Kerwin, Sean M.Taylor, Brandie C.2019-04-292019-04-292019-05Taylor, B. C. (2019). <i>Glucuronide prodrug of a naturally derived cytotoxic product</i> (Unpublished thesis). Texas State University, San Marcos, Texas.https://hdl.handle.net/10877/7991African Potato (Hypoxis hemerocallidea) is utilized as a medicinal plant in South Africa to treat disorders such as cancer, prostate hyperplasia, and cardiac disease. The corm of H. hemerocallidea contains high levels of the bis-glycoside hypoxoside, which undergoes hydrolysis in the gut to produce the aglycone, rooperol. In vitro studies indicate rooperol is active against cancer cells, while human studies report rooperol is mostly metabolized to inactive phase II metabolites. It is important to note that a minor amount of the active compound bis-β-glucuronide is also generated during the metabolic process. Despite these findings, a phase I study of orally-administered hypoxoside in advanced lung cancer patients demonstrated significant tumor arrest and even complete remission. Because tumor tissues can have high levels of extracellular β-glucuronidase activity, we hypothesize that the clinical activity of hypoxoside is due to the hydrolysis of the rooperol bis-glucuronide to rooperol by β-glucuronidase present in tumor tissue. The goal of this project is to chemically synthesize the bis-glucuronide of rooperol to study its use as a tumor-targeting prodrug. We have prepared a model 3,4- dihydroxy-substituted cinnamyl alcohol for use in the investigation of methods for the selective protection of the catechol and regioselective installation of a protected β- glucuronate group. Once conditions in the model system are established, we will apply this strategy to rooperol followed by global deprotection to generate rooperol bis- glucuronide. The final bis-β-glucuronide will be compared to the bis-β-glucuronate of rooperol generated from in vitro metabolism studies.Text59 pages1 file (.pdf)enSynthetic chemistryOrganic chemistryGlucuronideCancer--Treatment--ResearchChemistry, OrganicHpoxidaceaeThesis