ABSTRACT Cancer is the second leading cause of death in the United States. Breast cancer is common among women, and triple negative breast cancer accounts 10-20% of all breast cancer patients. Cancer has seemingly unlimited proliferative capacity and can spread easily to other parts of the body, making it difficult to treat. Cancer cells meet their high- energy requirement by changing their metabolic pathway in a process called “Warburg effect” via increased glycolysis independent of the presence or absence of oxygen. The increased glycolysis, which fuels hypoxic cancer cells for their high-energy demand, produces lactate. Transport of lactate and pyruvate through the plasma membrane is mediated by a group of integral membrane transport proteins, which are called monocarboxylate transporters (MCTs). Inhibition of MCT results in the starvation of tumor cells and, eventually, leads to their death. Therefore targeting MCTs could be an effective way to reduce aggressive spread of cancer in the body. In this thesis, a library of indole based small molecules have been synthesized and characterized. Furthermore their MCT1 inhibition has been evaluated in RBE4 cell line. It was found that most of the indole cyanoacrylic acids exhibited good MCT1 inhibition while compounds 1, 11-13 didn’t show any activity. Based on their good MCT1 inhibition, compounds 9 and 10 were selected as the lead candidate compounds. Future studies will include the evaluation of the lead candidates for their systemic toxicity, and in vivo anticancer efficacy in tumor xenograft models.
University of Minnesota M.S. thesis. December 2016. Major: Chemistry. Advisors: Joseph Johnson, Venkatram Mereddy. 1 computer file (PDF); vii, 106 pages.
Synthesis and Evaluation of Indole Cyanoacrylic Acids as Anticancer Agents.
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