Theoretical Chemistry, Heidelberg University, Im Neuenheimer Feld 229, D-69120 Heidelberg, Germany.
Molecules. 2022 Aug 8;27(15):5036. doi: 10.3390/molecules27155036.
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• (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.
阿托伐他汀（ATV）是一种广泛用于降低“坏”胆固醇（LDL）和心血管疾病的药物，其在制药领域的成功可追溯至其清除自由基的能力。然而，关于其抗氧化特性的信息却缺失或不可靠。在这里，我们报告了阿托伐他汀及其邻位和对位羟基代谢物（o-ATV、p-ATV）在甲醇相中的详细量子化学结果。这些结果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（键离解 BDE、电离 IP 和电子加成 EA、质子离解 PDE 和质子亲和 PA，以及电子转移 ETE）。有了这些性质，我们可以为实验结果提供第一个理论解释，即由于其自由基清除活性，阿托伐他汀的羟基代谢物而非母体阿托伐他汀，对 LDL 等具有显著的抑制作用。令人惊讶的是（因为这与目前已知的大多数情况相反），我们明确地发现，在甲醇相中，o-ATV 和 p-ATV 通过 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）来清除 DPPH•（1,1-二苯基-2-苦基肼基）自由基，这是热力学上更有利的途径。从量子化学的角度来看，所研究的阿托伐他汀物种令人惊讶，因为键离解能、键长、键序指数和相关伸缩频率之间存在着复杂的相关性，这与简单的化学直觉不符。
