title: Design and synthesis of substrate mimetics based on an indole scaffold: potential inhibitors of 17β-HSD type 1.
abstract: 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.
authors.forename: Štefan
authors.initials: Š
authors.lastname: Starčević
authors.forename: Polona
authors.initials: P
authors.lastname: Božnar
authors.forename: Samo
authors.initials: S
authors.lastname: Turk
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
authors.forename: Tea Lanišnik
authors.initials: TL
authors.lastname: Rižner