Anti-atherosclerosis effect of H2S donors based on nicotinic acid and chlorfibrate structures

Based on the structures of nicotinic acid and chlorfibrate, a series of new H₂S donors were synthesized and their anti-atherosclerosis activities using Ox-LDL RAW 264.6 cells as model were evaluated. The release test showed that all the compounds could release H₂S effectively and showed low cytotoxicity. In the bioactivity experiments, compounds 1, 3, 9 and 14 increased the survival rate of HUVEC cells treated by ox-LDL; among four compounds, compounds 1 and 3 displayed higher activity than the others. In the foam cell model, compounds 1 and 3 were found to inhibit the formation of foam cells and significantly reduced the content of TC and FC in foam cells. They had more obvious effects on lipid reduction than those of nicotinic acid and chlorfibrate. In anti-oxidation, compounds 1 and 3 significantly reduced ROS and MDA and increased the expression level of SOD, whereas the precursor compounds, niacin and chlorfibrate had little antioxidant effect. In addition, both compounds also inhibited the inflammatory response in foam cells, with reducing pro-inflammatory factor TNF-α and increasing anti-inflammatory cytokine IL-10. WB assay showed that the tested compounds inhibited the expression levels PI3K, Akt and NF-κb proteins. In conclusion, the compounds as H₂S donors could protect HUVEC cells from damage and inhibit the formation of foam cells by inhibiting PI3K/Akt/NF-κb signal pathway. All these suggest the compounds have potential to be candidate for anti-atherosclerosis medicines.