Synthesis and Antioxidant Activity of Peptide‐Based Ebselen Analogues

Abstract

A series of di- and tripeptide-based ebselen analogues has been synthesized. The compounds were characterized by (1)H, (13)C, and (77)Se NMR spectroscopy and mass spectral techniques. The glutathione peroxidase (GPx)-like antioxidant activity has been studied by using H(2)O(2) , tert-butyl hydroperoxide (tBuOOH), and cumene hydroperoxide (Cum-OOH) as substrates, and glutathione (GSH) as a cosubstrate. Although all the peptide-based compounds have a selenazole ring similar to that of ebselen, the GPx activity of these compounds highly depends on the nature of the peptide moiety attached to the nitrogen atom of the selenazole ring. It was observed that the introduction of a phenylalanine (Phe) amino acid residue in the N-terminal reduces the activity in all three peroxide systems. On the other hand, the introduction of aliphatic amino acid residues such as valine (Val) significantly enhances the GPx activity of the ebselen analogues. The difference in the catalytic activity of dipeptide-based ebselen derivatives can be ascribed mainly to the change in the reactivity of these compounds toward GSH and peroxide. Although the presence of the Val-Ala-CO(2) Me moiety facilitates the formation of a catalytically active selenol species, the reaction of ebselen analogues that has a Phe-Ile-CO(2) Me residue with GSH does not generate the corresponding selenol. To understand the antioxidant activity of the peptide-based ebselen analogues in the absence of GSH, these compounds were studied for their ability to inhibit peroxynitrite (PN)-mediated nitration of bovine serum albumin (BSA) and oxidation of dihydrorhodamine 123. In contrast to the GPx activity, the PN-scavenging activity of the Phe-based peptide analogues was found to be comparable to that of the Val-based compounds. However, the introduction of an additional Phe residue to the ebselen analogue that had a Val-Ala dipeptide significantly reduced the potency of the parent compound in PN-mediated nitration.

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

“…Attempted the synthesis of the Se‐carboxymethylated derivative 66 was also unsuccessful,48 it clearly indicates that the catalytically active selenol (e.g., 65 ) is not produced during the catalytic cycle. This is a characteristic catalytic feature of ebselen and its analogues 21. This observation is in sharp contrast with our computational results (natural charge calculations) on 52 / 34 a , which predicted that such system should overcome the thiol exchange to produce catalytically active selenol through desired electronic effects.…”

“…This attracted our attention towards the synthesis and studies on the GPx‐like activity of the ebselen analogues and diselenides that contain amino acid functions. During the course of our study, Satheeshkumar and Mugesh communicated the synthesis and GPx‐like activity of peptides that contain ebselen analogues and diselenides 21. It has been demonstrated that the presence of a valine residue in the peptide enhanced the antioxidant property by producing the catalytically active selenol intermediate, which is generally not predominant in the catalytic cycle of ebselen.…”

Identification of antioxidant peptides derived from egg‐white protein and its protective effects on H2O2‐induced cell damage

“…Kandhan et al . (Satheeshkumar & Mugesh, ) demonstrated that the introduction of valine at N‐terminus significantly enhanced the antioxidant activity. It is consistent with our results.…”

Water-dependent synthesis of biologically active diaryl diselenides

“…Direct reduction of benzisoselenazolones with different reducing agents -sodium borohydride, hydrazine, ascorbate or phosphoric acid (h), [33][34][35][36] nucleophilic substitution of o-iodobenzamides with lithium diselenide (i), 37 under radical conditions from the reaction of 2-benzylselenobenzamides with triphenyltin hydride and further treatment with benzoyl peroxide (j) 38 and few protocols starting from 2,2-diselenobis(benzoic acid) -through the formation of the corresponding dichloride and further reaction with amine (k) 39 or by EDC (l) 40 and DCCmediated (m) 41 coupling reactions (Scheme 2).…”