Synthesis of N-substituted N-nitrosohydroxylamines as inhibitors of mushroom tyrosinase.
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 microM), 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.
Shiino
M
M
Laboratory of Chemistry, School of Medicine, Keio University, 4-1-1 Hiyoshi, Kohoku-ku, Yokohama 223-0061, Japan. mitsuhir@hc.cc.keio.ac.jp
Watanabe
Y
Y
Umezawa
K
K
D000363:Agaricales / Q000201:enzymology*; D000577:Amides / Q000737:chemistry / Q000378:metabolism; D006898:Hydroxylamines / Q000138:chemical synthesis* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009603:Nitroso Compounds / Q000138:chemical synthesis* / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis* / Q000378:metabolism*
D000577:Amides; D006898:Hydroxylamines; D009603:Nitroso Compounds; D010455:Peptides; C002574:dopastin