N-butyl, N-methyl, 11-[3',17' beta-(dihydroxy)-1',3',5'(10')-estratrien-16' alpha-yl]-9(R/S)-bromo undecanamide: synthesis and 17 beta-HSD inhibiting, estrogenic and antiestrogenic activities.
The synthesis of a 16 alpha-(bromoalkylamide) derivative of estradiol (N-butyl, N-methyl, 11-[3',17' beta-(dihydroxy)-1',3',5' (10')-estratrien-16' alpha-yl]-9(R/S)-bromo undecanamide) was performed by two different approaches starting from estrone. Each approach has the same key intermediate, containing an aldehyde group, but differs by the bromination step and the timing of formation of the amide group. This compound was found to cause, at 100 microM, a complete inhibition of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) responsible for the interconversion of estrone and estradiol. The corresponding IC50 value was 10.6 microM. In the estrogen-sensitive ZR-75-1 human breast cancer cell line, this estradiol derivative has no estrogenic activity at 30 nM and only a minimal estrogenic activity (10% above the basal level) at 1 microM. At this latter concentration, this compound causes a 28% inhibition of 0.1 nM E2-induced cell proliferation (antiestrogenic activity). Thus, the introduction of a side-chain with a secondary bromide and a butyl methyl amide group at the 16 alpha-position of estradiol has two interesting effects; namely an inhibition of cytosolic 17 beta-HSD and a blockade of the estrogenic effect of estradiol.
Medicinal Chemistry Division, CHUL Research Center and Laval University, Québec, Canada.
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Pelletier
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Labrie
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Poirier
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D004970:Estrone / Q000378:metabolism*; D006801:Humans; D008722:Methods; D053284:Polyunsaturated Alkamides; D014407:Tumor Cells, Cultured
D004965:Estrogen Antagonists; D053284:Polyunsaturated Alkamides; D004970:Estrone; D004958:Estradiol; C051781:ICI 164384; D015067:17-Hydroxysteroid Dehydrogenases