Nitro-, Azo-, and Amino Derivatives of Ebselen: Synthesis, Structure, and Cytoprotective Effects

Abstract

Novel azo-bis-ebselen compounds 7 were prepared by reduction of 7-nitro-2-aryl-1,2-benzisoselenazol-3(2H)-ones 3 and 6 with sodium benzenetellurolate, NaTeC6H5, and by reaction of 2-bromo-3-nitrobenzamides with Na2Se2. The X-ray structure of 7b showed that the molecule, due to strong intramolecular secondary Se···N interactions, is completely planar. Azo-compounds 7 upon further reaction with NaTeC6H5 were reductively cleaved to provide two equivalents of the corresponding aromatic amine. The weak Se─N bond was not stable enough to survive the reaction conditions and diselenides 8 were isolated after work-up. Whereas azo-bis-ebselens 7 were poor mimics of the glutathione peroxidase (GPx)-enzymes, nitroebselens 3, 6 and 11b and diselenides 8 were 3-6 fold more active than ebselen. Based on 77 Se NMR spectroscopy, a catalytic cycle for diselenide 8b, involving aminoebselen 14, was proposed. As assessed by chemiluminescence measurements, the good GPx-mimics could reduce production of reactive oxygen species (ROS) in stimulated human mononuclear cells more efficiently than Trolox. No toxic effects of the compounds were seen in MC3T3-cells at 25 M.

Design, Synthesis and Anti‐Cancer Activities of Benzyl Analogues of Garlic‐Derived Diallyl Disulfide (DADS) and the Corresponding Diselenides

“…Plots for the peak shifts in the presence of different selenium compounds as compared to the untreated DMSO control shown in the supporting information section (Figure S42, supporting information). In contrast to the benzylic diselenides in the present study, the generation of intracellular ROS in human mononuclear cells (MNC) was inhibited by bis‐ebselen derivatives, which were shown to act as good mimics of antioxidant enzyme glutathione peroxidase (GPx) . On the other hand, the increase in ROS level was found to be almost negligible for disulfide at similar concentration (10 μM) and a slight increase was observed when the concentration of disulfide compounds were very high (50 μ M ).…”

Selenium‐NMR Spectroscopy in Organic Synthesis: From Structural Characterization Toward New Investigations

“…Additionally, Ebselen is a prominent target for the treatment of the novel coronavirus infection (COVID‐19), that emerged from Wuhan in 2019 [142] . In this context, Ebselen derivatives were recently prepared (Figure 17), and the cytoprotective effect was observed [143] . Engman and co‐workers have carried out a structural characterization, confirming the σ‐hole effect by X‐ray, 77 Se−{ 1 H} NMR chemical shift and DFT calculations.…”

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 ].…”