【作者】 邹建卫；

【导师】 俞庆森；

【作者基本信息】 浙江大学 ， 物理化学， 1999， 博士

【摘要】 本论文围绕溶质–溶剂相互作用这一主题,采用量子化学方法并结合药物分子设计开展了一些研究。主要内容分为三部分。第一部分,首先从溶剂敏感的异构化性质入手,用基于连续介质的自洽反应场理论方法对一类重要的生化模型体系?2(1H)-吡啶酮/2-羟基吡啶互变异构体系进行了研究,系统地考察了取代基性质、取代基位置、分子内氢键的形成以及互变异构竞争的存在对异构化平衡的影响。结果表明,2(1H)-吡啶酮类化合物在极性溶剂中表现出与气相或非极性溶剂中截然不同的的优势结构主要是由于各异构体分子极性上的差异引起的。取代基对异构化平衡的影响,除了取代后衍生物自身的能量因素外,还必须考虑到取代基通过改变异构体分子极性对溶剂化能所产生的影响。其后进一步运用自洽反应场方法对其它溶剂敏感体系进行了研究,考察了该方法的优缺点和适用性。我们认为自洽反应场方法比较适合于研究溶剂极化效应占主导的杂环体系,而运用于链状化合物体系时则必须谨慎从事。最后,对一类心血管类药物分子氨联吡啶酮和米利酮以及喹诺酮药物的几个模型分子进行了溶液中的理论研究,提出如下观点:(1)氨联吡啶酮和米利酮生物活性上的差异,除了构象上的因素外,还应该与甲基对互变异构的影响有关。(2)喹诺酮化合物的3-位应该是采用非内氢键的构型与受体发生作用的。考虑溶剂因素进行药物结构?活性关系的探讨,本文尚属首次。第二部分首先应用理论线性溶剂化能相关(TLSER)模型研究了两类局部麻醉药物的结构-疏水性质及活性关系,结果令人满意。接着针对该模型中分别表征溶质静电氢键酸度和静电氢键碱度的q~+和q~–项的局限性作了一些改进,应用于苄亚丙酮类抗诱变剂结构-疏水性关系的研究,取得了较满意的结果。最后,对初始的TLSER模型进行适当改进并首次建立起适于描述不同溶剂对体系理化性质影响以及溶质和溶剂同时变化时结构与性质关系的理论线性溶剂化能相关模型。通过应用于几类异构化反应的溶剂效应以及取代三甲胺类化合物在不同溶剂中结构与碱性关系的研究,证实了该改进模型的合理性。第三部分对2(1H)-吡啶酮类HIV-1逆转录酶抑制剂的定量结构-活性的关系进行了一些探讨,得到如下结论:(1) 3-[取代苯并噁唑甲基氨基]- 2(1H)-吡啶酮更多还原

【Abstract】 Quantum-chemical descriptors have been widely applied to structure-activity relationship studies in biochemistry or pharmaceutical chemistry. These descriptors are usually acquired by quantum chemical calculations in vacuum, however, all biochemical process refer to liquid media. Such contradiction intrigues us to investigate the solvent effects of molecular systems by quantum chemical methods. The main results in present article fall into three parts and can be summarized as follows.In the first part, the prototropic hydroxy-oxo tautomerisms of 2(1H)-pyridones/2-hydorxypyridines, one of the most important model systems in molecular biology, have been investigated with self-consistent reaction field method based on continuum model. The influence of the nature and position of substituent groups, the existence of intramolecular hydrogen bonding and tautomeric competition between 2-hydroxy and 4-hydroxy on the tautomeric equilibria have also been examined. The results obtained form theoretical calculations indicate that the hydroxyl- tautomer predominate in the gas phase or nonpolar solvents, while in solvents of high dielectric constant, the tautomeric equilibria is shift in favor of the oxo- tautomer can be mainly ascribed to the polarization effects. It is noticeable that the changes of polarity of two tautomers that caused by the substituent groups, beside the total energies of the derivative compounds themselves, must be taken into account in examining the influences of substituent groups on the tautomeric equilibria.Other isomeric systems which be sensitive to the nature of solvents, including the tautomerisms of 2(1H)-pyridazinone and its derivatives, tetramic acids, imidazole-1-ylacetic acid, and the Z-E isomerism of enaminones have further been examined. According to the results obtained form the studies on above systems, we point out that it is reasonable to investigate the solvent effects with SCRF approach on those systems contained heterocycles which the polarization effects is dominant, but for the chain molecule, it deserve careful consideration.Quantum chemical calculations account for solvent effects have been performed for two bipyridine cardiotonic drugs and several model quinolone molecules, two piece of viewpoint have been elucidated. (1) Beside the factor of conformation, the更多还原