期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 10, 页码 4082-4092出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm4003654
关键词
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资金
- DoD [W81XWH-11-1-0105]
- NIH-MBRS SCORE by the Foroozesh research group [S06 GM 08008]
- NIH-RCMI Grant from National Institute on Minority Health and Health Disparities [8G12MD007595-04]
Selective inhibition of P450 enzymes is the key to block the conversion of environmental procarcinogens to their carcinogenic metabolites in both animals and humans. To discover highly potent and selective inhibitors of P450s 1A1, 1A2, and 1B1, as well as to investigate active site cavities of these enzymes, 14 novel flavone derivatives were prepared as chemical probes. Fluorimetric enzyme inhibition assays were used to determine the inhibitory activities of these probes toward P450s 1A1, 1A2, 1B1, 2A6, and 2B1. A highly selective P450 1B1 inhibitor 5-hydroxy-4'-propargyloxyflavone (5H4'FPE) was discovered. Some tested compounds also showed selectivity between P450s 1A1 and 1A2. a-Naphthoflavone-like and 5-hydroxyflavone derivatives preferentially inhibited P450 1A2, while beta-naphthoflavone-like flavone derivatives showed selective inhibition of P450 1A1. On the basis of structural analysis, the active site cavity models of P450 enzymes 1A1 and 1A2 were generated, demonstrating a planar long strip cavity and a planar triangular cavity, respectively.
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