Nucleobase-Derived Nitrones: Synthesis and Antioxidant and Neuroprotective Activities in an In Vitro Model of Ischemia-Reperfusion.

Herein, we report the synthesis, antioxidant, and neuroprotective properties of some nucleobase-derived nitrones named -. The neuroprotective properties of nitrones, -, were measured against an oxygen-glucose-deprivation in vitro ischemia model using human neuroblastoma SH-SY5Y cells. Our results indicate that nitrones, -, have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone () and are similar to N-acetyl-L-cysteine (), a well-known antioxidant and neuroprotective agent. The nitrones with the highest neuroprotective capacity were those containing purine nucleobases (nitrones , , B = adenine, theophylline), followed by nitrones with pyrimidine nucleobases with H or F substituents at the C5 position (nitrones , ). All of these possess EC values in the range of 1-6 μM and maximal activities higher than 100%. However, the introduction of a methyl substituent (nitrone , B = thymine) or hard halogen substituents such as Br and Cl (nitrones , , B = 5-Br and 5-Cl uracil, respectively) worsens the neuroprotective activity of the nitrone with uracil as the nucleobase (). The effects on overall metabolic cell capacity were confirmed by results on the high anti-necrotic (ECs ≈ 2-4 μM) and antioxidant (ECs ≈ 0.4-3.5 μM) activities of these compounds on superoxide radical production. In general, all tested nitrones were excellent inhibitors of superoxide radical production in cultured neuroblastoma cells, as well as potent hydroxyl radical scavengers that inhibit in vitro lipid peroxidation, particularly, , , , presenting the highest lipoxygenase inhibitory activity among the tested nitrones. Finally, the introduction of two nitrone groups at and (bis-nitronas , ) did not show better neuroprotective effects than their precursor mono-nitrones. These results led us to propose nitrones containing purine (, ) and pyrimidine (, ) nucleobases as potential therapeutic agents for the treatment of cerebral ischemia and/or neurodegenerative diseases, leading us to further investigate their effects using in vivo models of these pathologies.