Synthesis and Optimization of the Sphingosine Kinase Inhibitor with Improved Hydrophilicity
Session Title
Other Abstracts
Faculty Mentor
T. Christian Grattan, Ph.D.
College
College of Arts and Sciences
Department
Chemistry, Physics, Geology, & the Environment
Abstract
Cancer is a very prominent disease worldwide and has been studied time and time again. Recently, targeted therapy has shown positive results as it can selectively prevent cancer cell proliferation by promoting apoptotic activity of mutated cells. Metabolites of the sphingomyelin pathway are responsible for the pro-apoptotic and anti-apoptotic effects on cancer cells. Inhibition of sphingosine kinase leads to a build-up of sphingosine and ceramide, the pro-apoptotic metabolites, and decreases the intracellular concentration of sphingosine-1-phosphate (S1P), an anti-apoptotic metabolite known to cause cellular proliferation. A current inhibitor of sphingosine kinase, known as SKI-1, has been successful in-vitro but lacks success in-vivo. The objective of this project is to synthetically modify the structure of SKI-1 to make it more hydrophilic in order to increase its inhibition effects in-vivo. Modifications of SKI-1 were done in a 3-step process. Five novel inhibitors were synthesized, purified and confirmed by 1H NMR based on calculated log-P values, which describes the inhibitor's ability to be hydrophilic in an in-vivo environment. The log-P value for an orally bioavailable drug should ideally be less than 5, but the original SKI-1 has a value of 5.67. In the future, each modified inhibitor will be analyzed via mass spectrometry and carbon-13 NMR, then sent off for bioassay testing to compare modified structures to the parent molecule for in vitro and in vivo effectiveness as compared to in-silico docking studies. From there, further modifications to each zone of the current inhibitor will be made and tested to find the combination of modified zones that produces the best results for bioavailability.
Grant Support?
Supported by an SC-INBRE grant from the National Institute for General Medical Sciences (P20GM103499).
Start Date
15-4-2023 12:00 PM
Synthesis and Optimization of the Sphingosine Kinase Inhibitor with Improved Hydrophilicity
Cancer is a very prominent disease worldwide and has been studied time and time again. Recently, targeted therapy has shown positive results as it can selectively prevent cancer cell proliferation by promoting apoptotic activity of mutated cells. Metabolites of the sphingomyelin pathway are responsible for the pro-apoptotic and anti-apoptotic effects on cancer cells. Inhibition of sphingosine kinase leads to a build-up of sphingosine and ceramide, the pro-apoptotic metabolites, and decreases the intracellular concentration of sphingosine-1-phosphate (S1P), an anti-apoptotic metabolite known to cause cellular proliferation. A current inhibitor of sphingosine kinase, known as SKI-1, has been successful in-vitro but lacks success in-vivo. The objective of this project is to synthetically modify the structure of SKI-1 to make it more hydrophilic in order to increase its inhibition effects in-vivo. Modifications of SKI-1 were done in a 3-step process. Five novel inhibitors were synthesized, purified and confirmed by 1H NMR based on calculated log-P values, which describes the inhibitor's ability to be hydrophilic in an in-vivo environment. The log-P value for an orally bioavailable drug should ideally be less than 5, but the original SKI-1 has a value of 5.67. In the future, each modified inhibitor will be analyzed via mass spectrometry and carbon-13 NMR, then sent off for bioassay testing to compare modified structures to the parent molecule for in vitro and in vivo effectiveness as compared to in-silico docking studies. From there, further modifications to each zone of the current inhibitor will be made and tested to find the combination of modified zones that produces the best results for bioavailability.
