title: Synthesis and activity of novel 16-dehydropregnenolone acetate derivatives as inhibitors of type 1 5α-reductase and on cancer cell line SK-LU-1.
abstract: Testosterone (T) plays a crucial role in prostate growth. In androgen-dependent tissues T is reduced to dihydrotestosterone (DHT) because of the presence of the 5α-reductase enzyme. This androgen is more active than T, since it has a higher affinity for the androgen receptor (AR). When this mechanism is altered, androgen-dependent diseases, including prostate cancer, could result. The aim of this study was to synthesize several 16-dehydropregnenolone acetate derivatives containing a triazole ring at C-21 and a linear or alicyclic ester moiety at C-3 of the steroidal skeleton. These steroids were designed as potential inhibitors of the activity of both types (1 and 2) of 5α-reductase. The cytotoxic activity of these compounds was also evaluated on a panel of PC-3, MCF7, and SK-LU-1 human cancer cell lines. The results from this study showed that with the exception of steroids 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3β-yl-propionate and 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3β-yl-pentanoate, the compounds exhibit a lower inhibitory activity for both isoenzymes of 5α-reductase than finasteride. Furthermore the 3β-hydroxy-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-20-one and 20-oxo-21-(1H-1,2,4-triazole-1-yl)pregna-5,16-dien-3β-yl-acetate derivatives display 80% cytotoxic activity on the SK-LU-1 cell line. These results also indicated that the triazole derivatives, which have a hydroxyl or acetoxy group at C-3, could have an anticancer effect, whereas the derivatives with a alicyclic ester group at C-3 do not show biological activity.
authors.affiliation: Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Av. Universidad 3000, Copilco Universidad, Coyoacán, 04510 Ciudad de México, Distrito Federal, México D.F., Mexico. Electronic address: aylinsilva@hotmail.es.
authors.forename: Aylin Viviana
authors.initials: AV
authors.lastname: Silva-Ortiz
authors.affiliation: Faculty of Chemistry, Department of Pharmacy (Departamento de Farmacia), National Autonomous University of Mexico in Mexico City (Universidad Nacional Autónoma de México), Mexico. Electronic address: eugene@unam.mx.
authors.forename: Eugene
authors.initials: E
authors.lastname: Bratoeff
authors.affiliation: Intituto de Quimica, Universidad Nacional Autónoma de México, Av. Universidad 3000, Copilco Universidad, Coyoacán, 04510 Ciudad de México, Distrito Federal, México D.F., Mexico. Electronic address: mtrapan@unam.mx.
authors.forename: Teresa
authors.initials: T
authors.lastname: Ramírez-Apan
authors.affiliation: Departamento de Sistemas Biológicos y de Producción Agrícola y Animal, Universidad Autónoma Metropolitana-Xochimilco, Calzada del Hueso 1100, Col. Villa Quietud, 04960 Ciudad de México, México D.F. C.P. 04960, Mexico. Electronic address: ymheuze@gmail.com.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Heuze
authors.affiliation: Departamento de Sistemas Biológicos y de Producción Agrícola y Animal, Universidad Autónoma Metropolitana-Xochimilco, Calzada del Hueso 1100, Col. Villa Quietud, 04960 Ciudad de México, México D.F. C.P. 04960, Mexico. Electronic address: ara_sm89@live.com.mx.
authors.forename: Araceli
authors.initials: A
authors.lastname: Sánchez
authors.affiliation: Departamento de Patología, Hospital General de México, Dr. Balmis 148, México D.F., Mexico. Electronic address: juansorianor@hotmail.com.
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, Calzada del Hueso 1100, Col. Villa Quietud, 04960 Ciudad de México, México D.F. C.P. 04960, Mexico. Electronic address: marisa@correo.xoc.uam.mx.
authors.forename: Marisa
authors.initials: M
authors.lastname: Cabeza
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042944:Cholestenone 5 alpha-Reductase / Q000378:metabolism; D006801:Humans; D008297:Male; D008647:Mesocricetus; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011284:Pregnenolone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats
chemical_list: D058891:5-alpha Reductase Inhibitors; D000970:Antineoplastic Agents; C003592:16-dehydropregnenolone; D011284:Pregnenolone; D042944:Cholestenone 5 alpha-Reductase
keywords: 5α-Reductase 1 inhibitors; Antiproliferative activity on SKLU-1 cells; Synthesis of derivatives dehydropregnenolone