Nitric oxide donors and superoxide probes: Synthesis and properties

This dissertation describes my Ph.D. work that focused on the synthesis and properties of “cyclic-SNO” as novel nitric oxide donors, the trityl derivatives as superoxide probes, and sugar nitric oxide donor conjugates as prodrugs.

In chapter 1, a new synthetic approach to cyclic-RSNO was established, and four such derivatives were synthesized. These compounds have strong vasodilatation effects making them potential novel NO donors. A kinetic mechanism to explain the NO-releasing property was proposed, and this hypothesis was well supported by the computational studies, EPR spectra and MS analyses. It should be addressed that the NO-releasing rate of these compounds was found to be 1^st order and dependent on [H⁺].

In chapter 2, three new radical molecular probes were synthesized and characterized. They can specifically detect superoxide radicals by changes in intensity of the fluorescence spectrum or by EPR signals.

In chapter 3, a new class of fluorescence tagged glycosides (indolizine-3-yl-glycosides) were synthesized. The enzymatic glycosidation of these substrates caused the disappearance of fluorescence. These glycosides are novel probes in studying glycosidase.

In chapter 4, a new sialated diazeniumdiolate was synthesized as a prodrug of self-stable diazeniumdiolate NO donor. The self-stable prodrug could be triggered to release NO upon treatment of neuraminidase. Such a design provided a novel approach to selectively release NO where neuraminidase activity exists (e.g. influenza viruses).

In chapter 5, a new class of NO donor prodrugs were developed which had sugar and a 3-morphorlinosydnonimine (SIN-1) moieties. These prodrugs could release NO in the presence of glycosidases. Such NO prodrugs may be used as enzyme-activated NO donors in biomedical research.

In chapter 6, a new class of 9-phenyl-9H-fluorene-derivative radicals were synthesized and characterized by EPR to develop novel radical probes for high-sensitive measurement and imaging of oxygen and superoxide in biological systems using EPR. However, this class of novel radicals turned out to be unstable in the presence of oxygen and further structural modification will be needed.