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Protective effect of piceatannol and bioactive stilbene derivatives against hypoxia-induced toxicity in H9c2 cardiomyocytes and structural elucidation as 5-LOX inhibitors


Stilbenes with known antioxidant and antiradical properties are useful in various diseases, including cardiovascular diseases. The present research was conducted to investigate the potential protective effect of resveratrol (1) and piceatannol (2) against hypoxia-induced oxidative stress in the cardiomyoblastic cell line H9c2 and the underlying mechanisms. Compounds 1 and 2 significantly inhibited peroxynitrite release and thiobarbituric acid levels at zero or submicromolar concentrations; this effect was most pronounced in piceatannol-treated cells, which significantly increased MnSOD protein levels in a concentration-dependent manner.

Furthermore, as piceatannol, which is much less abundant in natural sources, showed higher bioactivity than the parent compound, we report a very rapid synthesis and detailed design based on the structure of a targeted library of stilbenes. Finally, taking into account that hypoxia-induced ROS accumulation also increases the expression and activity of 5-lipoxygenase (5-LOX) with leukotriene production, we revealed the key structural factors crucial for 5-LOX activity. Among the synthesised analogues (3-7), compound 7 was the most effective in enhancing cardiomyocyte viability and inhibiting 5-LOX. In conclusion, the modelling and experimental studies provided the basis for further optimisation of stilbene analogues as multi-target inhibitors of inflammatory and oxidative pathways.