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 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• (1,1-diphenyl-2-picrylhydrazyl) radicals.

中文翻译：

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为什么邻羟基和对羟基代谢物可以清除母体阿托伐他汀不能清除的自由基？量子化学的重要药理学见解

阿托伐他汀 (ATV) 是一种广泛使用的对抗“坏”胆固醇 (LDL) 和心血管疾病的药物，其药物成功可追溯到其清除自由基的能力。不幸的是，有关其抗氧化特性的信息缺失或不可靠。在这里，我们报告了甲醇相中 ATV 及其邻羟基和对羟基代谢物（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序指数和自旋密度以及所有相关的反应焓（键解离 BDE、电离 IP 和电子附着 EA、质子脱离 PDE 和质子亲和性 PA，以及电子转移 ETE）。有了这些特性，我们可以对实验发现提供第一个理论解释，即由于它们的自由基清除活性，ATV羟基代谢物而非母体ATV对LDL等具有显着抑制作用。令人惊讶的是（因为它与目前已知的大多数情况相反），我们明确地发现 HAT（直接氢原子转移）而不是 SPLET（顺序质子损失电子转移）或 SET-PT（逐步电子转移质子转移）在热力学上是优选的甲醇相中 o-ATV 和 p-ATV 清除 DPPH• (1,1-diphenyl-2-picrylhydrazyl) 自由基的途径。