Modification of a Zone 4 Reaction on a Known Sphingosine KinaseInhibitor to Improve Oral Bioavailability

Targeted therapy is a new and developing technique that has the ability to target a specific molecule and pathway, increasing the efficiency of attacking abnormal cancerous cells. The sphingomyelin pathway is important in cell regulation, signaling, and determining a cells fate. Inhibition of the sphingosine kinase enzyme (SK1) leads to a buildup of sphingosine and ceramide, two molecules directly linked to cell apoptosis. It also decreases the intracellular concentration of sphingosine-1-phosphate (S1P), a molecule linked to cellular proliferation. Therefore, our project objective is to develop inhibitors of SK1 in order to lower the intracellular concentration of S1P and generate apoptosis through the buildup of sphingosine and ceramide molecules. Smith et al. discovered an inhibitor that was successful at inhibiting SK1 in vitro, however was unsuccessful in vivo. Therefore, this inhibitor must be modified to improve inhibition success in vivo. Microwave heating is used to synthesize successful modifications of the template inhibitor in zone 4. It is hypothesized that the addition of polar substituents will increase the hydrophillicity and oral bioavailability of these compounds. There have been fifteen successful inhibitors synthesized, all proven using high-resolution mass spectrometry. The inhibitors will be tested in vitro to see their interaction with human SK1 as well as inhibition success rate. It is projected that these inhibitors will be used in pharmaceutical drugs to aid in cancer treatment