Estrone and estradiol C-16 derivatives as inhibitors of type 1 17beta-hydroxysteroid dehydrogenase.
Three series of steroid derivatives, enones 1, enols 2 and saturated alcohols 3, were easily synthesized from estrone according to a sequence of three reactions: an aldol condensation with an aromatic aldehyde (R(a-g)CHO) to afford 1, the carbonyl reduction of 1 to obtain the enol 2, and the double bond reduction of 2 to give 3 with the R(a-g) group 16beta-oriented. All compounds were tested as inhibitors of type 1 17beta-HSD. The inhibitory potency increases in the following order 1<2<3, suggesting that the presence of a flexible 16beta-methylene group allows a better positioning of the aryl moiety. With an IC50 of 0.8 microM, the 16beta-benzyl-E2 (3a) is the best inhibitor in this series.
Poirier
Donald
D
Oncology and Molecular Endocrinology Research Center, CHUQ-Pavillon CHUL and University Laval, 2705 Laurier Boulevard, Que., Canada G1V 4G2. donald.poirier@crchul.ulaval.ca
Chang
Ho-Jin
HJ
Azzi
Arezki
A
Boivin
Roch P
RP
Lin
Sheng-Xiang
SX
D000438:Alcohols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003512:Cyclohexanones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004970:Estrone / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D011487:Protein Conformation
D000438:Alcohols; D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D004970:Estrone; D004958:Estradiol; D004960:Estradiol Dehydrogenases