Premium
Synthesis and Identification of Pregnenolone Derivatives as Inhibitors of Isozymes of 5α‐Reductase
Author(s) -
ChávezRiveros Alejandra,
Bratoeff Eugene,
Heuze Yvonne,
Soriano Juan,
Moreno Isabel,
SánchezMárquez Araceli,
Cabeza Marisa
Publication year - 2015
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201500220
Subject(s) - chemistry , pregnenolone , steroid , in vivo , dihydrotestosterone , enzyme , in vitro , isozyme , testosterone (patch) , reductase , biochemistry , stereochemistry , androgen , endocrinology , hormone , biology , microbiology and biotechnology
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.