Abstract
Steroidogenic enzyme type 3 17β-hydroxysteroid dehydrogenase (17β-HSD) is an important therapeutic target for androgen-sensitive diseases. This enzyme selectively reduces the C17 ketone of 4-androstene-3,17-dione (Δ4-dione), thus producing testosterone (T) using NADPH as cofactor. Our group previously synthesized hybrid (estradiol/adenosine) inhibitors that successfully inhibit the biosynthesis of the potent estrogen estradiol by type 1 17β-HSD. To similarly lower the level of the potent androgen testosterone, inhibitors of type 3 17β-HSD were designed and synthesized applying the same hybrid (substrate/cofactor) strategy. Two chemical approaches were developed to join the three components of the bisubstrate inhibitor (the substrate Δ4-dione, an alkyl spacer and the cofactor moiety adenosine). An alkylation in the α position of steroidal 17-ketone or a cross-metathesis was used as a key step to efficiently join the substrate and the alkyl spacer, whereas an esterification was employed to link the spacer to adenosine. An enzymatic assay in homogenated HEK-293 cells overexpressing type 3 17β-HSD revealed that the best inhibitors of that series are those bearing an alkyl side-chain spacer of 11 or 12 methylenes: inhibition of 69 and 78% at 1 μM were respectively observed. As expected, these bisubstrate inhibitors were less potent in intact cells than in homogenated cells. However, both enzymatic assays revealed that the strategy of substrate/cofactor dual inhibitors seems to work for type 3 17β-HSD, although the inhibitors designed have not been optimized yet.
Keywords: crossmetathesis, androgen, hormone, steroid, type 3 17β-HSD, 17β-hydroxysteroid dehydrogenase, enzyme, Inhibitor
Medicinal Chemistry
Title: Design, Synthesis and In Vitro Evaluation of 4-Androstene-3,17-dione/Adenosine Hybrid Compounds as Bisubstrate Inhibitors of Type 3 17β-Hydroxysteroid Dehydrogenase
Volume: 2 Issue: 4
Author(s): Marie Berube, Yannick Laplante and Donald Poirier
Affiliation:
Keywords: crossmetathesis, androgen, hormone, steroid, type 3 17β-HSD, 17β-hydroxysteroid dehydrogenase, enzyme, Inhibitor
Abstract: Steroidogenic enzyme type 3 17β-hydroxysteroid dehydrogenase (17β-HSD) is an important therapeutic target for androgen-sensitive diseases. This enzyme selectively reduces the C17 ketone of 4-androstene-3,17-dione (Δ4-dione), thus producing testosterone (T) using NADPH as cofactor. Our group previously synthesized hybrid (estradiol/adenosine) inhibitors that successfully inhibit the biosynthesis of the potent estrogen estradiol by type 1 17β-HSD. To similarly lower the level of the potent androgen testosterone, inhibitors of type 3 17β-HSD were designed and synthesized applying the same hybrid (substrate/cofactor) strategy. Two chemical approaches were developed to join the three components of the bisubstrate inhibitor (the substrate Δ4-dione, an alkyl spacer and the cofactor moiety adenosine). An alkylation in the α position of steroidal 17-ketone or a cross-metathesis was used as a key step to efficiently join the substrate and the alkyl spacer, whereas an esterification was employed to link the spacer to adenosine. An enzymatic assay in homogenated HEK-293 cells overexpressing type 3 17β-HSD revealed that the best inhibitors of that series are those bearing an alkyl side-chain spacer of 11 or 12 methylenes: inhibition of 69 and 78% at 1 μM were respectively observed. As expected, these bisubstrate inhibitors were less potent in intact cells than in homogenated cells. However, both enzymatic assays revealed that the strategy of substrate/cofactor dual inhibitors seems to work for type 3 17β-HSD, although the inhibitors designed have not been optimized yet.
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Berube Marie, Laplante Yannick and Poirier Donald, Design, Synthesis and In Vitro Evaluation of 4-Androstene-3,17-dione/Adenosine Hybrid Compounds as Bisubstrate Inhibitors of Type 3 17β-Hydroxysteroid Dehydrogenase, Medicinal Chemistry 2006; 2 (4) . https://dx.doi.org/10.2174/157340606777724086
DOI https://dx.doi.org/10.2174/157340606777724086 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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