O-alkylation of cupferron: Aiming at the design and synthesis of controlled nitric oxide releasing agents

O-Alkylation of N-nitroso-N-phenylhydroxylamine ammonium salt (cupferron) w as studied for the synthesis of novel nitric oxide (NO) releasing agents. T he alkylation occurred regioselectively at the terminal oxygen, leading to a single product N-(alkyloxy)-N'-phenyldiimide N'-oxide as indicated by NMR and X-ray analysis. The O-alkyl derivatives exhibited significantly improv ed stability compared to their parent compound, cupferron. It was demonstra ted that the cupferron O-alkyl derivatives could function as photoreleasing NO donor compounds. N-(N"-acetylphenylalanylmethylenyloxy)-N'-phenyldiimid e N'-oxide), which linked the cupferron portion with an amino acid via an a cetal moiety, was synthesized as an model NO prodrug where controlled NO re lease would occur either by increasing pH or by a protease-catalyzed hydrol ysis.