Design and synthesis of substrate mimetics based on an indole scaffold: potential inhibitors of 17β-HSD type 1

BACKGROUND: Human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) acts at a pre-receptor level. It catalyzes NADPH-dependent reduction of the weak estrogen estrone into the most potent estrogen estradiol, which exerts its proliferative effects via estrogen receptors. Overexpression of 17β-HSD1 in estrogen-responsive tissues is related to the development of hormone-dependent diseases, such as breast cancer and endometriosis. 17β-HSD1 thus represents an attractive target for development of new drugs. METHODS: We designed and synthesized a series of 3-, 5- and 6-phenyl indole derivatives as mimetics of the steroid substrate estrone. All of these compounds were evaluated for inhibition of recombinant human 17β-HSD1 from Escherichia coli, at concentrations of 0.6 μM and 6.0 μM. RESULTS: Among 14 indole derivatives, compound 9 was an initial hit inhibitor of 17β-HSD1, with moderate inhibition (64% at 6 μM). Molecular docking into the crystal structure of 17β-HSD1 (1A27) revealed that this 5-phenyl indole derivative binds to 17β-HSD1 similarly to co-crystalized E2. Compound 9 forms two H-bonds with 17β-HSD1: one between the indole nitrogen and His222, and the second between the phenolic OH group and catalytic Tyr155. CONCLUSIONS: The indole scaffold is one of the possible starting points for the design of substrate mimetics of the steroid substrate estrone. Our study shows that these 6- and, especially, 5-phenol indole derivatives can act as moderate inhibitors of 17β-HSD1. Based on inhibition assays and docking simulations, we can infer further improvements of the 5-phenol indole derivatives that might result in better inhibition profiles.