摘要
1，4-二氢吡啶(1，4-DHP)衍生物是一类厂泛便用的降血压药物。研究发现，1，4-DHP类药物在人体内的代谢过程是通过肝脏中的细胞色素P-450氧化成吡啶衍生物而产生药效的，因此，1，4-DHP衍生物的氧化过程引起了研究者的关注。其次，许多药物分子是通过与DNA的相互作用而产生药效的，因此，研究药物分子与DNA的相互作用对了解药物作用机理，进行药物体外筛选，还是利用药物的构效关系进行结构改造，设计活性更高、毒副作用更低的新药都具有十分重要的意义。因此，本论文用电化学和多种光谱方法研究了一系列1，4-DHP的衍生物的电化学行为，总结1，4-DHP的取代基和溶剂等对1，4-DHP电化学性能的影响。在这基础上，研究它们与DNA相互作用前后的电化学性能的变化，比较了不同取代基衍生物与DNA作用的差异，从而对药物的结构与活性的关系提供一些实验依据。所得主要结果如下：
1．1，4-DHP衍生物中的二氢吡啶基团能在玻碳电极上进行不可逆的电化学反应。拉曼光谱的结果证明，1，4-DHP衍生物电化学氧化时，它们的二氢吡啶基团会失去2个电子和2个质子，形成吡啶衍生物。
2．1，4-DHP衍生物的二氢吡啶基团的氧化峰和还原峰峰电位与二氢吡啶基团上的4位取代基的吸电子能力有关，当取代基的吸电子能力增强时，二氢吡啶基团上电子云密度减小，使还原容易而氧化难，因此氧化峰峰电位和还原峰峰电位正移。从循坏伏安曲线来看，1，4-DHP衍生物的二氢吡啶基团的氧化峰峰电流一般远大于还原峰峰电流，表明氧化容易而还原难。所以，二氢吡啶基团上的取代基的吸电子能力对其还原反应难易程度的影响要大于对氧化反应的影响。因此，当取代基的吸电子能力增强时，二氢吡啶基团的△Ep反而减小，表明电化学反应的可逆性增加。
3．1，4-DHP衍生物的二氢吡啶基团的电化学行为与溶剂的性质有关。首先，在无水的有机溶剂中，它们的二氢吡啶基团的电化学反应的不可逆性大，在有水的有机溶剂中的不可逆性小，这由于1，4-DHP衍生物的二氧吡啶基团的电化学反应牵涉到质子的得失而引起的。其次，在有些无水的有机溶剂，如乙腈(CH_3CN)中，1，4-DHP衍生物的二氢吡啶基团在玻碳电极上会发生不可逆的电化学反应，但在无水CHCl_3中，没有观察到电化学反应，这可能与溶剂分子的极性和共轭性有关。
摘要
4.1，4一DHP衍生物与小牛胸腺DNA(CT一DNA)的相互作用后，其氧化峰峰电位都发生
正移，表明1，4一DHP衍生物能部分嵌入到CT一DNA的双螺旋链中。嵌入的程度与样
品分子的空间位阻有关。其分子的空间位阻越小，嵌入的程度越大，峰电位正移也
越大。
5.圆二色谱(CD)谱的研究结果表明，1，4一DHP衍生物与CT一DNA的相互作用使CT一DNA
的构象产生变化，构象变化的程度也与1，4一DHP衍生物的结构有关。分子的平面性
越差，与CT一DNA的相互作用后，使CT一DNA分子构象的变化越大。
6.荧光光谱的研究结果表明，1，4一D即衍生物本身的发射荧光能力与样品分子的
结构有关，如样品分子的4位取代基是硝基苯基时，由于硝基为强吸电子基团，它
会减弱荧光。而且硝基在苯基上的位置对样品的荧光淬灭的程度依次为间位>对位
>邻位。其次，当激发光波长在31Onm左右时，有的样品的荧光峰强度随CT一DNA
浓度的增加而增加，表明样品和CT一DNA发生了嵌入作用。这是由于样品分子嵌入
CT一DNA后，使样品分子的刚性增强且碰撞淬灭减小，因而荧光显著增强。而对有
些样品，它的荧光峰强度随CT一DNA浓度的增加而降低，这就可能由于其分子的非
平面性大，因此不易嵌入到CT一DNA中的缘故。
1,4-dihydropyridine(1,4- DHP) derivatives are a kind of extensively applied drugs for reducing the blood pressure. It was found that this kind of drugs produces the medical efficacy only after they were oxidated by cytochrome P-450 in the liver during the metabolism in the human body. Therefore, the oxidation process of 1,4- DHP derivatives has been attracted the considerable attention. Secondly, the medical efficacy of many drugs is produced through the interaction between the drug and DNA. Thus, the study of the interaction between a drug and DNA is very important for understanding the mechanism of medical action, proceeding the extracorporeal filtration of drugs, reconstructing the structures of drugs with the relationship between the structure and medical efficacy and designing new drugs with high medical efficacy and low side-effect. In this thesis, using the spectroscopic and electrochemical methods, the electrochemical behaviors of 1,4-DHP derivatives were studied and summarized the effects of the sub
stituent groups of 1,4- DHP derivatives and solvent on the electrochemical behaviors of 1,4- DHP derivatives were summarized. Based on it, the changes in their electrochemical properties before and after the interaction of 1,4- DHP derivatives with DNA were investigated. The differences of the interactions of 1,4-DHP derivatives with different substituent groups with DNA were compared. It will offer some experimental basises for the relationships of structures of drugs with their medical efficacy. The main results obtained are as follows.
