S-ARYL-L-CYSTEINE S,S-DIOXIDES - DESIGN, SYNTHESIS, AND EVALUATION OF A NEW CLASS OF INHIBITORS OF KYNURENINASE

The design, preparation, and evaluation of S-aryl-L-cysteine S,S-dioxides, a new class of potent competitive inhibitors of kynureninase from Pseudomonas fluorescens, are described. The most potent of these compounds, S-(2-aminophenyl)-L-cysteine S,S-dioxide, has a K(i) value of 70 nM. These analogues form prominent visible absorption peaks at 500 nm, assigned to quinonoid intermediates, when bound to kynureninase. Titration of kynureninase with S-(2-aminophenyl)-L-cysteine S,S-dioxide demonstrates that 1 mol of the inhibitor is bound to the pyridoxal 5'-phosphate in each subunit. Comparative molecular field analysis of the effects of structural variation on inhibitory potency allows us to predict that the (S)-gem-diolate anion of L-kynurenine, a proposed reaction intermediate, binds with a K(D) of 19 nM. These results provide strong additional support for the intermediacy of a gem-diol or gem-diolate anion in the reaction mechanism of kynureninase.