1,4-addition reaction with thiols and conformational analysis with PM3 molecular orbital calculations of 19-oxygenated androst-4-ene-3,6,17-triones.
Reactions of androst-4-ene-3,6,17-trione (1) and its 19-hydroxy or 19-oxo derivative (2 or 3), suicide substrates of aromatase, with thiols were initially studied. Treatment of 4-ene-3,6-diones 1-3 with benzyl-mercaptan in MeOH at room temperature gave the corresponding 4 alpha-benzylthio-5 alpha-androstane-3,6-diones (4-6) as the major products in 24-80% yields. The C18 steroid, estr-5(10)-ene-3,6,17-trione (7), was also isolated on the treatment of 19-oxo steroid 3. Oxidation with NaIO4 and reduction with Raney Ni of the adducts gave the corresponding 4-ene-3,6-dione and desulfurized products, respectively. The results show that 19-oxygenated steroids 2 and 3 react with a thiol in a 1,4-addition manner. By means of PM3 molecular orbital calculations, the conformational features of the 19-oxygen functions of 4-ene-3,6-diones 2 and 3, 5 alpha-3,6-diones 10 and 11, and their 4 alpha-methylthio derivatives 14 and 15, model compounds of 1,4-adducts 5 and 6, were determined. In the compounds examined, the 19-hydroxy steroids favor a conformation having the hydroxyl group above the A-ring, whereas the 19-oxo substituent is oriented in the out-of-ring position (not above either A- or B-ring). These calculations suggest that compound 1 would inactivate aromatase by the same steric course of the oxygenation at C-19 as that of the natural substrate, androstenedione.
Numazawa
M
M
Tohoku College of Pharmacy, Sendai, Japan.
Oshibe
M
M
Matsuzaki
H
H
D000736:Androstenes / Q000737:chemistry*; D001141:Aromatase / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000737:chemistry*
D000736:Androstenes; D013438:Sulfhydryl Compounds; D009249:NADP; D001141:Aromatase