Structure of Cu2(indomethacin)4 and the reaction with superoxide in aprotic systems

Abstract

The copper complex of indomethacin (1-(p-chlorobenzoyl)-5-methoxy-2-methyl-indole acetate), a common anti-inflammatory drug, was prepared and characterized. Crystal structure determination revealed the dimeric form of the 1 : 2 complex, namely Cu2(indomethacin)4 x L2, in the unit cell. Surprisingly, the copper-copper distance (263 pm) was very close to metallic copper (256 pm). The two coordination sites in the copper-copper axis can be readily replaced by superoxide. An intriguing similarity to Cu2(acetate)4 was seen. Due to the lipophilic nature of the indomethacin ligand, this copper complex reacted with superoxide in aprotic solvents. the superoxide dismutating activity was successfully demonstrated in Me2SO/water and acetonitrile/water mixtures using the nitro-blue tetrazolium assay and pulse radiolysis. The second-order rate constant of 6 x 10(9) M-1 x s-1 in strictly aqueous systems dropped only slightly to 1.1 x 10(9) M-1 x s-1 when aprotic solvents were used. This is the fastest rate constant ever observed for a copper-dependent dismutation of superoxide. The KO2-induced lipid peroxidation in both erythrocytes and liver microsomes was suppressed by 70% in the presence of 1 x 10(-10) mol x ml-1 of Cu2(indomethacin)4. The inhibitory action dropped to 25% when Cu2Zn2superoxide dismutase was employed. The formation of copper x indomethacin in rat serum after administration of indomethacin was shown in vitro and vivo.