamine(EVO) and rutaecarpine(RUT), against MCF-7, SMMC-7721 and SW-1353 cells growth in vitro were investigated by MTT assay. The results showed that the anti-tumor effects of two alkaloids were remarkably different. In order to discover the relationship of antitumor activity and structures of the compounds, the dihedral angle, Natural Electron Configuration, frontier molecular orbital profiles(HOMO, LUMO)and bandgaps of these two compounds have been studied based on density functional theory(DFT)by means of DFT-B3LYP/6-31G(d) in Gaussian 03. The calculation results of dihedral angle showed that EVO, due to the existence of methyl group attached to the N(14) atom, have non-planar and twisted structures, which decrease the stability of EVO and increase the activity of EVO. Furthermore, the bandgaps of RUT are lower than that of EVO, indicating RUT has higher stability than EVO, so the activity of EVO is higher than that of RUT. In addition, the negative charge of N14 atom in EVO is lower than that of in RUT, so the positive charge of N(14) atom in EVO is higher than that of in RUT, which suggests that the nucleophile is easier to aggress the N(14) atom in EVO than that in RUT, so the reason of the different antitumor activities of EVO and RUT may be attacked by nucleophile.