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J Med Chem. 2015 Aug 27;58(16):6481-93. doi: 10.1021/acs.jmedchem.5b00494. Epub 2015 Aug 10.

A Ligand-Based Drug Design. Discovery of 4-Trifluoromethyl-7,8-pyranocoumarin as a Selective Inhibitor of Human Cytochrome P450 1A2.

Author information

1
Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States.
2
Cell and Molecular Biology Core, College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
3
RCMI Cancer Research Center, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States.
4
College of Pharmaceutical Sciences, Capital Medical University , Beijing 100069, P. R. China.
5
Faculty of Biomedical Science and Environmental Biology, Kaohsiung Medical University , Kaohsiung 807, Taiwan.

Abstract

In humans, cytochrome P450 1A2 is the major enzyme metabolizing environmental arylamines or heterocyclic amines into carcinogens. Since evidence shows that planar triangle-shaped molecules are capable of selectively inhibiting P450 1A2, 16 triangular flavone, and coumarin derivatives were designed and synthesized for these studies. Among these compounds, 7,8-furanoflavone time-dependently inhibits P450 1A2 with a K(I) value of 0.44 μM. With a 5 min preincubation in the presence of NADPH, 0.01 μM 7,8-furanoflavone completely inactivates P450 1A2 but does not influence the activities of P450s 1A1 and 1B1. Another target compound, 7,8-pyrano-4-trifluoromethylcoumarin, is found to be a competitive inhibitor, showing high selectivity for the inhibition of P450 1A2 with a K(i) of 0.39 μM, 155- and 52-fold lower than its K(i) values against P450s 1A1 and 1B1, respectively. In yeast AhR activation assays, 7,8-pyrano-4-trifluoromethylcoumarin does not activate aryl hydrocarbon receptor when the concentration is lower than 1 μM, suggesting that this compound would not up-regulate AhR-caused P450 enzyme expression. In-cell P450 1A2 inhibition assays show that 7,8-pyrano-4-trifluoromethylcoumarin decreases the MROD activity in HepG2 cells at concentrations higher than 1 μM. Thus, using 7,8-pyrano-4-trifluoromethylcoumarin, a selective and specific P450 1A2 action suppression could be achieved, indicating the potential for the development of P450 1A2-targeting cancer preventive agents.

PMID:
26222195
PMCID:
PMC4826332
DOI:
10.1021/acs.jmedchem.5b00494
[Indexed for MEDLINE]
Free PMC Article

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