1 .The electrochemical reaction of the dihydropyridine group of 1,4- DHP derivatives is irreversible at the glassy carbon electrode. The results of Raman spectroscopy demonstrated that when the electrochemical reactions of the 1,4- DHP derivatives occur, their dihydropyridine groups will lose two protons and two electrons forming the pyridine derivatives.
2.The anodic and cathodic peak potentials of the dihydropyridine groups of 1,4- DHP derivatives relate to the electron-accepting ability of 4-substituents of the dihydropyridine groups. When the electron-accepting ability increases, the density of
the electron cloud of the dihydropyridine groups decreases, so that the dihydropyridine group is easy to be reduced and difficult to be oxidized. Thus, the anodic peak potential shifts to the positive direction and the cathodic peak potential shifts to the negative direction. The results of cyclic voltammograms showed that the anodic peak current is much more larger than the cathodic peak current, proving that the oxidation of the dihydropyridine groups is easier than their reduction. Therefore, the effect of the electron-accepting ability of the 4-substituents on the oxidation reaction is larger than that the reduction reaction. Thus, when the electro-accepting ability increases, the difference between the anodic and cathodic peak potentials. AEp of the dihydropyridine groups decreases, illustrating that the reversibility of the electrochemical reactions of the dihydropyridine groups increases.
3.The electrochemical behaviors of the dihydropyridine group of 1,4- DHP derivatives is related the properties of the solvent. Firstly, in the organic solvent without water, the electrochemical irreversibility of the dihydropyridine group of 1,4- DHP derivatives is larger than that in the organic solvent with water. It is due to that the electrochemical reaction of the dihydropyridine group is related to obtaining or losing the protons. Secondary, in some organic solvent without water, such as CH3CN, the dihydropyridine group of 1,4- DHP can proceed the irreversible electrochemical reaction, but in CHCI3 without water, no electrochemical reaction of the dihydropyridine group can be observed. It maybe related to the polarity and conjugation of the solvent molecules. 4.After 1,4- DHP derivatives interact with calf thymus DNA (CT-DNA), their anodic peak potentials shift to the positive direction, indicating that 1,4- DHP derivatives can intercalate into the double-strand of CT-DNA. Th
引文
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