TY - JOUR
T1 - Structure-activity relationships for the inhibition of recombinant human cytochromes P450 by curcumin analogues
AU - Appiah-Opong, Regina
AU - de Esch, Iwan
AU - Commandeur, Jan N.M.
AU - Andarini, Mayagustina
AU - Vermeulen, Nico P.E.
PY - 2008/8
Y1 - 2008/8
N2 - 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.
AB - 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.
KW - (Q)SAR
KW - Curcumin analogues
KW - Cytochrome P450
KW - Drug-drug interactions
KW - Inhibition
UR - http://www.scopus.com/inward/record.url?scp=47949130458&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2007.10.034
DO - 10.1016/j.ejmech.2007.10.034
M3 - Article
C2 - 18249473
AN - SCOPUS:47949130458
SN - 0223-5234
VL - 43
SP - 1621
EP - 1631
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
IS - 8
ER -