Synthesis of new derivatives of 21-imidazolyl-16-dehydropregnenolone as inhibitors of 5α-reductase 2 and with cytotoxic activity in cancer cells.
The aim of this study was to synthesize several 16-dehydropregnenolone derivatives containing an imidazole ring at C-21 and a different ester moiety at C-3 as inhibitors of 5α-reductase 1 and 2 isoenzymes. Their binding capacity to the androgen receptor (AR) was also studied. Additionally, we evaluated their pharmacological effect in a castrated hamster model and their cytotoxic activity on a panel of cancer cells (PC-3, MCF7, SK-LU-1). The results showed that only the derivatives with an alicyclic ester at C-3 showed 5α-R2 enzyme inhibition activity, the most potent of them being 21-(1H-imidazol-1-yl)-20-oxopregna-5,16-dien-3β-yl-cyclohexanecarboxylate with an IC50of 29nM. This is important because prostatic benign hyperplasia is directly associated with the presence of 5α-R2. However, all the derivatives failed to inhibit 5α-R1 or bind to the AR. These alicyclic ester derivatives decreased the weight and size of androgen-dependent glands in the hamster, indicating they are very active in vivo and are not toxic. In addition, the 21-(1H-imidazol-1-yl)-20-oxopregna-5,16-dien-3β-yl-acetate derivative showed the highest cytotoxic activity on the three cancer cell lines studied. It is therefore important in the synthesis of steroidal compounds to consider the size of the ester moiety at C-3 of the steroid skeleton, which is key in obtaining biological activity, as observed in this experiment.
Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Av. Universidad 3000, Copilco Universidad, Coyoacán, 04510 Ciudad de México, CDMX México, Mexico. Electronic address: aylinsilva@hotmail.es.
Aylin Viviana
AV
Silva-Ortiz
Pharmacy Department, Faculty of Chemistry, National Autonomous University of Mexico, Avenida Universidad 3000, Ciudad de México, CDMX 04510, Mexico.
Eugene
E
Bratoeff
Instituto de Quimica, Universidad Nacional Autónoma de México, Av. Universidad 3000, Copilco Universidad, Coyoacán, 04510 Ciudad de México, CDMX México, Mexico. Electronic address: mtrapan@unam.mx.
Teresa
T
Ramírez-Apan
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, CDMX México, Mexico. Electronic address: ymheuze@gmail.com.
Yvonne
Y
Heuze
Departamento de Patología, Hospital General de México, Dr. Balmis 148, CDMX México, Mexico. Electronic address: juansorianor@hotmail.com.
Juan
J
Soriano
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, CDMX México, Mexico. Electronic address: catrina_04@hotmail.com.
Isabel
I
Moreno
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, CDMX México, Mexico. Electronic address: braru27@gmail.com.
Marisol
M
Bravo
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, CDMX México, Mexico. Electronic address: guci_luz01@hotmail.com.
Lucero
L
Bautista
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, CDMX México, Mexico. Electronic address: marisa@correo.xoc.uam.mx.
Marisa
M
Cabeza
D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology*; D000818:Animals; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D045744:Cell Line, Tumor; D042944:Cholestenone 5 alpha-Reductase / Q000187:drug effects*; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D011284:Pregnenolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D066244:Proton Magnetic Resonance Spectroscopy; D051381:Rats
D058891:5-alpha Reductase Inhibitors; C003592:16-dehydropregnenolone; D011284:Pregnenolone; D042944:Cholestenone 5 alpha-Reductase
16-Dehydropregnenolone acetate derivatives; 5-α-reductase; Alicyclic ester moiety at C-3 of the steroidal skeleton; Cell lines: PC-3; Cytotoxic activity; MCF7; SK-LU-1