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Breast cancer is the most diagnosed form of cancer in women in the United States. It is estimated that on average, every two minutes a woman is diagnosed with breast cancer; and one woman will die of the disease every thirteen minutes. Many anti-cancer drugs used to clinically treat breast cancer mediate tumor cell death through the initiation of apoptosis. Multidrug-resistance is a major cause of cancer chemotherapy failure in clinical treatment. As a result, molecular pathways involved in tumor cell proliferation, including the ceramide signaling pathway, have become potential targets for pharmacological intervention. Ceramides have been shown to potentiate signaling events that drive apoptosis, autophagic responses, and cell cycle arrest. Ceramide analogs can be designed to inhibit ceramide-metabolizing enzymes in order to increase intra-cellular ceramide levels in cancer cells, leading to increased cell death. Our approach is to design and synthesize such ceramide analogs. Some of our synthesized analogs have been shown to have greater efficacy and specificity than endogenous ceramides. Evidence shows that multidrug-resistant cancer cells are as sensitive as corresponding regular cancer cells under the exposure to some of our anti-cancer ceramide analogs. Previously, a number of ceramide analogs with a flavone moiety on the backbone were synthesized. Initial docking studies showed that flavone moieties are too big for the binding pocket of human ceramidase. Coumarin-containing ceramide analogs, however, are smaller in size, and are expected to have increased efficiency along with self-fluorescence. For this project, new ceramide analogs containing a coumarin moiety on the sidechain were synthesized in order to study their biological activities.
Xavier University of Louisiana
Synthesis, Biological Evaluation, New Ceramide Analogs
Wilson, Karyn; Do, Camilla; Ponnapakkam, Tulasi; Goyal, Navneet; and Foroozesh, Maryam, "Synthesis and Biological Evaluation of New Ceramide Analogs" (2020). Building Infrastructure Leading to Diversity (BUILD). 14.