title: 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.
authors.affiliation: Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, Distrito Federal, México, D. F., Mexico.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Chávez-Riveros
authors.affiliation: Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, Distrito Federal, México, D. F., Mexico.
authors.forename: Eugene
authors.initials: E
authors.lastname: Bratoeff
authors.affiliation: Departamento de Sistemas Biológicos y de Producción Agrícola y Animal, Universidad Autónoma Metropolitana-Xochimilco, Ciudad de México, México, D. F., Mexico.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Heuze
authors.affiliation: Departamento de Patología, Hospital General de México, México, D. F., Mexico.
authors.forename: Juan
authors.initials: J
authors.lastname: Soriano
authors.affiliation: Departamento de Sistemas Biológicos y de Producción Agrícola y Animal, Universidad Autónoma Metropolitana-Xochimilco, Ciudad de México, México, D. F., Mexico.
authors.forename: Isabel
authors.initials: I
authors.lastname: Moreno
authors.affiliation: Departamento de Sistemas Biológicos y de Producción Agrícola y Animal, Universidad Autónoma Metropolitana-Xochimilco, Ciudad de México, México, D. F., Mexico.
authors.forename: Araceli
authors.initials: A
authors.lastname: Sánchez-Márquez
authors.affiliation: Departamento de Sistemas Biológicos y de Producción Agrícola y Animal, Universidad Autónoma Metropolitana-Xochimilco, Ciudad de México, México, D. F., Mexico.
authors.forename: Marisa
authors.initials: M
authors.lastname: Cabeza
keywords: (p-Fluoro)benzoyloxy 21-esters of pregnenolone derivatives; 5α-Reductase; Hamster prostate gland; Hamster seminal vesicles; Steroidal esters