Synthesis and Analysis of Potential Sphingosine Kinase 1 Inhibitors
Poster Number
006
College
College of Arts and Sciences
Department
Chemistry, Physics, Geology, & the Environment
Faculty Mentor
T. Christian Grattan, Ph.D.
Abstract
The sphinogmyelin metabolic pathway is a popular target area of research due to the potential for apoptosis in cancer cells. In the pathway, sphinogmyelin may be converted to the final product of sphingosine-1-phosphate. Sphingosine-1-phosphate is associated with cell proliferation in cancer cells. This is due to the over-expression of sphingosine kinase 1, an enzyme that catalyzes the phosphorylation of sphingosine to form sphingosine-1-phosphate. Inhibition of sphingosine kinase 1 would prevent proliferation and lead to the desired apoptotic outcome, if a potent inhibitor can been identified. Beginning with a promising lead molecule based on in vitro studies, synthetic production of a number of structurally modified variations of the inhibitor were prepared to improve the overall hydrophilicity of the lead compound. These variations have been successfully synthesized and purified; they are now being tested against the enzyme for effective in vitro activity relative to the template inhibitor. Using a sphingosine kinase activity assay kit, the inhibitors are tested in the presence of ATP, sphingosine, and sphingosine kinase at varying concentrations to optimize the results. Our assays show activities and inhibition results relative to our template structure. We hope to continue to optimize and realize the potential of these inhibitors as a possible treatment option in this cancerous pathway.
Previously Presented/Performed?
Summer Undergraduate Research Experience (SURE) Symposia, Winthrop University, June and September 2017; Southeast Regional Meeting of the American Chemical Society (SERMACS), Charlotte, North Carolina, November 2017; American Chemical Society (ACS) National Meeting, New Orleans, Louisiana, March 2018
Grant Support?
Supported by an SC INBRE grant from the National Institute of General Medical Sciences (NIH-NIGMS)
Start Date
20-4-2018 12:00 PM
End Date
20-4-2018 2:00 PM
Synthesis and Analysis of Potential Sphingosine Kinase 1 Inhibitors
Rutledge
The sphinogmyelin metabolic pathway is a popular target area of research due to the potential for apoptosis in cancer cells. In the pathway, sphinogmyelin may be converted to the final product of sphingosine-1-phosphate. Sphingosine-1-phosphate is associated with cell proliferation in cancer cells. This is due to the over-expression of sphingosine kinase 1, an enzyme that catalyzes the phosphorylation of sphingosine to form sphingosine-1-phosphate. Inhibition of sphingosine kinase 1 would prevent proliferation and lead to the desired apoptotic outcome, if a potent inhibitor can been identified. Beginning with a promising lead molecule based on in vitro studies, synthetic production of a number of structurally modified variations of the inhibitor were prepared to improve the overall hydrophilicity of the lead compound. These variations have been successfully synthesized and purified; they are now being tested against the enzyme for effective in vitro activity relative to the template inhibitor. Using a sphingosine kinase activity assay kit, the inhibitors are tested in the presence of ATP, sphingosine, and sphingosine kinase at varying concentrations to optimize the results. Our assays show activities and inhibition results relative to our template structure. We hope to continue to optimize and realize the potential of these inhibitors as a possible treatment option in this cancerous pathway.
