Investigation and Optimization of the Synthesis of the Sphingosine Kinase 1 Inhibitor
Poster Number
116
Session Title
Physical Sciences, Math, and Computer Science
College
College of Arts and Sciences
Department
Chemistry, Physics, Geology, & the Environment
Abstract
Phospholipids such as sphingolipids are main components of the lipid bilayer of the cell membrane. Sphingolipids are bioactive signaling molecules that play roles in cell division, proliferation, and death. Sphingosine kinase-1 (SK1) is an enzyme that regulates levels of sphingolipid metabolites, such as ceramide, sphingosine, and sphingosine-1-phosphate (S1P). In the sphingolipid metabolic pathway, ceramide is metabolized to sphingosine, which is phosphorylated to become S1P through the catalysis of SK1. Ceramide induces cell-cycle arrest and apoptosis, whereas S1P induces cell survival, proliferation, and migration. Malignant, cancerous cells have an overexpression of SK1, which causes over-production of S1P and leads to cancer cell proliferation, increased motility, and metastasis. The balance of ceramide, sphingosine, and S1P can therefore determine the fate of cancer cells. Due to its contribution to cancer progression, SK1 can be targeted in cancer therapy within the sphingolipid metabolic pathway. Inhibition of SK1 would deter cancer proliferation and result in apoptosis of cancer cells, which is the focus of any cancer therapy. A successful in vitro inhibitor, sphingosine kinase inhibitor-1 (SKI-1), was located, but is not an effective in vivo inhibitor due to its hydrophobicity and resulting low bioavailability. Derivatives of this inhibitor have been synthesized and analyzed to ultimately increase hydrophilicity and bioavailability of the parent inhibitor; these derivatives should exhibit the same in vitro effectiveness, as well as increased bioavailability, resulting in a more effective inhibitor in vivo as a possible treatment option in this pathway. The synthetic process used to synthesize derivatives of SKI-1 is being optimized. Previously, the Claisen condensation reaction of the synthetic scheme was optimized by using a microwave reactor. The overall synthesis is currently being further optimized to perform a one-pot synthesis of each derivative using the microwave reactor, and to maximize the yield and purity of the final product.
Honors Thesis Committee
Christian Grattan, Ph.D.; Aaron Hartel, Ph.D.; and Maria Gelabert, Ph.D.
Start Date
24-4-2020 12:00 AM
Investigation and Optimization of the Synthesis of the Sphingosine Kinase 1 Inhibitor
Phospholipids such as sphingolipids are main components of the lipid bilayer of the cell membrane. Sphingolipids are bioactive signaling molecules that play roles in cell division, proliferation, and death. Sphingosine kinase-1 (SK1) is an enzyme that regulates levels of sphingolipid metabolites, such as ceramide, sphingosine, and sphingosine-1-phosphate (S1P). In the sphingolipid metabolic pathway, ceramide is metabolized to sphingosine, which is phosphorylated to become S1P through the catalysis of SK1. Ceramide induces cell-cycle arrest and apoptosis, whereas S1P induces cell survival, proliferation, and migration. Malignant, cancerous cells have an overexpression of SK1, which causes over-production of S1P and leads to cancer cell proliferation, increased motility, and metastasis. The balance of ceramide, sphingosine, and S1P can therefore determine the fate of cancer cells. Due to its contribution to cancer progression, SK1 can be targeted in cancer therapy within the sphingolipid metabolic pathway. Inhibition of SK1 would deter cancer proliferation and result in apoptosis of cancer cells, which is the focus of any cancer therapy. A successful in vitro inhibitor, sphingosine kinase inhibitor-1 (SKI-1), was located, but is not an effective in vivo inhibitor due to its hydrophobicity and resulting low bioavailability. Derivatives of this inhibitor have been synthesized and analyzed to ultimately increase hydrophilicity and bioavailability of the parent inhibitor; these derivatives should exhibit the same in vitro effectiveness, as well as increased bioavailability, resulting in a more effective inhibitor in vivo as a possible treatment option in this pathway. The synthetic process used to synthesize derivatives of SKI-1 is being optimized. Previously, the Claisen condensation reaction of the synthetic scheme was optimized by using a microwave reactor. The overall synthesis is currently being further optimized to perform a one-pot synthesis of each derivative using the microwave reactor, and to maximize the yield and purity of the final product.
