二甲双胍化学反应性的密度泛函理论及实验研究

Density Functional Theory and Experimental Study on the Chemical Reactivity of Metformin

二甲双胍是一个非常优良的降血糖药,一直是治疗Ⅱ型糖尿病(T2DM)的首选药物,但其脂溶性较差,也存在引起胃肠道不适等副作用,对其结构修饰和衍生化,特别是将其研制成前药具有一定的临床意义。为了探明二甲双胍化学反应的性能特点,本文基于密度泛函理论(DFT)开展了二甲双胍的化学内禀性质研究,包括各种可能互变异构体的单点能和量子化学反应性指数。此外,还对各异构体互变过程的过渡态以及它们的反应路径进行了研究。在此基础上,对二甲双胍与亲电试剂的化学反应机理进行了初探,并用化学合成反应来验证,从而让我们能够从理论上弄清楚二甲双胍化学反应的特殊性质。

Metformin is a very good hypoglycemic agent and has been the drug of choice for the treatment of type Ⅱ diabetes. However, its fat solubility is poor, and also causes side effects such as gastrointestinal discomfort. Therefore, its structural modification and derivatization, especially its development into a prodrug has certain clinical significance. To find out the performance characteristics of metformin in chemical reaction, the chemical intrinsic properties of metformin were studied based on density functional theory(DFT), including the single point energy of various possible tautomers and the quantum chemical reactivity index. In addition, the transition states of each isomer and their reaction paths are studied. On this basis, the mechanism of the chemical reaction between metformin and the electrophilic reagent has also been preliminarily explored and verified by the chemical synthesis reaction, so that we can theoretically understand the special properties of the chemical reaction of metformin.