Effect of a Bromo Substituent on the Glutathione Peroxidase Activity of a Pyridoxine-like Diselenide

Abstract

In search for better mimics of the glutathione peroxidase enzymes, pyridoxine-like diselenides 6 and 11, carrying a 6-bromo substituent, were prepared. Reaction of 2,6-dibromo-3-pyridinol 5 with sodium diselenide provided 6 via aromatic nucleophilic substitution of the 2-bromo substituent. LiAlH4 caused reduction of all four ester groups and returned 11 after acidic workup. The X-ray structure of 6 showed that the dipyridyl diselenide moiety was kept in an almost planar, transoid conformation. According to NBO-analysis, this was due to weak intramolecular Se···O (1.1 kcal/mol) and Se···N-interactions (2.5 kcal/mol). That the 6-bromo substituent increased the positive charge on selenium was confirmed by NPA-analysis and seen in calculated and observed (77)Se NMR-shifts. Diselenide 6 showed a more than 3-fold higher reactivity than the corresponding des-bromo compound 3a and ebselen when evaluated in the coupled reductase assay. Experiments followed for longer time (2 h) confirmed that diselenide 6 is a better GPx-catalyst than 11. On the basis of (77)Se-NMR experiments, a catalytic mechanism for diselenide 6 was proposed involving selenol, selenosulfide and seleninic acid intermediates. At low concentration (10 μM) where it showed only minimal toxicity, it could scavenge ROS produced by MNC- and PMNC-cells more efficiently than Trolox.

Toxicology and pharmacology of synthetic organoselenium compounds: an update

“…The performance of cyclic and acyclic diorganyl selenides, and aryl and heteroaryl diselenides (Bhabak and Mugesh 2010 ; Sands et al 2018 ) on the GPx-like assays has been investigated trying to overcome their low solubility in water, instability, and poor availability, which limit their therapeutic applications, and specially challenging to replicate in vivo conditions that require aqueous media and glutathione as the stoichiometric thiol (Sands et al 2018 ). The studies have addressed synthetic approaches (Saeed et al 2016 ), the merits of assays for measuring GPx-like activity, the nature of peroxides and thiols, the use of different solvents, the solubility of the reactants; their catalytic activities, redox mechanisms, and structure–activity relationships (Bhowmick and Mugesh 2018 ; Elsherbini et al 2014 ; Hodage et al 2012 ; Ibrahim et al 2015 ; Jiang et al 2015 ; Prabhu et al 2012 ; Selvakumar et al 2011 ; Singh et al 2014 , 2015 ; Thomas et al 2012 ; Yu et al 2018 ). The GPx-like activity of natural selenium-containing amino acids, selenocystine, methylselenocysteine, and selenomethionine has been also investigated and revealed selenocystine as the most efficient mimetic (Kumar et al 2011 ).…”

Selenium- and Tellurium-Based Antioxidants for Modulating Inflammation and Effects on Osteoblastic Activity

“…Organotellurium compounds have been used as immunomodulatory, anti-inflammatory, and anti-apoptotic in Parkinson’s and diabetes models [28,29]. Previously, we synthesized organic compounds containing Se or Te which showed excellent antioxidative behavior [30,31,32,33,34]. These regenerable compounds greatly inhibited the rate of linoleic acid peroxidation in a two-phase peroxidation system, and showed GPx-like behavior in model systems.…”

Glutathione Peroxidase-Like Activity of Amino-Substituted Water-Soluble Cyclic Selenides: A Shift of the Major Catalytic Cycle in Methanol

“…From a view point of drug design for antioxidant therapy, much effort has been directed for decades toward development of organoselenium compounds [ 2 , 3 , 4 , 5 , 6 , 7 ], which can act as GPx-like catalysts, and also toward elucidation of their catalytic mechanisms [ 8 , 9 , 10 , 11 ]. Various GPx model compounds, most of which are aromatic diselenides (ArSeSeAr), have been developed and their catalytic activities have been evaluated [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. In the meantime, aliphatic and/or aromatic monoselenides (RSeR′) are also known to act as GPx-like catalysts through a unique selenide/selenoxide redox cycle ( Scheme 1 , cycle A), in which selenide 1 is oxidized by H 2 O 2 to the corresponding selenoxide 2 , which is reduced back to 1 by a thiol substrate (RSH) [ 26 , 27 , 28 , 29 ].…”