Event Title

Investigation and Optimization of the Synthesis of the Sphingosine Kinase 1 Inhibitor

Poster Number

116

Session Title

Physical Sciences, Math, and Computer Science

Document Type

Poster Presentation

College

College of Arts and Sciences

Department

Department of Chemistry, Physics, and Geology

Honors Thesis Committee

Christian Grattan, Ph.D.; Aaron Hartel, Ph.D.; and Maria Gelabert, Ph.D.

Description

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.

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Apr 24th, 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.