caa a22 4500 605507473 CHVBK 20210128100632.0 cr unu---uuuuu 210128e20150601xx s 000 0 eng 10.1007/s00775-015-1252-8 doi (NATIONALLICENCE)springer-10.1007/s00775-015-1252-8 Bio-activation of 4-alkyl analogs of 1,4-dihydropyridine mediated by cytochrome P450 enzymes [Elektronische Daten] [Xiao-Xi Li, Xiaoqian Zhang, Qing-Chuan Zheng, Yong Wang] 4-Alkyl-substituted 1,4-dihydropyridines (DHP) exhibit inhibitory activity toward certain cytochrome P450 enzymes (P450) during their biotransformation by these enzymes, which is called mechanism-based inactivation. Though much experimental evidence had proved the essentiality of alkyl radical for P450 inactivation, the underlying mechanism of such radical formation remains elusive. In the present study, density functional calculations were employed to investigate the dealkylation mechanism of 4-alkyl-substituted DHPs mediated by P450. Interestingly, our results indicate that the initial N-H activation proceeds via a proton-coupled electron transfer process, not via the long presumed hydrogen atom transfer mechanism or the stepwise electron transfer/proton transfer one, to form the amino radical and Cpd II complex. Subsequently, homolytic C-C bond cleavage at the 4-position occurs to afford the product complex involving an alkyl radical, an aromatic pyridine derivative. This C-C cleavage step is rate determining for the whole metabolic reaction, with an energy barrier of 7.9/7.9kcal/mol on the quartet/doublet state, to which aromatization contributes as an essential intrinsic driving force. The 4-substituent groups induce differences in activation energy barriers and in the transition state structures of hydrogen abstraction process. The substrate reactivity correlates well with the stability of the generated alkyl radical as well as the C-C bond dissociation energy. Understanding the metabolic mechanism of DHP analogs is indeed essential for the related design of safer and more efficient drugs. Furthermore, our findings also enrich the mechanistic picture of amine oxidation catalyzed by P450. SBIC, 2015 Cytochrome P450 enzyme nationallicence Density functional calculations nationallicence C-C bond cleavage nationallicence Bond dissociation energy nationallicence Proton-coupled electron transfer nationallicence Li Xiao-Xi International Joint Research Laboratory of Nano-Micro Architecture Chemistry, State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, 130023, Changchun, People's Republic of China aut Zhang Xiaoqian College of Physics and Electronic Engineer, Henan Normal University, 453007, Xinxiang, People's Republic of China aut Zheng Qing-Chuan International Joint Research Laboratory of Nano-Micro Architecture Chemistry, State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, 130023, Changchun, People's Republic of China aut Wang Yong State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, 730000, Lanzhou, People's Republic of China aut JBIC Journal of Biological Inorganic Chemistry Springer Berlin Heidelberg 20/4(2015-06-01), 665-673 0949-8257 20:4<665 2015 20 775 https://doi.org/10.1007/s00775-015-1252-8 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00775-015-1252-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Li Xiao-Xi International Joint Research Laboratory of Nano-Micro Architecture Chemistry, State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, 130023, Changchun, People's Republic of China aut NATIONALLICENCE 700 1- Zhang Xiaoqian College of Physics and Electronic Engineer, Henan Normal University, 453007, Xinxiang, People's Republic of China aut NATIONALLICENCE 700 1- Zheng Qing-Chuan International Joint Research Laboratory of Nano-Micro Architecture Chemistry, State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, 130023, Changchun, People's Republic of China aut NATIONALLICENCE 700 1- Wang Yong State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, 730000, Lanzhou, People's Republic of China aut NATIONALLICENCE 773 0- JBIC Journal of Biological Inorganic Chemistry Springer Berlin Heidelberg 20/4(2015-06-01), 665-673 0949-8257 20:4<665 2015 20 775