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SYNTHESIS OF CARIPORIDE DERIVATIVES FOR SODIUM-PROTON EXCHANGE INHIBITION Jacob Vervynckt Western Kentucky University, Department of Chemistry, 1906 College Heights Boulevard, Bowling Green, KY 42101 Each year, more than 200,000 people in the United States are diagnosed with malignant brain tumors, the most prevalent and deadly type of adult brain cancer. The life expectancy of these individuals is approximately 9-12 months from the time of diagnosis. Current therapeutic methods (i.e., chemotherapy and radiotherapy) prove ineffective at treating this type of cancer due to the inability to target cancer cells selectively in the brain. Recent research has shown that brain cancer cells (e.g., gliomas) are heavily dependent on the sodium-proton exchanger (NHE) and sodium-calcium exchanger (NCX). These two important ion transport systems allow cells to maintain intracellular pH and regulate cell volume. Gliomas are more dependent on NHE/NCX due to their increased metabolic activity. By inhibiting the function of these transport proteins, the intricate pH and ion balances within cancer cells can be disrupted to a much greater extent than in normal cells, leading to selective cancer cell death. Meanwhile, healthy brain cells are not affected by this approach due to their minimal usage of the NHE/NCX. Thus, NHE/NCX inhibition allow for selective targeting of brain cancer cells. Currently, various NHE/NCX inhibitors are known; the challenge that still remains in using these compounds as a treatment is finding a way to effectively deliver them to poorly vascularized tissues (i.e., the necrotic center of a brain tumor). As part of our target-specific approach to treating brain cancer, we have synthesized analogs of cariporide, a potent (e.g., nanomolar IC50 activity) NHE inhibitor, to address these delivery challenges. The preparation and biological activities of our cariporide analogs will be discussed.