Steroidal spiro-γ-lactones that inhibit 17β-hydroxysteroid dehydrogenase activity in human placental microsomes

Article abstract of DOI:10.1021/jm00022a018

The important enzyme 17β-hydroxysteroid dehydrogenase (17β-HSD) is known to regulate intracellular levels of biologically active steroids, namely, androgens and estrogens. In an effort to develop potent inhibitors of 17β- HSD for reducing the levels of active steroids, we found that steroidal spiro-γ-lactones inhibit 17β-HSD activity. In this report, we describe the synthesis of 11 spiro-γ-lactone analogs containing a steroidal C-18 or C-19 nucleus and compare their relative inhibitory effects on 17γ-HSD activity in the human placenta microsomes that catalyze the interconversion of androgens and estrogens. To avoid the interaction of the cytosolic 17β-HSD activity that is specific for the interconversion of estrone and estradiol, we used 4- androstenedione as substrate. Analysis of the inhibitory effect exerted by these analogs on microsomal 17β-HSD activity indicates that spiro-γ- lactones containing the C-18 nucleus are more potent inhibitors than C-19 nucleus analogs. The best inhibition was obtained with the phenolic spiro- γ-lactone 7 (3-hydroxy-19-nor-17α-pregna-1,3,5(10)-triene 21,17- carbolactone), which has an IC₅₀ value of 0.27 μM, and was much lower than the competitive effect of the unlabeled substrate 4-androstenedione, which has an IC₅₀ value of 1.40 μM. Preincubation with lactone 7 did not inactivate 17β-HSD activity. The results thus suggest that lactone 7 is a reversible inhibitor. Lactone 7 is selective for microsomal 17β-HSD activity, as no inhibition was observed for cytosolic 17β-HSD activity.