Stereoselective inhibition of human placental aromatase.
We have synthesized the (19R)- and (19S)-isomers (2 and 3 respectively) of 10 beta-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)-10 beta-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.
D047072:Aromatase Inhibitors; D055598:Chemical Phenomena; D002621:Chemistry; D004963:Estrenes / Q000138:chemical synthesis / Q000494:pharmacology*; D005260:Female; D006801:Humans; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy; D013237:Stereoisomerism
D047072:Aromatase Inhibitors; D004963:Estrenes; C051664:10-oxirane-4-estrene-3,17-dione