The antioxidant effect of the mesoionic compound SYD-1 in mitochondria

The sydnone SYD-1 (3-[4-chloro-3-nitrophenyl]-1,2,3-oxadiazolium-5-olate] possesses important antitumor activity against Sarcoma 180 and Ehrlich tumors. We previously showed that SYD-1 depresses mitochondrial phosphorylation efficiency, which could be involved in its antitumoral activity. Considering the important role of mitochondria in the generation of reactive oxygen species (ROS) and the involvement of ROS in cell death mechanisms, we evaluated the effects of SYD-1 on oxidative stress parameters in rat liver mitochondria. SYD-1 (0.5 and 0.75 μmol mg⁻¹ protein) inhibited the lipoperoxidation induced by Fe³⁺/ADP-oxoglutarate by approximately 75% and promoted total inhibition at the highest concentration tested (1.0 μmol mg⁻¹ protein). However, SYD-1 did not affect lipoperoxidation started by peroxyl radicals generated by α-α′-azodiisobutyramidine dihydrochloride. The mesoionic compound (0.25–1.0 μmol mg⁻¹ protein) demonstrated an ability to scavenge superoxide radicals, decreasing their levels by 9–19%. The activities of catalase and superoxide dismutase did not change in the presence of SYD-1 (0.25–1.0 μmol mg⁻¹ protein). SYD-1 inhibited mitochondrial swelling dependent on the formation/opening of the permeability transition pore induced by Ca²⁺/phosphate by approximately 30% (1.0 μmol mg⁻¹ protein). When Ca²⁺/H₂O₂ were used as inducers, SYD-1 inhibited swelling only by approximately 12% at the same concentration. NADPH oxidation was also inhibited by SYD-1 (1.0 μmol mg⁻¹ of protein) by approximately 48%. These results show that SYD-1 is able to prevent oxidative stress in isolated mitochondria and suggest that the antitumoral activity of SYD-1 is not mediated by the increasing generation of ROS.