Cytotoxic and Antioxidant Activities of Imine Analogs of Trans-Resveratrol towards Murine Neuronal N2a Cells

Abstract

Trans-resveratrol is a natural polyphenol showing numerous biological properties, especially anti-tumoral and antioxidant activity. Among numerous resveratrol derivatives, aza-stilbenes, which bear an imine bound, show interesting biological activities. In the present study, we synthesized a series of imine analogs of trans-resveratrol (seven aza-stilbenes) following an easy and low-cost procedure of green chemistry. The toxicity of synthesized aza-stilbenes, which is currently unknown, was evaluated on murine neuronal N2a cells, comparatively to trans-resveratrol, by considering: cell density evaluated by staining with sulforhodamine 101; esterase activity, which is a criteria of cell viability, by staining with fluorescein diacetate; and transmembrane mitochondrial potential, which is known to decrease during cell death, by staining with DiOC6(3) using flow cytometry. In addition, the antioxidant activity was quantified with the KRL (Kit Radicaux Libres) assay, the DPPH (2,2′-diphenyl-1-picrylhydrazyl radical) assay and the FRAP (ferric reducing antioxidant power) assay. The PAOT (Pouvoir Antioxidant Total) score was also used. The aza-stilbenes provide different cytotoxic and antioxidant activities, which are either higher or lower than those of trans-resveratrol. Based on their cytotoxic and antioxidant characteristics, all synthesized aza-stilbenes are distinguished from trans-resveratrol.

Characterization of Cell Death Induced by Imine Analogs of Trans-Resveratrol: Induction of Mitochondrial Dysfunction and Overproduction of Reactive Oxygen Species Leading to, or Not, Apoptosis without the Increase in the S-Phase of the Cell Cycle

“…The synthesis of structural analogues is one of the possible strategies for the preservation of important RSV health properties and to oppose its catabolism. This led us to the synthesis of aza-stilbenes [ 15 ]. These molecules have shown cytotoxic activities on N2a cells in vitro and high anti-free radical properties when measured by various biochemical tests (DPPH, FRAP, and PAOT) and with the KRL assay performed in the presence of AAPH on red blood cells [ 15 ].…”

“…Currently, several synthetic derivatives of RSV have been developed that retain the original stilbene structure and preserve its water-soluble character. Moreover, the C=C bond may be replaced with an isosteric fragment as an aromatic heterocycle [ 12 ] or with a C=N bond or an N=N bond to provide aza-stilbenes (AZA-ST) [ 13 ] and azo-stilbenes [ 14 ], respectively [ 15 ] ( Figure 1 ).…”

“…We previously reported the synthesis of a series of seven imine analogs of RSV (AZA-ST 1a–g) ( Figure 2 ) by an easy and low-cost green chemistry procedure [ 15 ]. In this study, the different AZA-STs were chemically characterized [ 15 ].…”

“…We previously reported the synthesis of a series of seven imine analogs of RSV (AZA-ST 1a–g) ( Figure 2 ) by an easy and low-cost green chemistry procedure [ 15 ]. In this study, the different AZA-STs were chemically characterized [ 15 ]. We showed that all AZA-ST 1a–g synthesized could be distinguished from RSV based on their cytotoxic and antioxidant characteristics.…”

“…In this previous study, the cytotoxicity was evaluated with the sulforhodamine 101 (SR101), the fluorescein diacetate (FDA), and the DiOC 6 (3) assays, but the type of cell death was not characterized. However, the antioxidant activity of AZA-ST 1a–g was quantified with the KRL kit (Radicaux Libres) assay, the DPPH (2,2′-diphenyl-1-picrylhydrazyl radical) assay, the FRAP (Ferric Reducing Antioxidant Power) assay, and the PAOT (Pouvoir AntiOxidant Total) score [ 15 ]. Based on their cytotoxic and antioxidant characteristics, the AZA-ST 1a–g was distinguishable from the RSV.…”