Synthesis and biological evaluation of (6- and 7-phenyl) coumarin derivatives as selective nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1

Stefan Starcević, Petra Brozic, Samo Turk, Jozko Cesar, Tea Lanisnik Rizner, Stanislav Gobec
Journal of medicinal chemistry · 2011 · doi:10.1021/jm101104z · PMID:21138273
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This study synthesized coumarin derivatives and found that 6a exhibited potent and selective inhibition of 17β-HSD1, an enzyme implicated in hormone-dependent diseases.

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The paper reports the synthesis and biological evaluation of (6- and 7-phenyl) coumarin derivatives designed as selective nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). In vitro inhibition was assessed using recombinant human 17β-HSD1 expressed in Escherichia coli BL21 (DE3)-RIL, with competitive displacement of [3H]estrone, yielding reported Ki and IC50 values across multiple ligand–target pairs. A key finding is that several coumarin derivatives inhibited 17β-HSD1 with measurable nanomolar to micromolar potency (e.g., IC50 ~5 nM and Ki ~143 nM for specific entries). The limitation explicitly present in the excerpt is that the provided text does not include broader experimental context such as selectivity profiling beyond the assays described. Relevance to endometriosis: the paper is centrally about inhibiting 17β-HSD1, an enzyme linked to steroid metabolism relevant to endometriosis biology, though the provided excerpt does not explicitly mention endometriosis.

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Abstract

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is an enzyme that catalyzes NADPH-dependent reduction of the weak estrogen, estrone, into the most potent estrogen, estradiol, which exerts proliferative effects via the 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; thus, 17β-HSD1 represents an attractive target for the development of new therapies. We have discovered that simple coumarines 1 and 2 significantly inhibit 17β-HSD1 in a recombinant enzyme assay, with high selectivity against 17β-HSD2. We postulated that the introduction of various p-substituted phenyl moieties to position 6 or 7 of the coumarin core using the Suzuki-Miyaura cross-coupling reaction would provide mimetics of steroidal structures with improved inhibition of 17β-HSD1. The best inhibitor in the series proved to be 6a, with an IC(50) of 270 nM, and with exceptional selectivity for 17β-HSD1 over 17β-HSD2 and against the α and β estrogen receptors.
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Report error Found 11 Enz. Inhib. hit(s) with all data for entry = 50039346 Affinity DataIC50: 5nMAssay Description:Inhibition of 17beta-HSD1More data for this Ligand-Target Pair Affinity DataKi: 143nMAssay Description:Displacement of [3H]estrone human recombinant 17beta-HSD1 expressed in Escherichia coli BL21 (DE3)-RIL by competitive inhibition assay in presence of...More data for this Ligand-Target Pair Affinity DataKi: 173nMAssay Description:Displacement of [3H]estrone human recombinant 17beta-HSD1 expressed in Escherichia coli BL21 (DE3)-RIL by competitive inhibition assay in presence of...More data for this Ligand-Target Pair Affinity DataIC50: 270nMAssay Description:Displacement of [3H]estrone human recombinant 17beta-HSD1 expressed in Escherichia coli BL21 (DE3)-RIL by scintillation counting in presence of bacte...More data for this Ligand-Target Pair Affinity DataIC50: 360nMAssay Description:Displacement of [3H]estrone human recombinant 17beta-HSD1 expressed in Escherichia coli BL21 (DE3)-RIL by scintillation counting in presence of bacte...More data for this Ligand-Target Pair Affinity DataKi: 585nMAssay Description:Displacement of [3H]estrone human recombinant 17beta-HSD1 expressed in Escherichia coli BL21 (DE3)-RIL by competitive inhibition assay in presence of...More data for this Ligand-Target Pair Affinity DataKi: 585nMAssay Description:Displacement of [3H]estrone human recombinant 17beta-HSD1 expressed in Escherichia coli BL21 (DE3)-RIL by competitive inhibition assay in presence of...More data for this Ligand-Target Pair Affinity DataKi: 911nMAssay Description:Displacement of [3H]estrone human recombinant 17beta-HSD1 expressed in Escherichia coli BL21 (DE3)-RIL by competitive inhibition assay in presence of...More data for this Ligand-Target Pair Affinity DataIC50: 1.14E+3nMAssay Description:Displacement of [3H]estrone human recombinant 17beta-HSD1 expressed in Escherichia coli BL21 (DE3)-RIL by scintillation counting in presence of bacte...More data for this Ligand-Target Pair Affinity DataIC50: 1.24E+3nMAssay Description:Displacement of [3H]estrone human recombinant 17beta-HSD1 expressed in Escherichia coli BL21 (DE3)-RIL by scintillation counting in presence of bacte...More data for this Ligand-Target Pair Affinity DataIC50: 1.93E+3nMAssay Description:Displacement of [3H]estrone human recombinant 17beta-HSD1 expressed in Escherichia coli BL21 (DE3)-RIL by scintillation counting in presence of bacte...More data for this Ligand-Target Pair

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Condition tags

endometriosis

MeSH descriptors

Coumarins Estradiol Dehydrogenases Binding, Competitive Catalytic Domain Coumarins Coumarins Coumarins Estradiol Dehydrogenases Estrogen Receptor alpha Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptor beta Humans Models, Molecular Radioligand Assay Recombinant Proteins Recombinant Proteins Structure-Activity Relationship

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europepmc
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pubmed
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