Novel alpha cyanocinnamate derivatives as monocarboxylate transporter-1 inhibitors.

Abstract

Ryan J. Connell, Novel α-Cyanocinnamate Derivatives as Monocarboxylate Transporter-1 Inhibitors, Master of Science (Department of Chemistry and Biochemistry), University of Minnesota. Tumors contain aerobic and hypoxic regions and hypoxia is associated with an elevated risk of local advancement and metastasis. Hypoxic tumor cells in general, are resistant to chemotherapy and radiation, leading to treatment failure and patient mortality. Cancer cells under hypoxic conditions convert glucose to lactate and aerobic cancer cells consume the lactate for oxidative phosphorylation. This way, the limited glucose available to the tumor is used most efficiently and this existence of a “metabolic symbiosis” between hypoxic and aerobic cancer cells is crucial for their propagation. The key molecular component in this symbiotic relationship is the monocarboxylate transporter-1 (MCT1). MCT1 is an integral membrane protein that transports lactate into cancer cells. Cellular expression of MCT1 protein has been detected exclusively in nonhypoxic regions of human cancers. When MCT1 is inhibited, this metabolic symbiosis is disrupted and aerobic cancer cells consume large amounts of glucose rather than lactate leading to the death of hypoxic cancer cells due to glucose deprivation. The purpose of this project involves design, synthesis and validation of novel α-cyanocinnamate derivatives as MCT-1 inhibitors. We utilized Knoevenagel type condensation of aldehydes with cyanocinnamic acid to synthesize several CHC analogs. These analogs have been evaluated using a cell culture based assay of MCT1 transport function and identified potential lead molecules for further optimization and development. The potential outcome of this project will be a new class of anti-cancer agents with higher affinity and specificity than previously available.