title: Structure-activity relationships for the inhibition of recombinant human cytochromes P450 by curcumin analogues.
abstract: Inhibition of cytochrome P450 (CYP) is a major cause of drug-drug interactions. In this work, inhibitory potentials of 33 curcumin analogues, i.e. 2,6-dibenzylidenecyclohexanone (A series), 2,5-dibenzylidenecyclopentanone (B series) and 1,4-pentadiene-3-one (C series) substituted analogues of curcumin towards recombinant human CYP1A2, CYP3A4, CYP2B6, CYP2C9 and CYP2D6, all important for drug metabolism, were studied in vitro. Fluorescence plate reader and high performance liquid chromatography (HPLC) assays were used to evaluate CYP-inhibitory activities. MOE-based Quantitative structure-activity relationship (QSAR) analysis suggested that electrostatic and hydrophobic interactions and lipophilicity are important factors for CYP inhibition. Apart from insights in important molecular properties for CYP inhibition, the present results may also guide further design of curcumin analogues with less susceptibility to drug-drug interactions.
authors.affiliation: Divisions of Molecular Toxicology, Leiden/Amsterdam Center for Drug Research, Department of Pharmacochemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Regina
authors.initials: R
authors.lastname: Appiah-Opong
authors.forename: Iwan
authors.initials: I
authors.lastname: de Esch
authors.forename: Jan N M
authors.initials: JN
authors.lastname: Commandeur
authors.forename: Mayagustina
authors.initials: M
authors.lastname: Andarini
authors.forename: Nico P E
authors.initials: NP
authors.lastname: Vermeulen
mesh_terms: D002021:Buffers; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D002021:Buffers; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D003474:Curcumin