Synthesis, Structure, and Glutathione Peroxidase‐Like Activity of Amino Acid Containing Ebselen Analogues and Diaryl Diselenides

Abstract

The synthesis of some ebselen analogues and diaryl diselenides, which have amino acid functions as an intramolecularly coordinating group (Se···O) has been achieved by the DCC coupling procedure. The reaction of 2,2'-diselanediylbis(5-tert-butylisophthalic acid) or the activated ester tetrakis(2,5-dioxopyrrolidin-1-yl) 2,2'-diselanediylbis(5-tert-butylisophthalate) with different C-protected amino acids (Gly, L-Phe, L-Ala, and L-Trp) afforded the corresponding ebselen analogues. The used precursor diselenides have been found to undergo facile intramolecular cyclization during the amide bond formation reaction. In contrast, the DCC coupling of 2,2'-diselanediyldibenzoic acid with C-protected amino acids (Gly, L/D-Ala and L-Phe) affords the corresponding amide derivatives and not the ebselen analogues. Some of the representative compounds have been structurally characterized by single-crystal X-ray crystallography. The glutathione peroxidase (GPx)-like activities of the ebselen analogues and the diaryl diselenides have been evaluated by using the coupled reductase assay method. Intramolecularly stabilized ebselen analogues show slightly higher maximal velocity (V(max)) than ebselen. However, they do not show any GPx-like activity at low GSH concentrations at which ebselen and related diselenides are active. This could be attributed to the peroxide-mediated intramolecular cyclization of the corresponding selenenyl sulfide and diaryl diselenide intermediates generated during the catalytic cycle. Interestingly, the diaryl diselenides with alanine (L,L or D,D) amide moieties showed excellent catalytic efficiency (k(cat)/K(M)) with low K(M) values in comparison to the other compounds.

Synthesis of a Hybrid between SOD Mimetic and Ebselen to Target Oxidative Stress

“…The GPx activity of the hybrid was determined using the coupled reductase assay, which resulted in a catalytic rate of k cat = 0.022 ± 0.003 m – 1 s –1 (Figures S21). By way of comparison, for ebselen alone we obtained a catalytic rate of k cat = 0.02 ± 0.01 m – 1 s –1 (Figure S22), being in accordance with the literature value ( k cat = 0.0216 m – 1 s –1 ) . Thus, as we could experimentally observe the SOD and GPx activity of the two bioactive units remains unchanged upon their chemical coupling.…”

Multifunctional Antioxidants: Regenerable Radical‐Trapping and Hydroperoxide‐Decomposing Ebselenols

“…[10,11] Av ariety of derivatives of the selenacycle have been prepared [12][13][14] and evaluated for their capacity to mimic the natural enzymes. [10,11] Av ariety of derivatives of the selenacycle have been prepared [12][13][14] and evaluated for their capacity to mimic the natural enzymes.…”

Organodiselenides: Organic Catalysis and Drug Design Learning from Glutathione Peroxidase

“…In 2011, Selvakumar et al reported the synthesis of some diaryl diselenides bearing amino acid functions, intramolecularly coordinating the selenium atom [169]. These compounds were prepared by reacting 2,2'-diselanediyldibenzoic acid with C-protected amino acids using DCC coupling procedures.…”

“…Interestingly, the results for L-and D-derivatives were very similar, suggesting that, at least in this kind of experimental model, the chirality does not play a relevant role on catalysis. The authors also described the preparation of more hindered diselenides which anyway had low solubility issues and were thus discarded [169]. Nascimento et al carried out a more comprehensive study on amide-based aromatic and aliphatic diselenides, attempting to build a preliminary Structure-Activity Relationship (SAR) [170].…”