Synthesis, Neuroprotection, and Antioxidant Activity of 1,1'-Biphenylnitrones as α-Phenyl--butylnitrone Analogues in In Vitro Ischemia Models.

Herein, we report the neuroprotective and antioxidant activity of 1,1'-biphenyl nitrones () - as α-phenyl---butylnitrone analogues prepared from commercially available [1,1'-biphenyl]-4-carbaldehyde and [1,1'-biphenyl]-4,4'-dicarbaldehyde. The neuroprotection of - has been measured against oligomycin A/rotenone and in an oxygen-glucose deprivation in vitro ischemia model in human neuroblastoma SH-SY5Y cells. Our results indicate that - have better neuroprotective and antioxidant properties than α-phenyl---butylnitrone (), and they are quite similar to -acetyl-L-cysteine (), which is a well-known antioxidant agent. Among the nitrones studied, homo-bis-nitrone , bearing two --Bu radicals at the nitrone motif, has the best neuroprotective capacity (EC = 13.16 ± 1.65 and 25.5 ± 3.93 μM, against the reduction in metabolic activity induced by respiratory chain blockers and oxygen-glucose deprivation in an in vitro ischemia model, respectively) as well as anti-necrotic, anti-apoptotic, and antioxidant activities (EC = 11.2 ± 3.94 μM), which were measured by its capacity to reduce superoxide production in human neuroblastoma SH-SY5Y cell cultures, followed by mononitrone , with one -Bn radical, and , with only one --Bu substituent. The antioxidant activity of - has also been analyzed for their capacity to scavenge hydroxyl free radicals (82% at 100 μM), lipoxygenase inhibition, and the inhibition of lipid peroxidation (68% at 100 μM). Results showed that although the number of nitrone groups improves the neuroprotection profile of these , the final effect is also dependent on the substitutent that is being incorporated. Thus, bearing --Bu and -Bn groups show better neuroprotective and antioxidant properties than those substituted with Me. All these results led us to propose homo--nitrone as the most balanced and interesting nitrone based on its neuroprotective capacity in different neuronal models of oxidative stress and in vitro ischemia as well as its antioxidant activity.