Electronegativity of aromatic amines as a basis for the development of ground state inhibitors of lysyl oxidase

Benzylamine derivatives containing para substituents of differing electronegativity as well as isomers of aminomethylpyridine have been assessed for their substrate and inhibitor potentials toward lysyl oxidase. Substituted benzylamines with increasingly electronegative para substituents had the lowest KI values and thus were the most effective inhibitors of the oxidation of elastin by lysyl oxidase. The kcat values for these compounds as substrates of lysyl oxidase were also reduced with increasingly electronegative para substituents. Both the Dkcat and D(kcat/Km) kinetic isotope effects decreased with increasingly electronegative p-substituents in alpha, alpha'-2H]benzylamines. In contrast, there was no Dkcat solvent isotope effect with 2H] H2O while the D(kcat/Km) solvent isotope effect tended to increase with increasingly electronegative p-substituents. These results are consistent with the stabilization of an enzyme-generated substrate carbanion and thus the retardation of substrate oxidation by electronegative substituents. Such ground state stabilization thus can result in compounds with increased potential for the inhibition of the oxidation of protein substrates of lysyl oxidase.