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

[ Vol. 14 , Issue. 1 ]

Author(s):

Eugene Bratoeff, Isabel Moreno, Francisco Cortes-Benitez, Yvonne Heuze, Marisol Bravo and Marisa Cabeza*   Pages 36 - 50 ( 15 )

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.

Affiliation:

Pharmacy Department, Faculty of Chemistry, National Autonomous University of Mexico, Avenida Universidad 3000, Ciudad de Mexico, CDMX, 04510, Biological Systems and Agricultural and Animal Production Department, Autonomous Metropolitan University-Xochimilco, Calzada del Hueso 1100, Col. Villa Quietud, Ciudad de Mexico, CDMX, 04960, Pharmacy Department, Faculty of Chemistry, National Autonomous University of Mexico, Avenida Universidad 3000, Ciudad de Mexico, CDMX, 04510, Biological Systems and Agricultural and Animal Production Department, Autonomous Metropolitan University-Xochimilco, Calzada del Hueso 1100, Col. Villa Quietud, Ciudad de Mexico, CDMX, 04960, Biological Systems and Agricultural and Animal Production Department, Autonomous Metropolitan University-Xochimilco, Calzada del Hueso 1100, Col. Villa Quietud, Ciudad de Mexico, CDMX, 04960, Biological Systems and Agricultural and Animal Production Department, Autonomous Metropolitan University-Xochimilco, Calzada del Hueso 1100, Col. Villa Quietud, Ciudad de Mexico, CDMX, 04960

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