Diseño, síntesis y evaluación biológica de nuevos carbamatos selenados con actividades antioxidante, citotóxica y antiproliferativa

Abstract

Trace element selenium (Se) is fundamental to human health and, over the last years, research has focused on determining its beneficial role in cancer prevention and treatment. Three series of novel aliphatic, aromatic and heteroaromatic carbamates containing selenium were synthesised, obtaining forty-six compounds in which selenium is functionalised as Se-methylselenourea, selenocyanate or diselenide. Every compound was unequivocally identified using instrumental techniques such as infrared spectroscopy, nuclear magnetic resonance and mass spectrometry. Physical chemical characteristics were determined by thermal analysis techniques. Besides, molecule fragmentation was evaluated using Head-Space Gas Chromatography Mass Spectrometry (HS-GC-MS), assessing release by the compounds of active metabolites, such as methylselenol. Novel compounds showed an interesting in vitro cytotoxic profile and displayed GI50 values below 10 µM in at least one of the tested tumour cell lines, among them, derivatives containing Se-methylselenourea group are highly cytotoxic and selective in lung cell lines. Compound methyl N,N'-bis(propoxycarbonyl)imidoselenocarbamate induced apoptosis and cell cycle arrest involving caspases in a time- and dose-dependent manner in leukaemia and lung cancer cells. Compound methyl N,N'-bis(benzyloxycarbonyl)imidoselenocarbamate induced transcriptional up-regulation of AP-1 and Egr-1, involving Elk-1 in lung carcinoma cells and transient Egr-1 biosynthesis, with an expression peak 1 hour after treatment. Chemopreventive properties of compounds were evaluated determining radical scavenging activities. In a collateral research, compound methyl N,N'-bis(4-fluorophenoxycarbonyl)imidoselenocarbamate, used to determine the role of arbuscular mycorrhizal fungi in biofortification of selenium in lettuce, improved the effectiveness of AMF for enhancing growth, proteins and sugars in leaves of one greenhouse-grown cultivar of lettuce.