Copper(II) interactions with non-steroidal anti-inflammatory agents. III – 3-Methoxyanthranilic acid as a potential [rad]OH-inactivating ligand: A quantitative investigation of its copper handling role in vivo

Abstract

Pharmacological activities of copper(II) complexes are a direct function of the nature of their ligands associated with the metal ion in vivo. Some of these, defined as OH-inactivating ligands (G. Berthon, Agents Actions 39 (1993) 210–217), may act as specific “lures” for hydroxyl radicals at inflammatory sites and behave as pseudo-catalase-like agents. This property has been advanced for anthranilic acid (H. Miche, V. Brumas, G. Berthon, J. Inorg. Biochem. 68 (1997) 27–38). With a view to improve the chemical features required to render such inactive substances effective anti-inflammatory drugs through their association with copper(II), an in vitro investigation into copper(II) interactions with the anionic form of an anthranilic acid derivative, namely 3-methoxyanthranilate (Man), has been performed under experimental conditions pertaining in vivo. Copper(II)–Man complex equilibria have been determined using glass electrode potentiometry, then checked by UV–vis and mass spectrometries. Given the prime role of histidine as a copper(II) ligand in blood plasma, copper(II)–histidine–Man ternary equilibria have also been studied. Subsequent computer simulations of the distribution of copper(II) in the extracellular fluid revealed that Man can specifically mobilize Cu(II) ions under inflammatory conditions without affecting their distribution under normal physiological conditions. Thiobarbituric acid reactive substances (TBARS) tests conducted with respect to standardized copper-mediated Fenton-type reactions (P. Maestre, L. Lambs, J.P. Thouvenot, G. Berthon, Free Rad. Res. 20 (1994) 205–218) have shown that, like anthranilic acid, Man can effectively both increase the Fenton-like reactivity of copper and decrease the amount of TBARS detected in solution, i.e., act as a potential OH-inactivating ligand.