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  • Design and synthesis of substrate mimetics based on an indole scaffold : potential inhibitors of 17ß-HSD type 1
    Starčević, Štefan ...
    Background: Human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-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 17beta-HSD1 in estrogen-responsive tissues is related to the development of hormone-dependent diseases, such as breast cancer and endometriosis. 17beta-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 17beta-HSD1 from Escherichia coli, at concentrations of 0.6 mM and 6.0 mM. Results: Among 14 indole derivatives, compound 9 was an initial hit inhibitor of 17beta-HSD1, with moderate inhibition (64% at 6 mM). Molecular docking into the crystal structure of 17beta-HSD1 (1A27) revealed that this 5-phenyl indole derivative binds to 17b-HSD1 similarly to co-crystalized E2. Compound 9 forms two H-bondswith 17beta-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 17beta-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.
    Source: Hormone molecular biology and clinical investigation. - ISSN 1868-1883 (Vol. 6, issue 1, 2011, str. 201-209)
    Type of material - article, component part
    Publish date - 2011
    Language - english
    COBISS.SI-ID - 28061913
    DOI

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