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Importance of Azo‐Hydrazo Tautomerization in the Oxidative Degradation of Procarbazine by Cytochrome P450: Computational Insights
ChemistrySelect ( IF 2.1 ) Pub Date : 2018-06-08 , DOI: 10.1002/slct.201800633 Saber Mirzaei 1 , Avat Arman Taherpour 2 , Hossein Khalilian 3
ChemistrySelect ( IF 2.1 ) Pub Date : 2018-06-08 , DOI: 10.1002/slct.201800633 Saber Mirzaei 1 , Avat Arman Taherpour 2 , Hossein Khalilian 3
Affiliation
This 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.
中文翻译:
偶氮-羟基互变异构在细胞色素P450氧化降解丙卡巴嗪中的重要性:计算洞察力
这项工作为细胞色素P450酶的活性种化合物I(Cpd I)的对称双取代肼(SDSH)的前药丙卡巴肼的氧化降解提供了全面的计算研究。两种模型化合物R-CH 2 -NH-NH-CH 3(R = Me and Ph)被选择用于本研究,并模拟了其氧化降解的所有可能的酶和非酶相。丙卡巴肼的活化具有三个酶促过程。脱氢是导致偶氮化合物释放的第一步。此步骤是自发的(R = Me)或具有非常低的势垒高(R = Ph)。偶氮系统还有另一个互变异构体,肼,尽管它具有更高的稳定性,但迄今尚未被认为。第二个酶促阶段是由偶氮或肼化合物生产the氧基化合物。计算结果表明,肼氧化反应转变为a氧基化合物的过渡态(4.09 / 8.23 kcal.mol -1对于Me / Ph取代基而言,几乎是N2-偶氮氧化的一半。在最后的酶促步骤中,a氧基转化为羟基‐氧基化合物。与偶氮互变异构体相比,对于偶氮互变异构体,第三酶促相的过渡态势垒也较低(对于R = Ph,其为6.55 vs. 19.39 kcal.mol -1)。更高的稳定性和更低的势垒能表明,偶氮互变异构体在SDSH衍生物的分解代谢中具有非常重要的意义。羟az氧基不稳定,会分解生成代谢产物。
更新日期:2018-06-08
中文翻译:
偶氮-羟基互变异构在细胞色素P450氧化降解丙卡巴嗪中的重要性:计算洞察力
这项工作为细胞色素P450酶的活性种化合物I(Cpd I)的对称双取代肼(SDSH)的前药丙卡巴肼的氧化降解提供了全面的计算研究。两种模型化合物R-CH 2 -NH-NH-CH 3(R = Me and Ph)被选择用于本研究,并模拟了其氧化降解的所有可能的酶和非酶相。丙卡巴肼的活化具有三个酶促过程。脱氢是导致偶氮化合物释放的第一步。此步骤是自发的(R = Me)或具有非常低的势垒高(R = Ph)。偶氮系统还有另一个互变异构体,肼,尽管它具有更高的稳定性,但迄今尚未被认为。第二个酶促阶段是由偶氮或肼化合物生产the氧基化合物。计算结果表明,肼氧化反应转变为a氧基化合物的过渡态(4.09 / 8.23 kcal.mol -1对于Me / Ph取代基而言,几乎是N2-偶氮氧化的一半。在最后的酶促步骤中,a氧基转化为羟基‐氧基化合物。与偶氮互变异构体相比,对于偶氮互变异构体,第三酶促相的过渡态势垒也较低(对于R = Ph,其为6.55 vs. 19.39 kcal.mol -1)。更高的稳定性和更低的势垒能表明,偶氮互变异构体在SDSH衍生物的分解代谢中具有非常重要的意义。羟az氧基不稳定,会分解生成代谢产物。