10455-14-8Relevant articles and documents
Role of hydrophilic interaction in binding of hydroxylated 3-deoxy C19 steroids to the active site of aromatase
Numazawa,Yamada,Nitta,Sasaki,Kidokoro
, p. 4277 - 4283 (2001)
As part of our investigation into the structure - activity relationship of a novel class of aromatase inhibitors, C19 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). 4α,19-Diol 25 was synthesized from tert-butyldimethylsilyoxyandrost-4-ene steroid (9) through its OsO4 oxidation, giving the 4α,5α-dihydroxy derivative 12, as a key reaction. Acetylation of 5β,6α-dihydroxy-19-acetate 30 and its 5α,6β-analogue 31 followed by dehydration with SOCl2 and alkaline hydroxysis gave 6α,19-diol 36 and its 6βisomer 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 1H NMR spectroscopy in each case. 4β,19-Diol 27, previously synthesized, was identified as an extremely powerful competitive inhibitor of aromatase (Ki = 3.4 nM). In contrast, its 4α,19-dihydroxy isomer 25 and other series of diol compounds, 6,19-dihydroxy-4-en-17-one steroids, were moderate to poor competitive inhibitors (Ki = 110-800 nM). Through this series of analyses, it was concluded that hydrophilic interaction of a 4β,19-diol function with the active site of aromatase plays a critical role in the tight binding of 3-deoxy-5-ene steroids.
