Antioxidant activity of some diarylselenides in biological systems

Abstract

The selenoorganic compounds di(4-aminophenyl)selenide (10) and 4-nitro-4′-amino-diphenylselenide (36) were shown to inhibit lipid peroxidation in ADP/Fe 2+/ascorbate-treated microsomes and tert-butylhydroperoxide-treated hepatocytes with IC 50s of 3 and 10 μM, and 14 and 10 μM, respectively. In the former system, these inhibition constants compare favourably with those of Ebselen and classical antioxidants such as butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA). In the cell system, these selenium compounds were equipotent with BHA but more potent than Ebselen and its analogues. The diamino compound (10) was also an effective inhibitor of lipid peroxidation initiated by diquat redox cycling in hepatocytes, again being equipotent with BHA but more potent than Ebselen and its analogues, which actually stimulated lipid peroxidation in this test system. Manipulation of the amino functions of (10) and (36) by alkylation or acylation altered the antioxidant capacity. Optimal activity in this series was achieved by N-ethylation or N-isobutylation of (10). This produced antioxidants having IC 50s below 1 μM in the microsome system, 3–13 μM in the tert-butylhydroperoxide system, and being 100% effective in the diquat model at 50 μM. On the other hand, acylation or alkylation of the amino groups with long chain acyl or alkyl groups reduced the efficacy of the structures below that of the parent diamine. As with other antioxidant compounds, several of the chalcogenides were relatively selective inhibitors of monocyte 5′lipoxygenase-dependent secretionn of LTB 4 as compared to their effect on cyclooxygenase-dependent secretion of PGE 2 (for example compound 42 had IC 50s of 0.6 μM and 10 μM, respectively). No correlation was observed between the redox-properties of the chalcogenides and their respective abilities to inhibit these enzymes.