Targeting cytochrome P450 (CYP) 1B1 with steroid derivatives.
Inhibition of cytochrome P450 1B1 (CYP1B1) represents a promising therapeutic strategy, because it would enable action at three different levels: (1) by inhibiting the formation of mutagenic 4-hydroxy-estradiol, (2) by inhibiting the bioactivation of procarcinogens, and (3) by reducing drug-resistance. Surprisingly, few steroids were reported as inhibitors of CYP1B1. From a screening performed with 90 steroid derivatives, we identified thioestrone (B19) as an inhibitor (IC50=3.4μM) of CYP1B1. Molecular modeling studies showed that the 3-SH group of B19 is closer (3.36Å) to the iron atom of the heme system than the 3-OH group of enzyme substrates estrone and estradiol (4.26Å and 3.58Å, respectively). B19 also produced a better docking GOLD score that correlated with the inhibitory results obtained. The estrane derivative B19 represents an interesting lead compound that can be easily modified to extend the structure-activity relationship study and to provide a next generation of more powerful CYP1B1 inhibitors.
Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center (CHUL, T4-42), 2705 Laurier Boulevard, Québec (Québec) G1V 4G2, Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec (Québec), Canada. Electronic address: donald.poirier@crchul.ulaval.ca.
Donald
D
Poirier
Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center (CHUL, T4-42), 2705 Laurier Boulevard, Québec (Québec) G1V 4G2, Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec (Québec), Canada.
Jenny
J
Roy
Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center (CHUL, T4-42), 2705 Laurier Boulevard, Québec (Québec) G1V 4G2, Canada; Department of Pharmacy, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City, Mexico.
Francisco
F
Cortés-Benítez
Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center (CHUL, T4-42), 2705 Laurier Boulevard, Québec (Québec) G1V 4G2, Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec (Québec), Canada.
Raphaël
R
Dutour
D065633:Cytochrome P-450 CYP1B1 / Q000037:antagonists & inhibitors*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004967:Estrogens / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
D065607:Cytochrome P-450 Enzyme Inhibitors; D004967:Estrogens; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1
CYP1B1; Enzyme; Inhibitor; Screening; Steroid