Year of Award

2014

Document Type

Thesis

Degree Type

Master of Science (MS)

Degree Name

Pharmaceutical Sciences

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Richard Bridges

Committee Co-chair

Sarj Patel

Commitee Members

Philippe Diaz, Donna Beall

Keywords

Excitatory amino acid, Transporter, xCT, Uptake, Glutathione, Glutamate

Abstract

The System xc- antiporter is plasma membrane transporter that mediates the exchange of extracellular L-cystine with intracellular L-glutamate. This exchange is significant within the context of the CNS because the import of L-cystine is required for the synthesis of the antioxidant glutathione, while the efflux of L-glutamate has the potential to contribute to either excitatory signaling or excitotoxic pathology. Changes in the activity of the transport system have been suggested to contribute to the underlying pathological mechanisms of a variety of CNS disorders, one of the most prominent of which is it highly enriched expression glial brain tumors. In an effort to produce more potent System xc- blocker, we have been using amino-3-carboxy-5-methylisoxazole propionic acid (ACPA) as a scaffold for inhibitor development. We previously demonstrated that the addition of lipophilic aryl groups to either the #4 or #5 position on the isoxazole ring markedly increased the inhibitory activity at System xc-. In the present work a novel series of analogues has been prepared in which aryl groups have been introduced at both the #4 and #5 positions. In contrast to the competitive action of the mono-substituted analogues, kinetic analyses indicate that the di-substituted isoxazoles block System XC--mediated uptake of 3H-L-glutamate into SNB-19 activity by a noncompetitive mechanism. These new analogues appear to be the first noncompetitive inhibitors identified for this transport system, as well as being among the most potent blockers identified to date. These diaryl-isoxazoles should be of value in assessing the physiological roles and molecular structure of System xc-.

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© Copyright 2014 Jayme Lee Hartzell