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Bioorg Med Chem. 2019 Jun 6. pii: S0968-0896(19)30432-8. doi: 10.1016/j.bmc.2019.06.012. [Epub ahead of print]

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

Author information

1
Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou 730000, China.
2
Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou 730000, China. Electronic address: zhaoqy@lzu.edu.cn.
3
Institute of Medicinal Chemistry, School of Pharmacy of Lanzhou University, Lanzhou 730000, China. Electronic address: zhenw@lzu.edu.cn.
4
GLP Lab Centre, School of Basic Medicine of Lanzhou University, Lanzhou 730000, China.
5
School of Stomatology of Lanzhou University, Lanzhou 730000, China.

Abstract

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.

KEYWORDS:

Anti-atherosclerosis effect; Anti-inflammatory; Anti-oxidation effect; H(2)S donors; Toxicity

PMID:
31204228
DOI:
10.1016/j.bmc.2019.06.012

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