论文部分内容阅读
拉米夫定(LMVD)是重要的爱滋病毒(HIV)抑制剂,为更深入地探究LMVD的降解机理和验证Bedse G等的实验研究,本文采用量子化学GAMESS软件,用Hartree-Fock方法,在3-21G水平上计算LMVD分子和水解、氧化、质谱裂解过程可能中间产物的电荷分布、键级、静态势能和偶极,从理论上推测LMVD在不同条件下的降解机理和质谱裂解机理。LMVD在中性水溶液中稳定,在酸性、碱性水溶液中易水解。LMVD在酸性、碱性水溶液中的水解历程相似,都有2种水解机理。分别是:C6位亲核反应,C6-N7键断裂,降解产物为V,进而C8位亲核反应,N3-C8键断裂,降解产物为Ⅱ;C8位亲核反应,N3-C8键断裂,降解产物为Ⅰ。碱性条件下,羟基有更大的亲核反应活性,LMVD电荷分布和键级分布更有利于亲核反应,所以,水解速度更快。在H_2O_2水溶液中,LMVD可被氧化,氧化产物Ⅲ和Ⅳ比LMVD更稳定,不易被进一步水解。质谱裂解首先发生在最弱的化学键。本文研究的结果与Bedse G等的实验结果很好的吻合。表明应用GAMESS量子化学软件计算推测和解释药物的降解机理和质谱裂解机理是方便可行的。
In order to further explore the mechanism of LMVD degradation and validate the experimental study of Bedse G and so on, lamivudine (LMVD) is an important HIV inhibitor. In this paper, quantum chemistry GAMESS software, Hartree-Fock method, LMVD molecules and the charge distribution, bond order, static potential energy and dipole of LMVD molecules, hydrolysis, oxidation and mass spectrometry cleavage processes were calculated at the 3-21G level, and the degradation mechanism and mass spectroscopic cleavage mechanism of LMVD under different conditions were theoretically estimated. LMVD is stable in neutral aqueous solution and is easily hydrolyzed in acidic and basic aqueous solution. LMVD hydrolysis process in acidic, alkaline aqueous solution is similar, there are two kinds of hydrolysis mechanism. Respectively, the C6 nucleophilic reaction, the C6-N7 bond cleavage, the degradation product V, then the C8 nucleophilic reaction, the N3-C8 bond cleavage, the degradation product was Ⅱ; C8 nucleophilic reaction, N3-C8 bond rupture, the degradation product was Ⅰ. Alkaline conditions, the hydroxyl nucleophilic greater nuclear activity, LMVD charge distribution and bond-level distribution is more conducive to the nucleophilic reaction, so hydrolysis faster. In H 2 O 2 aqueous solution, LMVD can be oxidized, and the oxidation products Ⅲ and Ⅳ are more stable than LMVD and can not be further hydrolyzed. Mass spectrometry cleavage first occurs at the weakest chemical bond. The results of this study are in good agreement with the experimental results of Bedse G et al. It shows that it is convenient and feasible to use GAMESS quantum chemistry software to calculate and infer the mechanism of degradation and mass spectrometry cleavage.