Synthesis of simplified hybrid inhibitors of type 1 17beta-hydroxysteroid dehydrogenase via cross-metathesis and sonogashira coupling Reactions.
[structure: see text] The inhibitor of type 1 17beta-hydroxysteroid dehydrogenase EM-1745 (1) exhibits affinity for both the substrate (estrone or estradiol) and the cofactor (NAD(P)H) binding domains. However, to increase its bioavailability, this compound needs to be simplified. The efficient and convergent synthesis of simplified substrate/cofactor hybrid inhibitors (compounds 2) involving a cross-metathesis and a Sonogashira coupling reaction as key steps is described. Compounds 2a-c were also tested as enzyme inhibitors and compared to EM-1745.
Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center and Université Laval, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, 2705 Laurier Boulevard, Quebec, Qc, G1V 4G2, Canada.
Marie
M
Bérubé
Donald
D
Poirier
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D002384:Catalysis; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004970:Estrone / Q000138:chemical synthesis / Q000494:pharmacology; D015394:Molecular Structure
C503691:EM-1745; D004791:Enzyme Inhibitors; D004970:Estrone; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases