【作者】 曲瑞娟；

【导师】 王遵尧； 杨曦；

【作者基本信息】 南京大学 ， 环境科学， 2012， 硕士

【摘要】 定量结构-活性相关(QSAR)是对有机化合物进行环境生态风险评价的一个重要手段,它可以用于预测有机化合物在环境中的迁移、转化和分布等行为。在有机化合物的QSAR研究中,密度泛函理论(DFT)是获得热力学参数和分子结构参数的重要方法。多羟基咕吨酮(polyhydroxylated xanthones, PHOXTHs)是一类呫吨酮衍生物,它们所具有的生物活性和药理特性使其在制药和医药行业中得到了广泛的应用。到目前为止,对于PHOXTHs系列化合物的热力学参数和物理化学参数,还没有较为完整全面的报道。而了解PHOXTHs的热力学性质、理化性质和光谱学性质,对于设计新型药物以及研究其环境行为具有重要的意义。本文对PHOXTHs系列化合物进行了研究,构建了相关模型。本论文的主要研究内容和结论如下：1.分析了PHOXTHs中羟基的空间取向及分子内氢键的种类和大小,发现PHOXTHs中存在三种分子内氢键,键能大约为52kJ·mol-1、12kJ·mol-1和20kJ·mol-1。探讨了分子内氢键对分子稳定性的影响。设计等键反应,计算了XTH和135个PHOXTH分子的标准生成焓(△fHθ)和标准生成吉布斯自由能(△fGθ)。建立了热力学参数(Sθ,△fHθ和△fHθ)和羟基取代数目和位置(NPHOS)之间的QSAR模型,各模型的相关系数R2都较大,其值分别为0.986、1.000和1.000,标准误差SE都较小,其值分别为3.910、5.350和5.304,表明各热力学参数都与NPHOS有较好的相关性,可以根据NPHOS预测各热力学参数。2.优化设计出两条新的反应路线合成了咕吨酮、3种甲氧基咕吨酮和3种羟基咕吨酮。其中,合成路线1以邻二溴苯和水杨醛或甲氧基水杨醛为原料,合成路线2以水杨酸为基础底物。采用红外光谱和核磁共振氢谱对合成的样品进行了结构鉴定,使用高效液相色谱仪测定了样品的纯度,还测定了样品的熔点。比较了两条合成路线的优缺点,发现路线1反应步骤少,后处理也相对较为简单,但其反应原料邻二溴苯和催化剂四三苯基膦钯较昂贵；路线2所用原料毒性很小,价格较为便宜,反应条件比较温和,但反应步骤较多、耗时稍长。3.分析比较了所合成的几种咕吨酮类化合物的红外光谱。重点研究了2-羟基咕吨酮的红外光谱,确定了该化合物中各种化学键的振动模式,拟合得到实验频率值和两种基组水平下的Gaussian理论计算频率校正值之间的相关方程,R2都大于0.98,表明两者之间存在良好的线性关系,但大基组并没有明显提高振动频率计算的准确性。因此,为了缩短计算时间,可以选用较小的基组,而不致于降低计算精度。4.使用基于基团贡献法的Molinspiration方法计算了136个多羟基咕吨酮分子的logKow值,分别拟合得到logKow与分子结构参数和NPHOS之间的相关方程,对这些相关方程进行了稳定性分析和比较,发现以NPHOS为理论描述符构建的模型具有较大的相关系数R2(0.981)和较小的标准误差.SE(0.069),拟合优度较高。同时采用慢搅拌法测定了咕吨酮母体和3个羟基咕吨酮的logKow值,并用实验数值校正了logKow的相关方程,确定了预测logKow的最佳模型。更多还原

【Abstract】 Quantitative structure-activity relationship (QSAR) is an important means of environmental and ecological risk assessment on organic compounds. It can be used to predict the migration, transformation and distribution behavior of organic compounds in the environment. In QSAR studies on organic compounds, density functional theory (DFT) is a major method to obtain thermodynamic parameters and structural parameters of molecules.Polyhydroxylated xanthones (PHOXTHs) is a kind of xanthone derivatives, which have extensive applications in pharmaceutical and medical industries due to their biological activities and pharmacological properties. So far, there are no complete and comprehensive reports concerning the thermodynamic and physicochemical parameters of PHOXTHs. Understanding the thermodynamic, physicochemical and spectroscopic properties of PHOXTHs is of great significance for the design of new drugs and the researches on their environmental behavior. In the current paper, PHOXTHs were studied, and the appropriate models were constructed. The main contents and the corresponding conclusions are as follows:1. The spatial orientation of hydroxyl groups in PHOXTHs and the type and strength of the intramolecular hydrogen bonds, were analyzed. There are three types of intramolecular hydrogen bonds in PHOXTHs. The bond energy is about52kJ·mol-1,12kJ·mol-1,20kJ·mol-1, respectively. The influences of the intramolecular hydrogen bonds on molecular stability were discussed. The standard enthalpies of formation (△fHθ) and the standard Gibbs energies of formation (△fGθ) of XTH and135PHOXTHs were calculated with the design of isodesmic reactions. The QSAR models between thermodynamic parameters (Sθ,△fHθ and△fGθ) and the number and position of HO-substitution (NPHOS) were established. All the squared correlation coefficients R2are larger, with values being0.986,1.000and1.000, and all the standard error SE are smaller, with values being3.910,5.350and5.304, indicating these thermodynamic parameters all have close relationships with NPHOS· Consequently, these thermodynamic parameters can be predicted from the NPHOS·2. Two new reaction routes were devised and optimized to synthesize xanthone,3methoxyl-substituted xanthones and3hydroxyl-substituted xanthones. The starting materials of the synthetic route1are o-dibromobenzene and salicylaldehyde or methoxyl-substituted salicylaldehydes, and the substrate of the synthetic route2is salicylic acid. Infrared spectra and1H NMR spectra were adopted for structural identification of the samples synthesized, high performance liquid chromatography was employed to determine the purities of the samples, and the melting points were measured. The advantages and disadvantages of the two synthetic routes were compared with each other. For the route1, the reaction steps are less and the post-processing is relatively simple, but the substrate o-dibromobenzene and the catalyst triphenylphosphine palladium are expensive. Although the route2has less toxic and cheaper raw materials, and mild reaction conditions, it is time-consuming with more reaction steps.3. The infrared spectra of the several xanthones synthesized were analyzed and compared. The infrared spectrum of2-hydroxyxanthone was comprehensively studied, the vibrational modes of various chemical bonds in the compound were determined, and the correlation equation between the experimental frequencies and the scaled theoretical frequencies calculated at the two computational levels was obtained. The squared correlation coefficients R2are larger than0.98, indicating that good linearity relationships exist between the scaled and experimental frequencies. However, the larger set does not show evident improvement in the accuracy of the vibration frequencies. Consequently, in order to shorten the calculation time, one can adopt the smaller basis set without reducing the computational accuracy.4. The n-octanol-water partition coefficient (logKow) values of136polyhydroxylated xanthones were calculated using the Molinspiration method, based on group contributions. The correlation equation between logKow and structural parameters or NPHOS was obtained respectively, and the stability analysis of the two equations was carried out and comparisons were made. The results show that the model with NPHOS as the theoretical descriptors has a higer fitting goodness due to the larger squared correlation coefficient R2(0.981) and the smaller standard error SE (0.069). Meanwhile, the logKow values of xanthone and3hydroxyl-substitued xanthones were determined with the slow-stirring method, the logKow correlation equation was then corrected using the experimental values, and the best model for the prediction of logKow was finally determined.更多还原