Abstracts Chemistry

Inhibition of human steroidogenic enzymes: steroid 5-alpha reductase and cytochrome P450 aromatase

by Mark A. (Mark Anton) Titus

The metabolites of testosterone, dihydrotestosterone and estrogen, play important hormonal roles in regulating prostate physiology in health and disease. Both dihydrotestosterone and estrogen contribute to sustaining normal prostate cellular and tissue function but they can also support prostatic diseases. In the adult male, the enzymes steroid 5alpha-Reductase type I and II, and cytochrome P450 aromatase convert testosterone to dihydrotestosterone and estrogen, respectively. Inhibitors that control the activity of the above enzymes are one approach for treatment of prostate disease states, such as, benign prostate hypertrophy.Inhibitors have been designed with knowledge of the enzymatic mechanism of steroid 5alpha-reductase type I and II isozymes. The trifluoromethylated steroids, 4-trifluoromethyl-4-cholesten-3-one, 4-trifluoromethyl-4-pregnen-3,20-dione, and their unsaturated analogs, as well as, 4-hydroxy-4-cholesten-3-one and 4-hydroxy-4-pregnen-3,20-dione have been synthesized as transition state mimics and tested for inhibitory activity and isozyme specificity. Additional inhibitors, 4alpha,5alpha-cyclopropylcholestan-3-one, 4alpha,5alpha-epoxy-cholestan-3-one, 4alpha,5alpha-epoxy-pregnan-3,20-dione, and their diastereomers have been synthesized as 3-keto-4-ene conjugation analogs and also tested for inhibitory activity, and isozyme specificity. All compounds possess decreased inhibitory activity compared to the azasteroids, 4-aza-5alpha-cholestan-3-one, N-methyl-4-aza-5alpha-cholestan-3-one, 4-aza-5alpha-pregnan-3,20-dione, and N-methyl-4-aza-5alpha-pregnan-3,20-dione.A novel androstenedione analog, 4-trifluoromethyl-1,4,6-androstatrien-3,17-dione, was also synthesized and tested for the ability to inhibit cytochrome P450 aromatase and 5alpha-reductase type I and II isozymes. 4-Trifluoromethyl-1,4,6-androstatrien-3,17-dione showed mechanism-based inhibition of cytochrome P450 aromatase and competitive inhibition of 5alpha-reductase type I and II isozymes. When compared to the known mechanism based inhibitor 4-hydroxy-androsten-3,17-dione, the 4-trifluoromethyl-1,4,6-androstatrien-3,17-dione steroid was a less potent mechanism-based inhibitor of cytochrome P450 aromatase and showed decreased competitive inhibition of 5alpha-reductase type I and II isozymes.