Benzyne formation in the mechanism-based inactivation of cytochrome P 450 by 1-aminobenzotriazole and N-benzyl-1-aminobenzotriazole: Computational insights was written by Chuanprasit, Pratanphorn;Goh, Shu Hui;Hirao, Hajime. And the article was included in ACS Catalysis in 2015.Synthetic Route of C6H6N4 This article mentions the following:
Cytochrome P 450 isoforms (P 450s) are ubiquitously distributed heme enzymes that play catalytic roles in the essential oxidative biotransformation of a wide range of exogenous and endogenous organic compounds Strong inhibition of P 450s through mechanism-based inactivation (MBI) essentially should not occur, because it would affect important metabolic processes adversely. However, accumulated evidence shows that the MBI of a P 450 is not a rare event. MBIs can also be exploited for useful applications such as reaction phenotyping. Thus, MBI is clearly one of the major problems concerning P 450s, but the reaction mechanisms underlying MBIs are not very clear in many cases. Here, the authors used DFT calculations to understand how a metabolite (benzyne) is formed from 2 mechanism-based inactivators of P 450s: 1-aminobenzotriazole (ABT) and N-benzyl-1-aminobenzotriazole (BBT). ABT has been widely used for reaction phenotyping. The DFT calculations showed that the formation of benzyne from ABT occurred via 2 sequential H-abstraction reactions from the exocyclic N-H bonds, similar to the reaction of 1,1-dimethylhydrazine. The transition states for these H-abstractions were stabilized by a proton-coupled electron transfer effect. The formation of benzyne from BBT was also triggered by H-abstraction from the N-H bond. However, in this case, the 2nd step was H-abstraction from a benzylic C-H bond. In addition, for the formation of benzyne from BBT, another catalytic cycle should be necessary. A computational study therefore elucidated the difference in reaction mechanisms between ABT and BBT, providing new insights into the processes involved in the MBI caused by these compounds In the experiment, the researchers used many compounds, for example, 1H-Benzo[d][1,2,3]triazol-1-amine (cas: 1614-12-6Synthetic Route of C6H6N4).
1H-Benzo[d][1,2,3]triazol-1-amine (cas: 1614-12-6) belongs to triazole derivatives. Among the nitrogen-containing heterocyclic compounds, triazoles emerge with superior pharmacological applications. Triazole growth retardants such as uniconazole and paclobutrazol have been known to inhibit the biosynthesis of gibberellins by blocking kaurene oxidase, an P450 enzymeSynthetic Route of C6H6N4
Referemce:
1,2,3-Triazole – Wikipedia,
Triazoles – an overview | ScienceDirect Topics