title: Synthesis and biological activity of two pregnane derivatives with a triazole or imidazole ring at C-21.
abstract: Pregnane derivatives are studied as agents for the treatment of different hormone-dependent diseases. The biological importance of these steroids is based on their potential use against cancer. In this study, we report the synthesis, characterization and biological activity of two pregnane derivatives with a triazole (3β-hydroxy-21-(1H-1,2,4-triazol-1-yl)pregna-5,16-dien-20-one; T-OH) or imidazole (3β-hydroxy-21-(1H-imidazol-1-yl)pregna-5,16-dien-20-one; I-OH) moieties at C-21. These derivatives were synthesized from 16-dehydropregnenolone acetate. The activity on cell proliferation of the compounds was measured on three human cancer cells lines: prostate cancer (PC-3), breast cancer (MCF7) and lung cancer (SK-LU-1). The cytotoxic and antiproliferative effects of T-OH and I-OH were assessed by using SBR and XTT methods, respectively. The gene expressions were evaluated by real time PCR. In addition, results were complemented by docking studies and transactivation assays using an expression vector to progesterone and androgen receptor. Results show that the two compounds inhibited the three cell lines proliferation in a dose-dependent manner. Compound I-OH downregulated the gene expression of the cyclins D1 and E1 in PC-3 and MFC7 cells; however, effect upon Ki-67, EAG1, BIM or survivin genes was not observed. Docking studies show poor interaction with the steroid receptors. Nevertheless, the transactivation assays show a weak antagonist effect of I-OH on progesterone receptor but not androgenic or antiandrogenic actions. In conclusion, the synthesized compounds inhibited cell proliferation as well as genes key to cell cycle of PC-3 and MCF7 cell lines. Therefore, these compounds could be considered a good starting point for the development of novel therapeutic alternatives to treat cancer.
authors.affiliation: Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico, D.F. 04510, Mexico.
authors.forename: Aylin Viviana
authors.initials: AV
authors.lastname: Silva-Ortiz
authors.affiliation: Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico, D.F. 04510, Mexico.
authors.forename: Eugene
authors.initials: E
authors.lastname: Bratoeff
authors.affiliation: Instituto de Química, Universidad Nacional Autónoma de México, México, D.F. 04510, Mexico.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Ramírez-Apan
authors.affiliation: Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Avenida Vasco de Quiroga No. 15, Col. Belisario Domínguez, Sección XVI, México, D.F. 14080, Mexico.
authors.forename: Rocío
authors.initials: R
authors.lastname: García-Becerra
authors.affiliation: Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Avenida Vasco de Quiroga No. 15, Col. Belisario Domínguez, Sección XVI, México, D.F. 14080, Mexico.
authors.forename: David
authors.initials: D
authors.lastname: Ordaz-Rosado
authors.affiliation: Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Avenida Vasco de Quiroga No. 15, Col. Belisario Domínguez, Sección XVI, México, D.F. 14080, Mexico.
authors.forename: Nancy
authors.initials: N
authors.lastname: Noyola-Martínez
authors.affiliation: Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico, D.F. 04510, Mexico.
authors.forename: Rafael
authors.initials: R
authors.lastname: Castillo-Bocanegra
authors.affiliation: Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Avenida Vasco de Quiroga No. 15, Col. Belisario Domínguez, Sección XVI, México, D.F. 14080, Mexico. Electronic address: barrera1912@gmail.com.
authors.forename: David
authors.initials: D
authors.lastname: Barrera
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D011245:Pregnadienes / Q000138:chemical synthesis* / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D065668:Vitamin D3 24-Hydroxylase / Q000378:metabolism
chemical_list: C000609779:3-hydroxy-21-(1H-1,2,4-triazol-1-yl)pregna-5,16-dien-20-one; C000609780:3-hydroxy-21-(1H-imidazol-1-yl)pregna-5,16-dien-20-one; D000970:Antineoplastic Agents; D007093:Imidazoles; D011245:Pregnadienes; D014230:Triazoles; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase
keywords: Breast cancer; Cyclin D1; Cyclin E1; Lung cancer; Pregnane derivatives; Prostate cancer