Synthesis of N-substituted N-nitrosohydroxylamines as inhibitors of Mushroom Tyrosinase

Abstract A series of N -substituted N -nitrosohydroxylamines including six new compounds were synthesized and examined for inhibition of mushroom tyrosinase. Corresponding hydroxylamines were reacted with n -butyl nitrite to give substituted nitrosohydroxylamines as their ammonium salt. The N -substituted hydroxylamines were prepared from the primary amines via the oxaziridine, or from the carbonyl compounds via the oxime. Most of the nitrosohydroxylamines tested inhibited mushroom tyrosinase. Among them, N -cyclopentyl- N -nitrosohydroxylamine exhibited the most potent activity (IC 50 =0.6 μM), as powerful as that of tropolone, one of the most powerful inhibitors. As removal of nitroso or hydroxyl moiety, the enzyme inhibitory activity was completely diminished. Both N -nitroso group and N -hydroxy group were suggested to be essential for the activity, probably by interacting with the copper ion at the active site of the enzyme. Lineweaver–Burk plotting showed that cupferron was a competitive inhibitor but that N -cyclopentyl- N -nitrosohydroxylamine was not.