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To gain insight into the binding aspects of 6alpha- and 6beta-methylandrostenediones (1 and 2), potent competitive inhibitors and effective substrates of aromatase, at the active site of the enzyme, we synthesized their 19-hydroxy and 19-oxo derivatives to determine their inhibition of aromatase activity as well as their aromatization rates in human placental microsomes. The 6beta- and 6alpha-methyl-19-ols 12 and 13 were produced from 19-(tert-butyldimethylsiloxy)androstenedione (6) in 6 steps in which the Grignard reaction of 5alpha,6alpha-epoxy steroid 8 with CH3MgBr was employed as a key reaction. Oxidation of the 19-ols 12 and 13 yielded the corresponding 19-als 14 and 15. The 6alpha-methyl steroids 13 and 15 were good competitive inhibitors of aromatase (Ki&lt; or =100 nM), and their aromatization rates obtained by gas chromatography-mass spectrometric analysis were 110 and 205 pmol/min/mg protein, respectively. In contrast, the 6beta-methyl isomers 12 and 14 were non-competitive inhibitors, with Ki values of more than 500 nM, and they were aromatized at rates of 16 and 20 pmol/min/mg protein, respectively. These results reveal that there is a marked difference in binding to the active site between the 19-oxygenated 6alpha-methyl and 6beta-methyl inhibitors where the binding manner of the 6alpha-steroids, rather than the 6beta-isomers, is suitable as a substrate for aromatase.

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Synthesis and Biochemical Studies of 19-Oxygenated Derivatives of 6.ALPHA.- and 6.BETA.-Methylandrostenediones as Catalytic Probes for the Active Site of Aromatase.