Why Ortho- and Para-Hydroxy Metabolites Can Scavenge Free Radicals That the Parent Atorvastatin Cannot? Important Pharmacologic Insight from Quantum Chemistry

Abstract

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.

Two Theorems and Important Insight on How the Preferred Mechanism of Free Radical Scavenging Cannot Be Settled

“…Table 6. The enthalpies reaction (in kcal/mol) characterizing the antioxidant activity of atorvastatin (ATV) and its ortho-and para-hydroxy metabolites (o-ATV, p-ATV) in methanolic phase [22] satisfy the two theorems stated in this paper. The values of the difference between IP + PDE = PA + ETE and BDE, identical for all molecular species and positions of H-atom abstraction, are equal to the ionization of the H-atom in methanol computed at the same B3LYP/6-31+G(d,p) of theory (cf.…”

“…As visible in Table 6 and Figure 1, the results for each molecular species (ATV, o-ATV, and p-ATV) and any possible H-atom donation -that is, for each of the three (ATV) or four (o-ATV, p-ATV) OH-groups and the NH-group (indicated for the molecular geometries presented in ref. [22]) -the ATV-based species satisfy both theorems. Table 6.…”

“…[46], where enormous values BDE ≈ 400 kcal/mol much larger than all the other reaction enthalpies were obtained (see refs. [47] and [22]). At odds with equation ( 7), the largest value of IP + PDE = PA + ETE reported there are smaller than BDE; none exceeds ∼ 150 kcal/mol (cf.…”

“…As a specific illustration for the latter aspect noted above, let us examine results computed for atorvastatin (ATV) and its ortho-and para-hydroxy metabolites (o-ATV, p-ATV) in methanol at the B3LYP/6-31+G(d,p) level of theory [22]. As visible in Table 6 and Figure 1, the results for each molecular species (ATV, o-ATV, and p-ATV) and any possible H-atom donation -that is, for each of the three (ATV) or four (o-ATV, p-ATV) OH-groups and the NH-group (indicated for the molecular geometries presented in ref.…”

“…An adequate analysis of the preferred radical scavenging mechanism should not only consider the properties of the antioxidant but also the properties of the radical [19,21,22]. Conclusions of such an analysis can be surprising, as in the case of atorvastation-based species [22].…”