title: A Ligand-Based Drug Design. Discovery of 4-Trifluoromethyl-7,8-pyranocoumarin as a Selective Inhibitor of Human Cytochrome P450 1A2.
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.
authors.affiliation: Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States.
authors.forename: Jiawang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Pham
authors.affiliation: Cell and Molecular Biology Core, College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Skripnikova
authors.affiliation: Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States.|RCMI Cancer Research Center, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States.
authors.forename: Shilong
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States.
authors.forename: La'nese J
authors.initials: LJ
authors.lastname: Lovings
authors.affiliation: College of Pharmaceutical Sciences, Capital Medical University , Beijing 100069, P. R. China.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States.
authors.forename: Navneet
authors.initials: N
authors.lastname: Goyal
authors.affiliation: Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States.
authors.forename: Sydni M
authors.initials: SM
authors.lastname: Bellow
authors.affiliation: Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States.
authors.forename: Lydia M
authors.initials: LM
authors.lastname: Mensah
authors.affiliation: Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States.
authors.forename: Amari J
authors.initials: AJ
authors.lastname: Chatters
authors.affiliation: Cell and Molecular Biology Core, College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
authors.forename: Melyssa R
authors.initials: MR
authors.lastname: Bratton
authors.affiliation: Cell and Molecular Biology Core, College of Pharmacy, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wiese
authors.affiliation: College of Pharmaceutical Sciences, Capital Medical University , Beijing 100069, P. R. China.|Faculty of Biomedical Science and Environmental Biology, Kaohsiung Medical University , Kaohsiung 807, Taiwan.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States.|RCMI Cancer Research Center, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States.
authors.forename: Guangdi
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, United States.
authors.forename: Maryam
authors.initials: M
authors.lastname: Foroozesh
mesh_terms: D045744:Cell Line, Tumor; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: C000602647:4-trifluoromethyl-7,8-pyranocoumarin; D003374:Coumarins; D065607:Cytochrome P-450 Enzyme Inhibitors; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D003577:Cytochrome P-450 Enzyme System; C076307:methoxyresorufin-O-demethylase; D019388:Cytochrome P-450 CYP1A2