title: Synthesis and biological evaluation of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) inhibitors based on a thieno[2,3-d]pyrimidin-4(3H)-one core.
abstract: Many breast tumors are hormone-dependent, and estrogens, especially estradiol (E2), have a pivotal role in their growth and development. 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is a key enzyme in the biosynthesis of female sex steroids, catalyzing the NADPH-dependent reduction of estrone into biologically active estradiol. In this study, a library of fused (di)cycloalkeno thieno[2,3-d]pyrimidin-4(3H)-one based compounds was synthesized, and the biological activities against 17beta-HSD1 in a cell-free and in a cell-based assay were evaluated. Several thieno[2,3-d]pyrimidin-4(3H)-one based compounds, at 0.1 and 1 muM test concentrations, were found to be potent 17beta-HSD1 inhibitors. For example, 4-(3-hydroxyphenylthio)-1,2,7,8,9,10,11,13-octahydro-13-oxo-[1]benzothieno[2',3':4,5]-pyrimido[1,2-a]azepine-3-carboxaldehyde (7f) is one of the most potent nonsteroidal 17beta-HSD1 inhibitors reported to date with 94% inhibition of the recombinant enzyme at 0.1 muM test concentration. Importantly, the majority of these compounds exhibited excellent selectivity over the oxidative isoform 17beta-HSD2 and lacked estrogenic effects in an estrogen receptor (ER) binding assay.
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, P.O. Box 55, FIN-00014 University of Helsinki, Finland.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Lilienkampf
authors.forename: Sampo
authors.initials: S
authors.lastname: Karkola
authors.forename: Sari
authors.initials: S
authors.lastname: Alho-Richmond
authors.forename: Pasi
authors.initials: P
authors.lastname: Koskimies
authors.forename: Nina
authors.initials: N
authors.lastname: Johansson
authors.forename: Kaisa
authors.initials: K
authors.lastname: Huhtinen
authors.forename: Kimmo
authors.initials: K
authors.lastname: Vihko
authors.forename: Kristiina
authors.initials: K
authors.lastname: Wähälä
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology; D045744:Cell Line, Tumor; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000737:chemistry; D047629:Estrogen Receptor beta / Q000737:chemistry; D004967:Estrogens / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008958:Models, Molecular; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000201:enzymology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C545538:1,2,7,8,9,10,11,13-octahydro-4-(3-hydroxyphenylthio)-13-oxo-(1)benzothieno-(2',3'-4,5)pyrimido(1,2-a)azepine-3-carboxaldehyde; D000970:Antineoplastic Agents; D001381:Azepines; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D007527:Isoenzymes; D011744:Pyrimidinones; D011994:Recombinant Proteins; D013876:Thiophenes; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D004960:Estradiol Dehydrogenases; C523763:HSD17B2 protein, human