Download synthesis of cariporide derviatives for sodium

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.