The antioxidant properties of Bucillamine (BUC), a di-thiol compound used for treatment of rheumatoid arthritis (RA) and its possible mode of action, were investigated. BUC exhibits potent antioxidant activity similar to those of trolox and ascorbic acid. It reduces the stable free radical diphenyl-2-picrylhydrazyl (DPPH) with IC50 of 18.5 +/- 0.1 mu mol, its relative antioxidant activity by the ferric reducing ability (FRAP) is 2.07 +/- 0.01 mM and by the trolox equivalent antioxidant capacity (TEAC), 1.46 +/- 0.05 mM. However, its superoxide and apparent hydroxyl radical scavenging activities are low (IC50 at millimolar concentrations). We found that BUC is a strong iron (11) and copper (11) chelator. This finding is very important since these metal ions are significantly higher in RA patients and may be involved in oxidative stress-induced damage. Our study suggests that BUC is a potent antioxidant which exerts its beneficial therapeutic activities in RA patients by metal chelation rather than by scavenging free radical species. (c) 2006 Elsevier Inc. All rights reserved.