Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
J Med Chem ; 58(16): 6481-93, 2015 Aug 27.
Article in English | MEDLINE | ID: mdl-26222195

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.


Subject(s)
Coumarins/chemical synthesis , Coumarins/pharmacology , Cytochrome P-450 CYP1A2/drug effects , Cytochrome P-450 Enzyme Inhibitors/chemical synthesis , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Cell Line, Tumor , Cytochrome P-450 Enzyme System/metabolism , Drug Design , Humans , Kinetics , Ligands , Models, Chemical , Receptors, Aryl Hydrocarbon/drug effects , Structure-Activity Relationship
2.
Chem Res Toxicol ; 27(8): 1431-9, 2014 Aug 18.
Article in English | MEDLINE | ID: mdl-25033111

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.


Subject(s)
Cytochrome P-450 CYP1A1/metabolism , Enzyme Inhibitors/chemistry , Flavones/chemistry , Binding Sites , Catalytic Domain , Cytochrome P-450 CYP1A1/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Flavones/chemical synthesis , Flavones/metabolism , Fluorometry , Kinetics , Molecular Dynamics Simulation , NADP/chemistry , NADP/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...