title: Synthesis and evaluation of pregnane derivatives as inhibitors of human testicular 17 alpha-hydroxylase/C17,20-lyase.
abstract: The pregnene derivatives with modifications at the 17,20-side chain and D-ring were synthesized and evaluated as inhibitors of human testicular 17 alpha-hydroxylase/C17,20-lyase. The results demonstrate that compounds which have 20-substituents with moderate to strong dipole properties, such as 20-oxime (3, 20), 20 beta-ol (24, 30), and 20 beta-carboxaldehyde (27), are potent inhibitors of this enzyme complex. The 20-substituents with hydrophobic property were devoid of inhibitory activity, e.g., the dimethylhydrazones 8 and 9. The 16-ene together with 20-oxime (20) showed the most potent inhibition of this enzyme complex, whereas 17(20)-ene modification as in 17(20)-ene-20-carbonitrile (14) did not increase activity in comparison to the 20 beta-carbonitrile (16). The bioisotere of 27 with 20-aza (19) also reduced the inhibitory activity. The results showed that isomeric configurations at the 20-position of some steroidal compounds are important factors which influence the potency of the inhibition significantly (e.g., 20 beta-ols 24 and 30 were 3-5-fold more potent than 20 alpha-ols 23 and 29). As expected, some compounds based on the pregn-5-en-3 beta-ol skeleton, which is similar to the natural substrate of human testicular 17 alpha-hydroxylase/C17,20-lyase in A- and B-rings, showed more potent inhibition than similar compounds which are based on the pregn-4-en-3-one skeleton (e.g., 23-25 compared to 29-31). These results suggest that A- and B-rings make significant contributions to the binding of these steroidal compounds to the 17 alpha-hydroxylase and C17,20-lyase. In comparison to ketoconazole, a nonsteroidal inhibitor of 17 alpha-hydroxylase and C17,20-lyase which has been used in the treatment of prostatic cancer, the steroidal compounds 20, 24, and 27 demonstrate more potent inhibition for this enzyme complex. These inhibitors warrant further investigation in biological systems. The structural features of these compounds may serve as leads in the design of new inhibitors.
authors.affiliation: Department of Pharmacology & Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore 21201, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: C
authors.initials: C
authors.lastname: Son
authors.forename: A M
authors.initials: AM
authors.lastname: Brodie
mesh_terms: D065607:Cytochrome P-450 Enzyme Inhibitors; D003687:Dehydroepiandrosterone / Q000378:metabolism; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008861:Microsomes / Q000201:enzymology; D011278:Pregnanes / Q000737:chemistry* / Q000494:pharmacology; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013737:Testis / Q000201:enzymology*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D011278:Pregnanes; D003687:Dehydroepiandrosterone; D013254:Steroid 17-alpha-Hydroxylase; C022433:pregnenolone 17-alpha-hydroxylase; D007654:Ketoconazole