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

Mourad Chioua,Estíbaliz Garagarza,Francisco López-Muñoz,Dimitra Hadjipavlou-Litina,David García-Vieira,Beatriz Chamorro,José Marco-Contelles,Daniel Diez-Iriepa,María Jesús Oset-Gasque

doi:10.3390/molecules26041127

Abstract

Herein, we report the neuroprotective and antioxidant activity of 1,1′-biphenyl nitrones (BPNs) 1–5 as α-phenyl-N-tert-butylnitrone analogues prepared from commercially available [1,1′-biphenyl]-4-carbaldehyde and [1,1′-biphenyl]-4,4′-dicarbaldehyde. The neuroprotection of BPNs 1-5 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 BPNs 1–5 have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone (PBN), and they are quite similar to N-acetyl-L-cysteine (NAC), which is a well-known antioxidant agent. Among the nitrones studied, homo-bis-nitrone BPHBN5, bearing two N-tert-Bu radicals at the nitrone motif, has the best neuroprotective capacity (EC50 = 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 (EC50 = 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 BPMN3, with one N-Bn radical, and BPMN2, with only one N-tert-Bu substituent. The antioxidant activity of BPNs 1-5 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 BPNs, the final effect is also dependent on the substitutent that is being incorporated. Thus, BPNs bearing N-tert-Bu and N-Bn groups show better neuroprotective and antioxidant properties than those substituted with Me. All these results led us to propose homo-bis-nitrone BPHBN5 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.

Highlights

The Reactive Oxygen Species (ROS) formed in the metabolism in living organisms play key roles acting at low to moderate concentrations in many important cell processes; at high concentrations, they produce negative effects in key physiological biomolecules, such as DNA, proteins, and lipids [1]
We have described the design, synthesis, antioxidant, and neuroprotective evaluation against oligomycin A/rotenone, in an in vitro oxygen–glucose deprivation ischemia model, in human neuroblastoma SH-SY5Y cells
The results obtained with these PBN-derived nitrones show that they are more potent than the reference PBN (Figure 1), showing quite similar neuroprotection and antioxidant activity as NAC

Summary

Introduction

The Reactive Oxygen Species (ROS) formed in the metabolism in living organisms play key roles acting at low to moderate concentrations in many important cell processes; at high concentrations, they produce negative effects in key physiological biomolecules, such as DNA, proteins, and lipids [1]. In the search for new scavenging ROS [4], nitrones, well-known organic molecules typically used as radical traps, appear as suitable drugs to treat CI [5]. PBN was the starting point of a number of new nitrones targeted for the therapy of CI, such as NXY-059, which was the first nitrone submitted to clinical trials, it failed in advanced phase III, as no significant effect was observed when compared with placebo [7]. Neuroprotective and antioxidant nitrones [8]

Methods

Results

Conclusion