Density Functional Study on the Cytochrome-Mediated <i>S</i>‑Oxidation: Identification of Crucial Reactive Intermediate on the Metabolic Path of Thiazolidinediones

Abstract

<i>S</i>-Oxidation is an important cytochrome P450 (CYP450)-catalyzed reaction, and the structural and energetic details of this process can only be studied by using quantum chemical methods. Thiazolidinedione (<b>TZD</b>) ring metabolism involving initial <i>S</i>-oxidation leads to the generation of reactive metabolites (RMs) and subsequent toxicity forcing the withdrawal of the glitazone class of drugs, thus, the study of the biochemical pathway of <b>TZD</b> ring metabolism is a subject of interest. The <i>S</i>-oxidation of the <b>TZD</b> ring and the formation of the isocyanate intermediate (<b>ISC</b>) was implicated as a possible pathway; however, there are several questions still unanswered in this biochemical pathway. The current study focuses on the CYP450-mediated <i>S</i>-oxidation, fate of the sulfoxide product (<b>TZDSO</b>), ring cleavage to <b>ISC</b>, and formation of nucleophilic adducts. The process of <i>S</i>-oxidation was explored by using <b>Cpd I</b> (iron­(IV)-oxo porphyrin, to mimic CYP450) at TZVP/6-311+G­(d) basis set. The barriers were calculated after incorporating dispersion and solvent corrections. The metabolic conversion from <b>TZDSO</b> to <b>ISC</b> (studied at B3LYP/6-311++G­(2df,3pd)//B3LYP/6-31+G­(d)) required a novel protonated intermediate, <b>TZDSOH</b>^<b>+</b>. The effect of higher basis sets (6-311+G­(d,p), aug-cc-pvqz) on this conversion was studied. <b>TZDSOH</b>^<b>+</b> was observed to be more reactive and thermodynamically accessible than <b>ISC</b>, indicating that <b>TZDSOH</b>^<b>+</b> is the actual reactive intermediate leading to toxicity of the <b>TZD</b> class of compounds