ANTIOXIDANT ACTIVITY OF SOME DIARYLSELENIDES IN BIOLOGICAL-SYSTEMS

The selenoorganic compounds di(4-aminophenyl)selenide (10) and 4-nitro -4'-amino-diphenylselenide (36) were shown to inhibit lipid peroxidati on in ADP/Fe2+/ascorbate-treated microsomes and tert-butylhydroperoxid e-treated hepatocytes with IC50s of 3 and 10 muM, and 14 and 10 muM, r espectively. In the former system. these inhibition constants compare favourably with those of Ebselen and classical antioxidants such as bu tylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA). In th e cell system, these selenium compounds were equipotent with BHA but m ore potent than Ebselen and its analogues. The diamino compound (10) w as also an effective inhibitor of lipid peroxidation initiated by diqu at redox cycling in hepatocytes, again being equipotent with BHA but m ore potent than Ebselen and its analogues. which actually stimulated l ipid peroxidation in this test system. Manipulation of the amino funct ions of (10) and (36) by alkylation or acylation altered the antioxida nt capacity. Optimal activity in this series was achieved by N-ethylat ion or N-isobutylation of (10). This produced antioxidants having IC50 s below 1 muM in the microsome system, 3-13 muM in the tert-butylhydro peroxide system, and being 100% effective in the diquat model at 50 mu M. On the other hand, acylation or alkylation of the amino groups with long chain acyl or alkyl groups reduced the efficacy of the structure s below that of the parent diamine. As with other antioxidant compound s, several of the chalcogenides were relatively selective inhibitors o f monocyte 5'-lipoxygenase-dependent secretion of LTB4 as compared to their effect on cyclooxygenase-dependent secretion of PGE2 (for exampl e compound 42 had IC50s of 0.6 muM and 10 muM, respectively). No corre lation was observed between the redox-properties of the chalcogenides and their respective abilities to inhibit these enzymes.