Copper(II) interaction with 3,5-Diisopropylsalycilic acid (DIPS), a non-steroidal antiinflammatory agent as a potential .OH inactivating ligand (OIL)
Résumé
Like iron, copper can trigger Fenton-type reactions which produce in vivo .OH radicals responsible of inflammation. However, it is known that copper(II) is used in the treatment of antiinflammatory diseases [1]. Indeed, the paradox that copper can play both anti-inflammatory and pro-oxidant role is not only apparent. Its pro-oxidant action in Fenton chemistry may result in anti-inflammatory effect if a ligand bound to the Cu2+ ions is involved in the Haber-Weiss reaction, which corresponds to the definition of an .OH inactivating ligand (OIL) [2]. In this kind of action, to be active, a potential OIL must firstly mobilise copper at the inflamed site. Presently, several hundred copper complexes have been proposed as potential antiinflammatory agents. The results of these studies have been reviewed [1, 3], and confirm that many complexing agents, which are pharmacologically inactive by themselves, display antiinflammatory properties in association with copper(II) [1], such as anthranilic acid [4] and its derivatives [5] Among inactive substances activated by copper(II), 3,5-diisopropylsalicylic acid (Dips) has attracted great interest because of its radioprotectant, antiinflammatory, anticancer, antimutagenic, antidiabetic, analgesic, antineoplastic and anticonvulsant activities. The purpose of this study was to identify the low-molar-mass complexes formed between copper(II) and Dips in physiological conditions. Copper(II)-Dips complex equilibria have been determined using glass electrode potentiometry and their solution structures have been checked by UV-vis spectrophotometry. Because of the low solubility of Dips in aqueous solution, the investigation of the equilibria was done in different water/ethanol mixtures. Formation constantshave been determined extrapolating these values at 100% water and then compared with the values obtained for the other anti-inflammatory drugs previously studied. Given the prime role of histidine as copper(II) ligand in blood plasma, copper(II)-histidine-Dips ternary equilibria have also been studied in such similar experimental conditions. Computer simulations of copper(II) distribution relative to different biofluids, gastrointestinal fluid (g.i), blood plasma and synovial fluid have been run and the results will be discussed on the presentation. [1] J. R.J. Sorenson in: G. Berthon (Ed.), Handbook of Metal-Ligand Interactions in Biological Fluids; Bioinorganic Medicine, vol. 2, Marcel Dekker, New York, 1995, pp. 1318. [2] G. Berthon, Agents Actions 39 (1993) 210. [3] J. E. Weder, C. T. Dillon, T. V. Hambley, B. J. Kennedy, P. A. Lay, J. R. Biffin, H. L. Regtop, N. M. Davies, Coord. Chem. Rev., 232 (2002) 95. [4] H. Miche, V. Brumas and G. Berthon, J. Inorg. Biochem,. 68 (1997) 27. [5] B.Halova-Lajoie, V. Brumas, M. Fiallo and G. Berthon, J. Inorg. Biochem., 100 (2006) 362.