Synthesis and biological evaluation of esters of 16-formyl-17-methoxy-dehydroepiandrosterone derivatives as inhibitors of 5α-reductase type 2

Abstract

In this study, we investigated the in vitro effect of 16-formyl-17-methoxy dehydroepiandrosterone derivatives on the activity of 5α-reductase type 2 (5α-R2) obtained from human prostate. The activity of different concentrations of these derivatives was determined for the conversion of labelled testosterone to dihydrotestosterone. The results indicated that an aliphatic ester moiety at the C-3 position of these derivatives increases their in vitro potency as inhibitors of 5α-R2 activity compared to finasteride®, which is considered to be a potent inhibitor of 5α-R2. In this case, the augmentation of the lipophilicity of these dehydroepiandrosterone derivatives increased their potency as inhibitors of 5α-R2. However, the presence of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings as the cycloaliphatic ester moiety at C-3 of the formyl methoxy dehydroepiandrosterone scaffold did not inhibit the activity of this enzyme. This may be due to the presence of steric factors between the enzyme and the spatial structure of these derivatives.

Claisen‐Schmidt Condensation and Domino Claisen‐Schmidt Condensation ‐ Michael Addition of 16‐Formyl Steroids in the Presence of Switchable Polarity Solvents

“…The chlorine atom can be replaced by different heterocycles, [19] and the aldehyde function can be modified in several ways. [20][21][22][23][24][25] The Vilsmeier-Haack reaction of steroidal substrates can yield valuable compounds with a variety of biological effects, e. g. 5α-reductase- [26] or 17α-lyase inhibitors, [19] antimicrobial [23] and antitumor compounds. [27] Based on these findings we envisaged the functionalization of C-16 of different steroidal skeletons via Claisen-Schmidt condensation of the formyl group and, eventually, the introduction of a heterocycle to C-17.…”

Synthesis and Pharmacological Properties of Modified A- and D-Ring in Dehydroepiandrosterone (DHEA): A Review

“…Methoxyformyl Dehydroepiandrosterone Derivatives. Marquez and teammates synthesized 16-formyl-17methoxy dehydroepiandrosterone derivatives 68a−j through a series of Vilsmeier−Haack, addition-substitution, and esterification reactions (Scheme 9) in 2016, 18 and the in vitro effect of 68a−j was investigated on the activity of 5α-reductase type 2 (5AR-2) obtained from the human prostate. Among them, the presence of an aliphatic ester moiety at the C-3 position of these derivatives enhances their in vitro potency as inhibitors of 5AR-2 activity compared to finasteride, recognized as a potent inhibitor of 5AR-2 (Figure 4).…”

“…All steroids exhibited more potency (lower IC 50 value) than finasteride to inhibit the 5AR-2 enzyme. IC 50 values: Concentration of compound required to inhibit 50% of the activity of 5α-reductase type 2 (5AR-2); RBA: Relative binding activity to the androgen receptor (AR) …”

“…IC 50 values: Concentration of compound required to inhibit 50% of the activity of 5α-reductase type 2 (5AR-2); RBA: Relative binding activity to the androgen receptor (AR). 18 …”