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 peroxidation in ADP/Fe2+/ascorbate-treated microsomes and tert-butylhydroperoxide-treated hepatocytes with IC50s of 3 and 10 microM, and 14 and 10 microM, 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 IC50s below 1 microM in the microsome system, 3-13 microM in the tert-butylhydroperoxide system, and being 100% effective in the diquat model at 50 microM. 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 secretion of LTB4 as compared to their effect on cyclooxygenase-dependent secretion of PGE2 (for example compound 42 had IC50s of 0.6 microM and 10 microM, respectively). No correlation was observed between the redox-properties of the chalcogenides and their respective abilities to inhibit these enzymes.
Andersson
C M
CM
Department of Medicinal Chemistry, Astra Draco AB, Lund, Sweden.
Hallberg
A
A
Linden
M
M
Brattsand
R
R
Moldéus
P
P
Cotgreave
I
I
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants; D001205:Ascorbic Acid / Q000494:pharmacology; D002478:Cells, Cultured; D005296:Ferrous Compounds / Q000494:pharmacology; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010545:Peroxides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018036:Selenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D020122:tert-Butylhydroperoxide
D000975:Antioxidants; D005296:Ferrous Compounds; D010545:Peroxides; D018036:Selenium Compounds; D017392:Thiobarbituric Acid Reactive Substances; D000244:Adenosine Diphosphate; D020122:tert-Butylhydroperoxide; D001205:Ascorbic Acid