Thiol-Containing Androgens as Suicide Substrates of Aromatase

Article abstract of DOI:10.1021/jm00383a014

The thiol-containing androgens 17β-hydroxy-10β-mercaptoestr-4-en-3-one (1) and 19-mercaptoandrost-4-ene-3,17-dione (2) were synthesized and tested in human placental microsomes for their ability to suicide inhibit aromatase.Both compounds showed time-dependent, pseudo-first-order rates of inactivation of aromatase with K_i's of 106 and 34 nM and k_cat's of 3.2E-3 and 1.2E-3 s^-1 respectively for 1 and 2 at 30 deg C.Diffusion dialysis failed to reactivate aromatase previously inactivated by either compound, and both compounds required that NaDPH and O2 be present for time -dependent inactivation of the enzyme.The presence of the substrate, androst-4-ene-3,17-dione (5.0 μM), protected the enzyme from inactivation while cysteine (1.0 mM) failed to protect aromatase from inactivation by either compound.The above evidence demonstrates that both compounds are potent suicide inhibitors of aromatase.