Pyranoflavones: a group of small-molecule probes for exploring the active site cavities of cytochrome P450 enzymes 1A1, 1A2, and 1B1.

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Liu J, Taylor SF, Dupart PS, Arnold CL, Sridhar J, Jiang Q, Wang Y, Skripnikova EV, Zhao M, Foroozesh M

Pyranoflavones: a group of small-molecule probes for exploring the active site cavities of cytochrome P450 enzymes 1A1, 1A2, and 1B1.

J Med Chem. 2013 May 23;56(10):4082-92. doi: 10.1021/jm4003654. Epub 2013 May 2.

PubMed ID
23600958 [ View in PubMed
]
Abstract

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. alpha-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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
alpha-NaphthoflavoneCytochrome P450 1A2IC 50 (nM)19N/AN/ADetails
beta-NaphthoflavoneCytochrome P450 1A2IC 50 (nM)470N/AN/ADetails