Stereoselective inhibition of human placental aromatase

Article abstract of DOI:10.1016/0039-128X(83)90066-1

We have synthesized the (19R)- and (19S)-isomers (2 and 3 respectively) of 10β-oxiranylestr-4-ene-3,17-dione.The configurations and conformations of these compounds were established by X-ray crystallographic analysis.Each of these compounds is a powerful competitive inhibitor of human placental microsomal aromatase, and stereoselectivity of inhibition was observed (Ki values for 2 and 3 were 7 and 75 nanomolar, respectively).Spectroscopic studies with purified aromatase indicate that the inhibition process involves reversible binding of oxirane oxygen to the heme iron of the enzyme.The (19R)- and (19S)-10β-thiiranes ( 6 and 7) corresponding to 2 and 3 have been synthesized from the oxiranes by a stereospecific process.The thiiranes are very effective competitive inhibitors of placental aromatase, and show even greater stereoselectivity in binding than the oxiranes (Ki values for 6 and 7 were 1 and 75 nanomolar, respectively).Spectroscopic studies with purified aromatase indicate that the inhibition process involves reversible binding of thiirane sulfur to heme iron.