New cholic acid analogs: synthesis and 17β-hydroxydehydrogenase (17β-HSD) inhibition activity

Abstract

Abstract The 17β-hydroxysteroid dehydrogenase (17β-HSD) enzyme family is involved in the biosynthesis of active steroids and its inhibition constitutes an interesting approach for treating estrogen-, androgen-dependent cancers and osteoporosis. In this study, a new series of cholic acid analogs was designed with the goal of improving the biological activity as 17β-HSD1 and 17β-HSD2 inhibitors. To this end, 23-cholyl amides 4–7, 3-O-p-toluenesulfonyl-23-cholyl amides 10–12, 23-cholyl-carbohydrazide 14, carbothioamide analog 15, and 23-cholyl-acylhydrazone derivatives 18–22 were synthesized from cholic acid (3) via coupling, sulfonation and substitution reactions. Basic treatment of keto group of 5 with p-bromoaniline afforded 8, meanwhile acidic treatment of 3 with thiosemicarbazide furnished the 23-cholyl-thiadiazole derivative 16. The synthesized compounds were evaluated for their inhibition activity against 17β-HSD1 and 17β-HSD2, and were found inactive at 1.0 μm concentration (inhibition <10%). However, the steroids 12, 21 and 22 showed inhibition of 21.1, 23.9 and 21.3%, respectively, against 17β-HSD2 at the same concentration. Therefore, these steroidal analogs can be further structurally modified to optimize their inhibition activity against 17β-HSD2 for the development of potential therapeutics.