Design, synthesis, and characterization of novel system xC − transport inhibitors: inhibition of microglial glutamate release and neurotoxicity

Abstract

Abstract Neuroinflammation appears to involve some degree of excitotoxicity promulgated by microglia, which release glutamate via the system xC − (SxC −) cystine-glutamate antiporter. With the aim of mitigating this source of neuronal stress and toxicity, we have developed a panel of inhibitors of the SxC − antiporter. The compounds were based on l-tyrosine, as elements of its structure align with those of glutamate, a primary physiological substrate of the SxC − antiporter. In addition to 3,5-dibromotyrosine, ten compounds were synthesized via amidation of that parent molecule with a selection of acyl halides. These agents were tested for the ability to inhibit release of glutamate from microglia activated with lipopolysaccharide (LPS), an activity exhibited by eight of the compounds. To confirm that the compounds were inhibitors of SxC −, two of them were further tested for the ability to inhibit cystine uptake. Finally, these agents were shown to protect primary cortical neurons from the toxicity exhibited by activated microglia. These agents may hold promise in reducing the neurodegenerative effects of neuroinflammation in conditions, such as encephalitis, traumatic brain injury, stroke, or neurodegenerative diseases.

Keywords

• Amino acid transport system xc protein
• Excitotoxicity
• Cell death
• Drug discovery
• Glutamic acid
• Microglia