title: Role of hydrophilic interaction in binding of hydroxylated 3-deoxy C(19) steroids to the active site of aromatase.
abstract: As part of our investigation into the structure-activity relationship of a novel class of aromatase inhibitors, C(19) steroids having no oxygen function at C-3, we tested aromatase inhibition activity of polar diol compounds 4,19-dihydroxyandrost-5-en-17-ones (25 and 27) and 6,19-dihydroxyandrost-4-en-17-ones (36 and 37). 4alpha,19-Diol 25 was synthesized from tert-butyldimethylsilyoxyandrost-4-ene steroid (9) through its OsO(4) oxidation, giving the 4alpha,5alpha-dihydroxy derivative 12, as a key reaction. Acetylation of 5beta,6alpha-dihydroxy-19-acetate 30 and its 5alpha,6beta-analogue 31 followed by dehydration with SOCl(2) and alkaline hydroxysis gave 6alpha,19-diol 36 and its 6beta-isomer 37, respectively. The stereochemistry of a hydroxy group at C-4 of compound 25 and that at C-6 of compounds 36 and 37 were determined on the basis of (1)H NMR spectroscopy in each case. 4beta,19-Diol 27, previously synthesized, was identified as an extremely powerful competitive inhibitor of aromatase (K(i) = 3.4 nM). In contrast, its 4alpha,19-dihydroxy isomer 25 and other series of diol compounds, 6,19-dihydroxy-4-en-17-one steroids, were moderate to poor competitive inhibitors (K(i) = 110-800 nM). Through this series of analyses, it was concluded that hydrophilic interaction of a 4beta,19-diol function with the active site of aromatase plays a critical role in the tight binding of 3-deoxy-5-ene steroids.
authors.affiliation: Tohoku Pharmaceutical University, 4-1 Komatsushima-4-chome, Aobaku, Sendai 981-8558, Japan. numazawa@tohoku-pharm.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Numazawa
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.forename: S
authors.initials: S
authors.lastname: Nitta
authors.forename: C
authors.initials: C
authors.lastname: Sasaki
authors.forename: K
authors.initials: K
authors.lastname: Kidokoro
mesh_terms: D000734:Androstenediols / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010920:Placenta / Q000201:enzymology / Q000648:ultrastructure; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000734:Androstenediols; D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D001141:Aromatase