Synthesis and Identification of Pregnenolone Derivatives as Inhibitors of Isozymes of 5α‐Reductase

Abstract

Hyperplasia of the prostate gland and prostate cancer have been associated with high levels of serum 5α-dihydrotestosterone. This steroid is formed from testosterone by the activity of the enzyme 5α-reductase (5α-R) present in the prostate. Thus, inhibition of this enzyme could be a goal for therapies to treat these diseases. This study reports the synthesis and effects of five different 21-esters of pregnenolone derivatives as inhibitors of 5α-R types 1 and 2. The activity of these steroidal compounds was determined using in vivo and in vitro experiments. The results indicate that of the five steroids studied, the 21(p-fluoro)benzoyloxypregna-4,16-diene-3,6,20-trione derivative, whose structure has not yet been reported, has the best molecular conformation to inhibit the in vitro activity of both types of 5α-R. In addition, this steroid also displayed activity in vivo. Apparently, its pharmacological effect was increased by the presence of a keto group at C-6, because this group decreased the possibility that the steroid would be metabolized by hepatic enzymes. In addition, the double bond present at C-4 of this compound also enhanced its inhibitory activity on 5α-R, and the C-21 ester moiety increased its liphophilicity. Therefore, its solubility in the cell membrane and its pharmacological activity were both increased.

Synthesis, In Vitro Biological Evaluation of Antiproliferative and Neuroprotective Effects and In Silico Studies of Novel 16E-Arylidene-5α,6α-epoxyepiandrosterone Derivatives

“…As an illustrative example, 5α,6α-epoxycholesterol ( Figure 1 ) is an oxysterol with several biological activities, including regulation of cell proliferation and cholesterol homeostasis [ 20 ]. Furthermore, other epoxysteroids have been described in the literature as potential neuroprotective agents, inhibitors of 5α-reductase (5AR), and antiproliferative agents [ 21 , 22 , 23 , 24 ]. In this scope, Chávez-Riveros and coworkers reported the synthesis and identification of pregnenolone derivatives as 5AR inhibitors (5ARIs), including an epoxysteroid, 21( p -fluoro)benzoyloxy-5α,6α-epoxy-3β-hydroxypregna-16-en-20-one ( Figure 1 ), which presented an IC 50 value of 179 nM against 5AR type 2 [ 22 ].…”

“…Furthermore, other epoxysteroids have been described in the literature as potential neuroprotective agents, inhibitors of 5α-reductase (5AR), and antiproliferative agents [ 21 , 22 , 23 , 24 ]. In this scope, Chávez-Riveros and coworkers reported the synthesis and identification of pregnenolone derivatives as 5AR inhibitors (5ARIs), including an epoxysteroid, 21( p -fluoro)benzoyloxy-5α,6α-epoxy-3β-hydroxypregna-16-en-20-one ( Figure 1 ), which presented an IC 50 value of 179 nM against 5AR type 2 [ 22 ]. Interestingly, 21 E -arylidene-5α,6α-epoxypregnenolone derivatives were already described as potential neuroprotective agents by Jiang and coworkers (a representative example is presented in Figure 1 ) [ 21 ].…”