Date of Award
Doctor of Philosophy (PhD)
SO2 is widely recognized as an air pollutant and is a known cause of acid rain. At a sufficiently high level, it also causes respiratory diseases. There is mounting evidence that SO2 is produced during normal cellular metabolism and may possibly function as a signaling molecule in normal physiology. One difficulty in studying the biological and pharmacological roles of SO2 is the lack of adequate tools for its controllable and precise delivery. Traditional methods of using SO2 gas or mixed sulfite salts do not meet research need for several reasons. Therefore, there has been increasing attention on the need of developing SO2 donors or prodrugs that can be used as tools for the elucidation of SO2’s physiological roles, pharmacological effects, and possiblemechanism(s) of action. In the first chapter, we provided two strategies to deliver SO2 in its molecule form to allow SO2 release with tunable release rate. Such SO2 donors and prodrugs would serve as useful tools for researchers to probe the mystery of SO2 as a gasotransmitter.
A decreased level of thiamine-dependent enzyme pyruvate dehydrogenase (PDH) is an important characteristic of cancer cells. Pyruvate dehydrogenase kinase (PDK) inhibits the activity of PDH which helps cancer cells to gain more energy by converting glucose into lactate. Therefore, inhibiting the activity of PDK can be a promising approach for cancer therapy. Thiamine at a high concentration was found to have inhibitory effect on cancer cell proliferation as a PDK inhibitor. From previous studies, a series of thiamine analogues were designed, synthesized, and tested in vitro for anti-proliferative effect. However, all the analogues demonstrate low inhibitory effect on cancer cell proliferation. We hypothesize that the low inhibitory activity may be due to a lack of phosphorylation inside the cell. A phosphate prodrug strategy that can release thiamine monophosphate mimetics inside the cell may overcome this problem. In the second chapter, we describe the design, synthesis, and preliminary biological evaluation of several prodrugs of thiamine monophosphate mimics. Cancer cell proliferation tests suggest significantly increased inhibitory effect of the phosphate prodrugs compared with respective thiamine analogues without the phosphate prodrug moiety.
Wang, Wenyi, "Design and Development of Prodrugs of Sulfur Dioxide and Design and Synthesis of Prodrugs of Thiamine Monophosphate Mimics as Pyruvate Dehydrogenase Kinase Inhibitors." Dissertation, Georgia State University, 2018.