17β-N-arylcarbamoylandrost-4-en-3-one Derivatives as Inhibitors of the Enzymes 3α-Hydroxysteroid Dehydrogenase and 5α-Reductase

Author(s): Eugene Bratoeff, Isabel Moreno, Francisco Cortes-Benitez, Yvonne Heuze, Marisol Bravo, Marisa Cabeza*.

Journal Name: Current Enzyme Inhibition

Volume 14 , Issue 1 , 2018

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Abstract:

Background: The involvement of 3α-hydroxysteroid dehydrogenase (3α-HSD AKR1C2) in the processes of liver metastasis and prostate cancer has been previously reported. Increased 5α- reductase 1 (5α-R1) activity in prostate cancer has also been reported. Therefore, overexpression of 3α-HSD and 5α-R1 could be related to drug resistance and disease progression of liver and prostate tumors.

Aim: The aim of this study was to identify the in vitro activity of 13 different 17β-Narylcarbamoylandrost- 4-en-3-one derivatives as inhibitors of 3α-hydroxisteroid dehydrogenase (AKR1C9) and 5α-R1 present in rat liver microsomes.

Methods: The methods for synthesis, molecular docking, and identification 13 different 17β-Narylcarbamoylandrost- 4-en-3-one derivatives as specific inhibitors of the activity of 5α-R1 or 3α-HSD (AKR1C9) were detailed in this paper. The activity of these enzymes was obtained using solubilized microsomes of rat liver in the presence or absence of each novel steroid.

Results: Data indicated some of these derivatives specifically inhibited the activity of 5α-R1, with a parallel decrease in 3α-diol formation. In addition, the other steroids prevented 3α-HSD activity, inducing the accumulation of 5α-DHT under conditions of reduction of the reaction. The steroid that inhibited 3α-HSD activity most strongly was 17β-N-(4-methoxyphenylcarbamoyl)androst-4-ene-3-one, since this compound performed key interactions; a hydrogen bond between the p-OCH3 group, and the side chain Arg133 present in 3α-HSD (AKR1C9). In addition, we identified the most potent inhibitors of 5α-R1 activity of this series as the 17β-N-(3-methoxyphenylcarbamoyl)androst-4-ene-3-one, and 17β-N-(3-fluorophenylcarbamoyl)androst-4-ene-3-one, which have hydrogen-bond-acceptor groups and the best molecular spatial arrangement to inhibit this enzyme.

Conclusion: The results suggested that inhibitors should be dual to prevent 5α-reductase 1 and 3α- HSD activity, since it should be considered the latter enzyme could increase intraprostatic 5α-DHT under oxidizing reaction conditions, whereas to prevent metastasis, it would be appropriate to use 3α- HSD inhibitors.

Keywords: 17β-N-arylcarbamoyl androst-4-en-3-one derivatives, 3α-hydroxysteroid dehydrogenase, liver metastasis, 5α- reductase 1, novel androstane inhibitors, prostate metastasis.

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Article Details

VOLUME: 14
ISSUE: 1
Year: 2018
Page: [36 - 50]
Pages: 15
DOI: 10.2174/1573408013666170504155043

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