The design, synthesis and use of N-nitrosoaniline compounds as nitric oxide-transferring agents

Date of Award




Degree Name

Doctor of Philosophy (Ph.D.)



First Committee Member

Peng George Wang - Committee Chair


The development of new substances and approaches to the generation of nitric oxide (NO) is important since NO is a crucial biological regulator of blood pressure, neurotransmission and the eradication of tumor cells. While NO is produced endogenously from arginine catalyzed by nitric oxide synthase (NOS), synthesis of stable, non-toxic derivatives which can generate controlled amounts of NO at specific locations and by specific activation mechanisms will prove important for biomedical and pharmaceutical applications.Through our studies of the naturally occurring protein tyrosine phosphatase (PTPase) inhibitor, dephostatin, and its derivatives, we found that the mechanism of inhibition was due to the nitrosation of the cysteine at the active site. As a result, an array of dephostatin derivatives have been synthesized as protein S-nitrosating agents, which function as pseudo irreversible inhibitors for cysteine dependent enzymes.Caspase is another class of cysteine dependent enzymes which can be inhibited by NO. These enzymes are involved in apoptosis (programmed cell death) and inhibition can improve such conditions as neurodegenerative diseases and ichemic damage. Such disorders are caused by excessive apoptosis. Caspase specific inhibitors have been designed, synthesized and assayed.Another set of compounds studied were developed to generate NO under redox sensitive conditions. This class of compounds, which are para substituted N-nitroso-N-oxybenzenamine ammonium salts, generate NO as a function of applied redox potential. Electrochemical or enzymatic oxidation of these compounds yield nitric oxide and the corresponding nitrosobenzene. NO release was found to be dependent on the substituent's properties and the applied potential. Based on the substituent, a profound effect on stability, oxidation potential and enzymatic kinetics was noted. This series of NO releasing agents comprise the first electrochemical-NO-generating system.


Chemistry, Biochemistry; Chemistry, Organic; Chemistry, Physical

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