C6-(N,N-butyl-methyl-heptanamide) derivatives of estrone and estradiol as inhibitors of type 1 17beta-hydroxysteroid dehydrogenase: Chemical synthesis and biological evaluation.
A series of estrone and estradiol derivatives having an N-butyl,methyl heptanamide side chain at C6-position were synthesized, tested as inhibitors of type 1 17beta-HSD and assessed for their possible estrogenic activity. A better type 1 17beta-HSD inhibition was obtained for the 6beta-side chain orientation over 6alpha; the C17-alcohols are more potent inhibitors than the corresponding ketones; introducing a 2-methoxy group decreased the inhibitory potency; and the replacement of a C-S bond by a C-C bond in the C6beta-side chain is not detrimental to inhibition. Interestingly, the new inhibitors were also found less estrogenic than the lead compound in two breast cancer cell lines, T-47D and MCF-7.
Cadot
Christine
C
Oncology and Molecular Endocrinology Research Center, CHUQ-Pavillon CHUL and Université Laval, Québec, Canada.
Laplante
Yannick
Y
Kamal
Fatima
F
Luu-The
Van
V
Poirier
Donald
D
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002855:Chromatography, Thin Layer; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors*; D004970:Estrone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D013058:Mass Spectrometry; D008958:Models, Molecular
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D007527:Isoenzymes; D004970:Estrone; D004958:Estradiol; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human