论文标题
为什么Ortho-和Para-Hydroxy代谢物可以清除父母Atorvastatin无法做到的自由基？量子化学的重要药理见解
Why Ortho- and Para-Hydroxy Metabolites Can Scavenge Free Radicals that the Parent Atorvastatin Cannot? Important Pharmacologic Insight from Quantum Chemistry
论文作者
论文摘要
Atorvastatin（ATV）的药物成功是一种针对“不良”胆固醇（LDL）和心血管疾病的药物，可以追溯到其清除自由基的能力。不幸的是，缺少或不可靠的有关其抗氧化特性的信息。在这里，我们报告了甲醇阶段中ATV及其正邻羟基代谢物（O-ATV，P-ATV）的详细量子化学结果。它们包括全局反应性指数，键阶指数和自旋密度以及所有相关反应的焓（键解离BDE，电离IP和电子附着EA，质子脱离PDE和质子亲和力PA和质子亲和力PA，以及电子传递等）。借助这些特性，我们可以对实验发现的第一个理论解释，该发现由于其自由基清除活性，ATV羟基代谢物而不是父型ATV，对LDL等具有实质性的抑制作用。 Surprisingly (because it is contrary to the most cases currently known), we unambiguously found that HAT (direct hydrogen atom transfer) rather than SPLET (sequential proton loss electron transfer) or SET-PT (stepwise electron transfer proton transfer) is the thermodynamically preferred pathway by which o-ATV and p-ATV in methanolic phase can scavenge DPPH$^\bullet$ （1,1-二苯基-2-苯羟基苯基）自由基。从量子化学的角度来看，所研究的ATV物种令人惊讶，因为键解离能量，键长，键长，粘结顺序指数和与拉伸频率有关，这不符合天真的化学直觉的框架。
The pharmaceutical success of atorvastatin (ATV), a widely employed drug against the "bad" cholesterol (LDL) and cardiovascular diseases, traces back to its ability to scavenge free radicals. Unfortunately, information on its antioxidant properties is missing or unreliable. Here, we report detailed quantum chemical results for ATV and its ortho- and para-hydroxy metabolites (o-ATV, p-ATV) in the methanolic phase. They comprise global reactivity indices, bond order indices, and spin densities as well as all relevant enthalpies of reaction (bond dissociation BDE, ionization IP and electron attachment EA, proton detachment PDE and proton affinity PA, and electron transfer ETE). With these properties in hand, we can provide the first theoretical explanation of the experimental finding that, due to their free radical scavenging activity, ATV hydroxy metabolites rather than the parent ATV, have substantial inhibitory effect on LDL and the like. Surprisingly (because it is contrary to the most cases currently known), we unambiguously found that HAT (direct hydrogen atom transfer) rather than SPLET (sequential proton loss electron transfer) or SET-PT (stepwise electron transfer proton transfer) is the thermodynamically preferred pathway by which o-ATV and p-ATV in methanolic phase can scavenge DPPH$^\bullet$ (1,1-diphenyl-2-picrylhydrazyl) radicals. From a quantum chemical perspective, the ATV's species investigated are surprising because of the nontrivial correlations between bond dissociation energies, bond lengths, bond order indices and pertaining stretching frequencies, which do not fit the framework of naive chemical intuition.
