Synthesis of N-substituted N-nitrosohydroxylamines as inhibitors of mushroom tyrosinase

A series of N-substituted N-nitrosohydroxylamines including six new compoun ds were synthesized and examined for inhibition of mushroom tyrosinase. Cor responding hydroxylamines were reacted with n-butyl nitrite to give substit uted nitrosohydroxylamines as their ammonium salt. The N-substituted hydrox ylamines were prepared from the primary amines via the oxaziridine, or from the carbonyl compounds via the oxime. Most of the nitrosohydroxylamines te sted inhibited mushroom tyrosinase. Among them, N-cyclopentyl-N-nitrosohydr oxylamine exhibited the most potent activity (IC50 = 0.6 muM), as powerful as that of tropolone, one of the most powerful inhibitors. As removal of ni troso or hydroxyl moiety, the enzyme inhibitory activity was completely dim inished. Both N-nitroso group and N-hydroxy group were suggested to be esse ntial for the activity, probably by interacting with the copper ion at the active site of the enzyme. Lineweaver-Burk plotting showed that cupferron w as a competitive inhibitor but that N-cyclopentyl-N-nitrosohydroxylamine wa s not. (C) 2001 Elsevier Science Ltd. All rights reserved.