title: Synthesis of 16-(bromoalkyl)-estradiols having inhibitory effect on human placental estradiol 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD type 1).
abstract: The activity of 17 beta-HSD type 1, the enzyme that converts estrone into its more potent metabolite estradiol, has been demonstrated in all classical steroidogenic tissues and almost all peripheral tissues from both rat and human. Since 17 beta-HSD is one of the most important enzymes involved in active steroid hormone formation, its inactivation could be a clinical approach to the treatment of hormono-dependent diseases like breast cancer. Herein we report the synthesis of 16-(bromoalkyl)-estradiols and their potency to inhibit the human placenta cytosolic estradiol 17 beta-HSD (type 1). Synthetic analogues possess various side chain lengths and orientation (alpha or beta) at position 16 of the steroidal D ring. The most potent inhibitory effect was observed when the length of the side chain was 3 or 4 carbons. However, the 16 beta-(bromopropyl)-estradiol easily undergoes cyclization and its effect on 17 beta-HSD is lost. Consequently, 16 alpha-(bromopropyl)-E2, 16 alpha-(bromobutyl)-E2, and 16 beta-(bromobutyl)-E2 were the best inhibitors discussed in this paper.
authors.affiliation: Medicinal Chemistry Division, CHUL Research Center, Quebec, Canada.
authors.forename: M R
authors.initials: MR
authors.lastname: Tremblay
authors.forename: S
authors.initials: S
authors.lastname: Auger
authors.forename: D
authors.initials: D
authors.lastname: Poirier
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D003600:Cytosol; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D010920:Placenta / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases