Bio-activation of 4-alkyl analogs of 1,4-dihydropyridine mediated by cytochrome P450 enzymes

CORC > 兰州化学物理研究所 > 中国科学院兰州化学物理研究所 > OSSO国家重点实验室

	Bio-activation of 4-alkyl analogs of 1,4-dihydropyridine mediated by cytochrome P450 enzymes
	Li, Xiao-Xi 1; Zhang, Xiaoqian 2; Zheng, Qing-Chuan 1; Wang, Yong 3
刊名	Journal of Biological Inorganic Chemistry
	2015
卷号	20 期号:4 页码:665-673
关键词	Cytochrome P450 enzyme Density functional calculations C-C bond cleavage Bond dissociation energy Proton-coupled electron transfer
ISSN号	0949-8257
通讯作者	Wang, Yong
英文摘要	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 7.9/7.9 kcal/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.
学科主题	物理化学与绿色催化
收录类别	SCI
资助信息	National Natural Science Foundation of China (Grant no. 21003116;21173211;21233008);OSSO State Key Laboratory
语种	英语
WOS记录号	WOS:000354709100005
内容类型	期刊论文
源URL	[http://210.77.64.217/handle/362003/18442]
专题	兰州化学物理研究所_OSSO国家重点实验室
作者单位	1.Jilin Univ, Inst Theoret Chem, Int Joint Res Lab Nanomicro Architecture Chem, State Key Lab Theoret & Computat Chem, Changchun 130023, Peoples R China 2.Henan Normal Univ, Coll Phys & Elect Engn, Xinxiang 453007, Peoples R China 3.Chinese Acad Sci, Lanzhou Inst Chem Phys, State Key Lab Oxo Synth & Select Oxidat, Lanzhou 730000, Peoples R China
推荐引用方式 GB/T 7714	Li, Xiao-Xi,Zhang, Xiaoqian,Zheng, Qing-Chuan,et al. Bio-activation of 4-alkyl analogs of 1,4-dihydropyridine mediated by cytochrome P450 enzymes[J]. Journal of Biological Inorganic Chemistry,2015,20(4):665-673.
APA	Li, Xiao-Xi,Zhang, Xiaoqian,Zheng, Qing-Chuan,&Wang, Yong.(2015).Bio-activation of 4-alkyl analogs of 1,4-dihydropyridine mediated by cytochrome P450 enzymes.Journal of Biological Inorganic Chemistry,20(4),665-673.
MLA	Li, Xiao-Xi,et al."Bio-activation of 4-alkyl analogs of 1,4-dihydropyridine mediated by cytochrome P450 enzymes".Journal of Biological Inorganic Chemistry 20.4(2015):665-673.