NOVEL INHIBITORS OF L-GLUTAMATE/L-CYSTINE EXCHANGER SYSTEM XC-

The system xc- (Sxc-) antiporter is a member of the heteromeric amino acid transporter (HAT) family, which mediates the obligate exchange of extracellular L-cystine for intracellular L-glutamate. Interestingly, both sides of this exchange reaction are important in the function of the central nervous system, as the import of L-cystine is needed for the synthesis of glutathione (GSH) and oxidative protection, while the exported L-glutamate can contribute to neuronal communication, as well as neuropathology. To study the various roles of Sxc-, our group has been developing small molecules that selectively inhibit the transporter. Previous studies carried out by the Natale lab demonstrated the utility of isoxazole-hydrazone derivatives as inhibitors of Sxc-. One problem with these compounds, however, is that their innate tendency to cyclize in solution significantly reduces their potency at Sxc-. In the present work we characterize a new collection of isoxazole-hydrazone derivatives that contain an additional carbonyl group that inhibits cyclization. The inhibitory activity of these analogues was assessed by quantifying their ability to block the uptake of [3H]-L-glutamate into SNB-19 human glioblastoma cells under conditions that were selective for Sxc--mediated uptake. A subset of the compounds were found to inhibit Sxc- with an affinity comparable to the endogenous substrate L-cystine. The findings help us to further refine the structure-activity-relationships that govern binding to the Sxc- transporter