Identification of fused 16β,17β-oxazinone-estradiol derivatives as a new family of non-estrogenic 17β-hydroxysteroid dehydrogenase type 1 inhibitors.
A new family of cyclic carbamate-estradiol derivatives has been designed to remove the intrinsic estrogenic activity of a parent acyclic compound reported as a potent inhibitor of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). The synthesis of two series of fused 16β,17β-oxazinone-estradiol derivatives, saturated compounds 7a-d and unsaturated compounds 10a-d, led to the identification of 10b, a 17β-HSD1 inhibitor (IC50 = 1.4 μM) without estrogenic activity in estrogen-sensitive T-47D cells. Interestingly, this compound was found selective over 17β-HSD2 and 17β-HSD12. A computational analysis of inhibitors into 17β-HSD1 by molecular docking also revealed interesting structure-activity relationships that could be helpful in the design of new generation of 16β,17β-oxazinone-estradiol analogs.
Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center (CHUL, T4) and Faculty of Medicine, Université Laval, Québec City, QC, Canada.
René
R
Maltais
Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center (CHUL, T4) and Faculty of Medicine, Université Laval, Québec City, QC, Canada.
Alexandre
A
Trottier
Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center (CHUL, T4) and Faculty of Medicine, Université Laval, Québec City, QC, Canada.
Audrey
A
Delhomme
Département de Chimie, Institut de Biologie Intégrative et Des Systèmes (IBIS), and Centre de Recherche sur la Fonction, la Structure et l'Ingénierie des Protéines (PROTEO), Université Laval, Québec City, QC, Canada.
Xavier
X
Barbeau
Département de Biochimie Microbiologie et Bio-informatique, Institut de Biologie Intégrative et des Systèmes (IBIS), and Centre de Recherche sur la Fonction, la Structure et l'Ingénierie des Protéines (PROTEO), Université Laval, Québec City, QC, Canada.
Patrick
P
Lagüe
Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center (CHUL, T4) and Faculty of Medicine, Université Laval, Québec City, QC, Canada. Electronic address: donald.poirier@crchul.ulaval.ca.
Donald
D
Poirier
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004958:Estradiol / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase
17beta-hydroxysteroid dehydrogenase; Chemical synthesis; Enzyme inhibitor; Molecular modeling; Oxazinone; Steroid