title: Ethynylflavones, highly potent, and selective inhibitors of cytochrome P450 1A1.
abstract: The flavone backbone is a well-known pharmacophore present in a number of substrates and inhibitors of various P450 enzymes. In order to find highly potent and novel P450 family I enzyme inhibitors, an acetylene group was incorporated into six different positions of flavone. The introduction of an acetylene group at certain locations of the flavone backbone lead to time-dependent inhibitors of P450 1A1. 3'-Ethynylflavone, 4'-ethynylflavone, 6-ethynylflavone, and 7-ethynylflavone (KI values of 0.035-0.056 μM) show strong time-dependent inhibition of P450 1A1, while 5-ethynylflavone (KI value of 0.51 μM) is a moderate time-dependent inhibitor of this enzyme. Meanwhile, 4'-ethynylflavone and 6-ethynylflavone are highly selective inhibitors toward this enzyme. Especially, 6-ethynylflavone possesses a Ki value of 0.035 μM for P450 1A1 177- and 15-fold lower than those for P450s 1A2 and 1B1, respectively. The docking postures observed in the computational simulations show that the orientation of the acetylene group determines its capability to react with P450s 1A1 and 1A2. Meanwhile, conformational analysis indicates that the shape of an inhibitor determines its inhibitory selectivity toward these enzymes.
authors.affiliation: Department of Chemistry, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
authors.forename: Navneet
authors.initials: N
authors.lastname: Goyal
authors.forename: Jiawang
authors.initials: J
authors.lastname: Liu
authors.forename: La'Nese
authors.initials: L
authors.lastname: Lovings
authors.forename: Patrick
authors.initials: P
authors.lastname: Dupart
authors.forename: Shannon
authors.initials: S
authors.lastname: Taylor
authors.forename: Sydni
authors.initials: S
authors.lastname: Bellow
authors.forename: Lydia
authors.initials: L
authors.lastname: Mensah
authors.forename: Erika
authors.initials: E
authors.lastname: McClain
authors.forename: Brandan
authors.initials: B
authors.lastname: Dotson
authors.forename: Jayalakshmi
authors.initials: J
authors.lastname: Sridhar
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Maryam
authors.initials: M
authors.lastname: Foroozesh
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D047309:Flavones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D005470:Fluorometry; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D009249:NADP / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D047309:Flavones; D009249:NADP; D019363:Cytochrome P-450 CYP1A1; C043562:flavone