Study of alpha-Gal epitope anti-alpha-Gal antibody binding using deoxy derivatives of alpha-Gal and the synthesis of biologically relevant molecules

The dissertation describes my Ph.D. work which focused on the synthesis of deoxy derivatives of α-Gal epitopes, the biological evaluation of these derivatives using anti-α-Gal antibodies, the synthesis of unnatural derivatives of tryptophan, the synthesis of isoform selective substrates of nitric oxide synthase, and the chemo-enzymatic synthesis of polyhydroxyazepanes.; α-Gal epitopes are carbohydrate structures bearing a Galα1→3Gal terminus. The interaction of these epitopes on the surface of animal cells with anti-α-Gal antibodies in human serum is believed to be the main cause of antibody-mediated hyperacute rejection in xenotransplantation. Four terminal deoxy trisaccharide derivatives of α-Gal epitope were designed and efficiently synthesized. Biological evaluation determined that derivation at the terminal C-4 position proved to significantly reduce recognition by the anti-α-Gal antibody. In contrast, derivation at the C-6 position did not appear to affect anti-α-Gal antibody recognition.; Indole and indole derivatives, such as tryptophan, are abundantly found in a variety of naturally occurring compounds that exhibit various physiological properties. Indolyl derivatives are key compounds that have been used as both pharmacological agents and as fundamental building blocks in larger alkaloid syntheses. A facile procedure is reported using ytterbium triflate to catalyze the formation of several 3-aminoalkylindoles. In a one-pot fashion these compounds were synthesized. Subsequent enzymatic resolution was conducted to obtain enantiomerically enriched derivatives.; Nitric oxide (NO) plays an important role in numerous physiological and pathological processes. Enzymatic generation of NO by nitric oxide synthase converts L-arginine to, a key intermediate, followed by a second step that converts N-hydroxy-L-arginine to NO and L-citrulline. To fully probe the substrate specificity of the second enzymatic step, an extensive structural screening was carried out using a series of N-alkyl- N′-hydroxyguanidines. A series of derivatives were synthesized and evaluated using nitric oxide synthase.; Polyhydroxyazepanes and related compounds have attracted considerable attention as a result of their potent inhibition of glycoprotein and glycolipid processing enzymes. A facile chemo-enzymatic approach was used to synthesize a variety of 7 membered polyhydroxyazepanes that incorporates inexpensive starting materials, employs only a few short steps, and negates the use of protecting and deprotecting schemes.