Novel di-aryl-substituted isoxazoles act as noncompetitive inhibitors of the system xc- cystine/glutamate exchanger

•Potent isoxazole-based noncompetitive inhibitors were developed for system xc-.•Mechanism of inhibition is dependent upon the placement of lipophilic aryl groups.•Action of the inhibitors suggests the presence of two distinct lipophilic domains. The system xc- antiporter is a plasma membrane transp...

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Bibliographic Details
Published in:Neurochemistry international 2014-07, Vol.73, p.132-138
Main Authors: Newell, J.L., Keyari, C.M., McDaniel, S.W., Diaz, P.J., Natale, N.R., Patel, S.A., Bridges, R.J.
Format: Article
Language:English
Subjects:
Amino Acid Transport System y+ - antagonists & inhibitors
Binding, Competitive
Cell Line, Tumor
Excitatory amino acid
Glutamates - chemistry
Glutamates - pharmacology
Glutamic Acid - metabolism
Glutathione
Humans
Isoxazoles - chemistry
Isoxazoles - pharmacology
Kinetics
Structure-Activity Relationship
Transporter
Uptake
xCT
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Summary:•Potent isoxazole-based noncompetitive inhibitors were developed for system xc-.•Mechanism of inhibition is dependent upon the placement of lipophilic aryl groups.•Action of the inhibitors suggests the presence of two distinct lipophilic domains. The system xc- antiporter is a 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 linked to the underlying pathological mechanisms of a variety of CNS disorders, one of the most prominent of which is its highly enriched expression in glial brain tumors. In an effort to produce more potent system xc- blockers, 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 cells 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 pharmacology of system xc-.
ISSN:0197-0186
1872-9754
DOI:10.1016/j.neuint.2013.11.012