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
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-