Therapeutically active Cu(II), Zn(II) and Fe(III) complexes with N-phenylanthranilic acid derivatives and their effect on redox reactions modeling inflammation

Abstract The amount of copper(II), zinc(II) and iron(III) involved in the majority of metalloferments during different diseases of inflammatory nature varies more than that of other metals. The possibility of bonding the metal involved in ferments by drugs of acidic nature has been established by studying the interaction between ceruloplasmin (CP) and N-phenylanthranilic acid derivatives (HL), antiinflammatory agents. The reaction CP +HL ⇄ K eq apoCP + CuL 2 yields low-molecular complexes, CuL 2 , as shown by the correlation between the equilibrium constants for the reaction, K eq , and the stability constants of Cu(II) complexes, CuL 2 . The latter are active metabolites of acids, i.e. , drugs. Comparison of the therapeutic activities of HL and their Cu(II), Fe(III) or Zn(II) complexes has shown that the therapeutic properties inherent in drugs are improved in the complexes; the toxicity decreases, the action of agents is prolonged, and antiulcerogenic, cytotoxic and other effects, unusual to drugs, appear. These complexes were found to affect the model reactions accompanying an inflammation at the molecular level: i.e. , the oxidation of ascorbic acid, biogenic amines and free radicals. The Cu(II) and Fe(III) complexes catalyze the oxidation of: a) ascorbic acid, b) p -aminophenol, the analog of serotonin, a biogenic amine. The Cu(II), Fe(III) and Zn(II) complexes interact with a free radical, triphenylverdazyl (RN • ) to yield a non-radical cation (RN + ). The rate of reactions (a) and (b) proceeding via the steps of alternate oxidation-reduction of the catalyst are the highest for coordinatively unsaturated complexes. For the Cu(II) complex the reaction rate exceeds that for CP and is lower for the Fe(III) complexes than for the Cu(II) ones. The Fe(III) complexes, under otherwise equal conditions, were shown to be more apt to form polynuclear species with a lower oxidation potential compared with the Cu(II) complexes. The Cu(II) and Fe(III) complexes oxidize the RN • to yield RN + after dissociation to solvated metal ions via the scheme: M n+ + RN • → M (n−1)+ + RN + (1) which is confirmed by the inverse relationship between the RN + concentration and stability constants of the complexes and also by the absence of the radical–complex interaction when the dissociation of the complex is suppressed. The Fe(III) complex oxidizes the RN • to a lower extent than the Cu(II) one due to its higher stability. The Zn(II) complex causes the disproportionation of RN • by reaction (2) involving the formation of an intermediate metal complex. The bridge metal ion in this complex facilitates the electron transfer from one RN • to another: This process is followed by the RN + escape from the inner coordination sphere of the intermediate complex to yield the products: RN + and M(RN − ). According to (1) [RN + ] = [RN • ] o − [RN • and (2) [RN + ] = 1 2 ([RN • ] o − [RN • ]) which was actually observed. The above data indicate that the therapeutic activity of the complexes under the study depends not only on their ability to act as low-molecular metabolites, active therapeutic species, but also on their ability to dissociate to the ionic species responsible for some catalytic and other effects.