Ajayi, Kehinde. The total synthesis of mycothiol and new inhibitors of carbohydrate processing enzymes. Retrieved from https://doi.org/doi:10.7282/T3QV3MMW
DescriptionThe work described in this dissertation covers a wide range of disciplines within organic chemistry, with the common goal of obtaining more information about various carbohydrate-processing enzymes. Carbohydrate-processing enzymes are garnering an increasing amount of attention relative to their more well-studied protein-processing counterparts, as they are ubiquitous and implicated in various regulatory, signaling and metabolic processes in eukaryotic cells. Chapter 1 involves the synthesis of anomeric phosphothioates as possible O-GlcNAc transferase inhibitors, and a mechanistic study on the anomeric Pudovik rearrangement of thiophosphites to thiophosphonates is described. Chapter 2 is an account of the development of a facile method for functionalizing 2-methyl thiazoline rings, and several selective GlcNAc-thiazoline-based O-GlcNAcase inhibitors were synthesized by this method. Chapter 3 details the 16-step total synthesis of the M. tuberculosis antioxidant carbohydrate mycothiol by a new intramolecular glycosylation method. The method is amenable to glycosylations of 2-deoxy-2-aminoglyosides, a unique aspect among such reactions. The efficiency of the synthetic route to mycothiol makes it attractive as a template from which to design analogs as potential inhibitors of enzymes involved in the biosynthesis of mycothiol. An apparently unprecedented 1,9-hydride shift is also described in the third chapter. Chapter 4 describes a tripartate prolonged-release drug delivery system, in which the drug of interest (ethynyl estradiol in this study) is coupled, through a variable linker, to another carrier drug with a long half-life and a relatively high inhibitory concentration. The effect of steric bulk on the in vitro release of ethynyl estradiol was evaluated, showing a direct relationship between steric bulk around the ester linkage and ethynyl estradiol release time. In vivo data from pigs also seemed to point to an increase in drug bioavailability with the 3-part system. Finally, chapter 5 describes early efforts to synthesize boronic acid analogs of folic acid and antifolates.