Importance of Azo‐Hydrazo Tautomerization in the Oxidative Degradation of Procarbazine by Cytochrome P450: Computational Insights

Abstract

AbstractThis work provides a comprehensive computational study on the oxidative degradation of prodrug procarbazine as a symmetrically disubstituted hydrazine (SDSH) by the active species of cytochrome P450 enzymes, compound I (Cpd I). Two model compounds, R‐CH2‐NH‐NH‐CH3 (R= Me and Ph), were selected for this study and all possible enzymatic and non‐enzymatic phases of their oxidative degradation were simulated. Procarbazine activation has three enzymatic processes. Dehydrogenation is the first step which leads to the release of azo compound. This step is either spontaneous (R=Me) or has very low barrier high (R=Ph). Azo system has another tautomer, hydrazo, which despite its more stability is not considered hitherto. Second enzymatic phase is the production of azoxy compound from either azo or hydrazo compound. The calculations revealed that the transition state of hydrazo oxidation to form azoxy compound (4.09/8.23 kcal.mol−1 for Me/Ph substituents), is almost half of the N2‐azo oxidation. In final enzymatic step the azoxy converts to hydroxyl‐azoxy compound. The transition state barrier of the third enzymatic phase is also lower for the hydrazo tautomer in comparison to the azo tautomer (6.55 vs. 19.39 kcal.mol−1 for R=Ph). The more stability and lower barrier energy showed very high importance of hydrazo tautomer in the catabolism of SDSH derivatives. The hydroxyl‐azoxy is not stable and undergoes decomposition to generate the metabolites.