Genomic action of permanently charged tamoxifen derivatives via estrogen receptor-α

• Published in: Bioorganic & medicinal chemistry 2010-08, Vol.18 (15), p.5593-5601
• Main Authors: Rivera-Guevara, Claudia, Pérez-Alvarez, Víctor, García-Becerra, Rocío, Ordaz-Rosado, David, Morales-Ríos, Martha Sonia, Hernández-Gallegos, Elizabeth, Cooney, Austin J., Bravo-Gómez, María Elena, Larrea, Fernando, Camacho, Javier
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents, Hormonal - chemistry; Antineoplastic Agents, Hormonal - pharmacology; Biological and medical sciences; Breast cancer; Cell Line, Tumor; Crystallography, X-Ray; Estrogen receptor; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; General aspects; Genomic action; Humans; Medical sciences; Molecular Conformation; Pharmacology. Drug treatments; Protein Binding; Structure-Activity Relationship; Tamoxifen; Tamoxifen - chemistry; Tamoxifen - pharmacology; Tamoxifen derivatives; Transcription, Genetic - drug effects
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.06.039

Tamoxifen is a selective estrogen receptor modulator widely used in oncology and reproductive endocrinology. In order to decrease its non-desirable effects and elucidate mechanisms of action, permanently charged tamoxifen derivatives (PCTDs) have been reported. Whether PCTDs have genomic effects remains controversial. Since the clinical relevance of tamoxifen, the necessity to have new anticancer drugs, and in order to gain insights into the mechanisms of action of PCTDs, we obtained six quaternary ammonium salts derived from tamoxifen including three new compounds. We characterized them by nuclear magnetic resonance, X-ray diffraction, electron microscopy, and/or high performance liquid chromatography, and detected them in cell lysates by liquid chromatography coupled to mass spectrometry. We evaluated their binding to estrogen receptor-α (ERα, their effect on the transcriptional activity mediated by ERα (gene reporter assays), and the proliferation of cancer cells (MCF-7 and cells from a cervical cancer primary culture). Structural studies demonstrated the expected identity of the molecules. All PCTDs did bind to ERα, one of them induced ERα-mediated transcription while two others inhibited such genomic action. Accordingly, PCTDs were detected in cell lysates. PCTDs inhibited cell proliferation, noteworthy, two of them displayed higher inhibition than tamoxifen. Structure–activity analysis suggests that PCTDs permanent positive charge and the length of the aliphatic chain might be associated to the biological responses studied. We suggest genomic effects as a mechanism of action of PCTDs. The experimental approaches here used could lead to a better design of new therapeutic molecules and help to elucidate molecular mechanisms of new anticancer drugs.