Seleninic Acid Potassium Salts as Water-Soluble Biocatalysts with Enhanced Bioavailability.

Magdalena Obieziurska,Angelika Długosz-Pokorska,Anna Laskowska,Jacek Ścianowski,Anna Janecka,Agata J Pacuła

doi:10.3390/ma13030661

Abstract

Organoselenium compounds are well-known glutathione peroxidase (GPx) mimetics that possess antioxidants/prooxidant properties and are able to modulate the concentration of reactive oxygen species (ROS), preventing oxidative stress in normal cells or inducing ROS formation in cancer cells leading to apoptosis. The purpose of this study was the synthesis of potent GPx mimics with antioxidant and anticancer activity along with improved bioavailability, as a result of good solubility in protic solvents. As a result of our research, glutathione peroxidase (GPx) mimetics in the form of water-soluble benzeneseleninic acid salts were obtained. The procedure was based on the synthesis of 2-(N-alkylcarboxyamido)benzeneselenenic acids, through the oxidation of benzisoselenazol-3(2H)-ones or analogous arenediselenides with an amido group, which were further converted to corresponding potassium salts by the treatment with potassium tert-butanolate. All derivatives were tested as potential antioxidants and anticancer agents. The areneseleninic acid salts were significantly better peroxide scavengers than analogous acids and the well-known organoselenium antioxidant ebselen. The highest activity was observed for the 2-(N-ethylcarboxyamido)benzeneselenenic acid potassium salt. The strongest cytotoxic effect against breast cancer (MCF-7) and human promyelocytic leukemia (HL-60) cell lines was found for 2-(N-cyclohexylcarboxyamido)benzeneselenenic acid potassium salt and the 2-(N-ethylcarboxyamido)benzeneselenenic acid, respectively. The structure–activity correlations, including the differences in reactivity of benzeneseleninic acids and corresponding salts were evaluated.

Highlights

Designing catalysts inspired by enzymes is one of the crucial tactics aimed at influencing cell physiology or reversing a pathological state that triggers a disease to develop
The first step of this study involved the synthesis of N-alkyl benzeneselenenic acids with o-amido function
Benzeneseleninic acids 10-15 were transformed to the corresponding benzeneseleninic salts 16–21

Summary

Introduction

Designing catalysts inspired by enzymes is one of the crucial tactics aimed at influencing cell physiology or reversing a pathological state that triggers a disease to develop. In the GPx-catalytic cycle, the initial redox-active -SeH, plays the crucial role at the enzyme’s active site and initiates the cycle through the rapid reaction with H2 O2. As it has been presented by Mugesh et al, the regulation of ROS concentrations depends on the levels of peroxide and the thiol co-factor, mostly. The active selenol 1 is first oxidized to the co-factor, mostly the glutathione (GSH) [4]. The active selenol 1 is selenenic acid 2 and regenerated in the presence of two GHS molecules. In stress, when the H2 O2 level is higher, with a lower amount of thiol, the cycle is extended and further the state of oxidative stress, when the H2O2 level is higher, with a lower amount of thiol, the cycle is oxidation of the seleninic acid 3 takes place (Scheme 1)

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