The goal of this project is to develop small molecule fluorescent probes for a transporter that is becoming increasingly recognized as a relevant physiological and therapeutic target, the glutamate/cystine transporter system Xc- (SXc-). Based upon its normal operation as an obligate exchanger, SXc- links the import of L-cystine (L-Cys2) with the export of L-Glu. The uptake of L-Cys2 is critical to glutathione (GSH) synthesis and oxidative protection, while the efflux of L-Glu represents a point source through which this excitatory transmitter could contribute to either signaling or excitotoxic pathology. SXc- has been linked to a number of important physiological processes in the CNS, including: presynaptic regulation of neurotransmitter release, receptor organization, synaptic plasticity, and oxidative protection. More recently, however, the export of L-Glu through SXc- has garnered considerable attention because of its association (and potential for therapeutic intervention) with two seemingly disparate pathological processes: brain tumor growth and drug addiction. Unfortunately, our growing appreciation for the potential roles of SXc- in these and other neurological disorders, as well as in normal CSN function, has rapidly outpaced the availability of pharmacological reagents and probes with which to assess or modify its activity. During the course of ongoing SAR studies on SXc- we have found that the addition of large lipophilic groups (including fluorophores) to specific positions on known inhibitors are not only tolerated by the transporter, but actually produce an increase inhibitory potency. In this project we will prepare a library of probes in which the fluorophore, tether and linkage will be systematically varied on three proven SXc- inhibitor/substrate templates. The proposed optimization of compounds and associated assay conditions should yield fluorescent probes of SXc- with considerable utility in an array of applications that range from pharmacological screenings via high-throughput assays to functional imaging in normal and pathological tissues.
The system Xc- transporter regulates the movement of two important amino acids into and out of cells in the brain: L-glutamate and L-cystine. The function and/or dysfunction of this transporter has been linked with a number of CNS disorders, including: addiction, tumor growth, and viral pathology. This project will develop fluorescent molecular probes for system Xc- that will advance our understanding of its roles in these disorders, as well as enhance the development of therapeutic agents with which to regulate its activity.
| Newell, J L; Keyari, C M; McDaniel, S W et al. (2014) Novel di-aryl-substituted isoxazoles act as noncompetitive inhibitors of the system Xc(-) cystine/glutamate exchanger. Neurochem Int 73:132-8 |
| Matti, Afnan A; Mirzaei, Joseph; Rudolph, John et al. (2013) Microwave accelerated synthesis of isoxazole hydrazide inhibitors of the system xc- transporter: Initial homology model. Bioorg Med Chem Lett 23:5931-5 |
| Mirzaei, Yousef R; Weaver, Matthew J; Steiger, Scott A et al. (2012) Improved synthesis of 3-aryl isoxazoles containing fused aromatic rings. Tetrahedron 68:10360-10364 |
| Bridges, Richard J; Natale, Nicholas R; Patel, Sarjubhai A (2012) System xcýýý cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharmacol 165:20-34 |
