Synthesis and evaluation of 19-aza- and 19-aminoandrostenedione analogs as potential aromatase inhibitors

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Abstract
Derivatives of 19-azaandrostenedione (10.beta.-amino-4-estrene-3,17-dione, 2) and 19-amino-4-androsterone-3,17-dione (3) were synthesized as potential inhibitors of aromatase (estrogen synthetase). Compound 2 and its derivatives were synthesized from 3,17-dioxo-4-androsten-19-oic acid via a Curtius rearrangement. Derivatives of 3 were synthesized from the intermediate 3,17-bis(ethylenedioxy)-5-androsten-19-al oxime, which was reduced to the corresponding amine (16) with Raney nickel. Attempts to synthesize the parent compound, 3 from 16 by several different methods were unsuccessful. The compounds obtained were tested for inhibitory activity in the tritiated water assay for aromatase, with human placental microsomes as the enzyme source and [1-3H]androst-4-ene-3,17-dione (83% 3H 1.beta.) as the substrate. All of the compounds caused less than 20% inhibition of enzyme activity when tested at 1 and 5 times the substrate concentration (0.25, 2.25 .mu.M) and were poorer inhibitors than 2 known inhibitors, 7.alpha.-[(p-aminophenyl)thio]androstenedione and 4-hydroxy-4-androstene-3,17-dione. [Estrogen''s association with certain types of cancers is discussed.].