Discovery of marine phidianidine-based Nrf2 activators and their potential against oxLDL- and HG-induced injury in HUVECs

Juan Zhang; Yong-Si Cai; Hua-Long Ji; Mengqi Ma; Jin-He Zhang; Zhi-Qiang Cheng; Kai-Ming Wang; Cheng-Shi Jiang; Chunlin Zhuang; Yang Hu; Ning Meng

doi:10.1016/j.bmcl.2023.129468

Discovery of marine phidianidine-based Nrf2 activators and their potential against oxLDL- and HG-induced injury in HUVECs

Bioorg Med Chem Lett. 2023 Oct 15:95:129468. doi: 10.1016/j.bmcl.2023.129468. Epub 2023 Sep 7.

Authors

Affiliations

¹ School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
² School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: bio_jiangcs@ujn.edu.cn.
³ School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Electronic address: zclnathan@163.com.
⁴ School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: mls_huy@ujn.edu.cn.
⁵ School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: mls_mengn@ujn.edu.cn.

PMID: 37689216
DOI: 10.1016/j.bmcl.2023.129468

Abstract

One effective strategy for treating atherosclerosis is to inhibit the injury of vascular endothelial cells (VECs) induced by oxidized low-density lipoprotein (oxLDL) and high glucose (HG). This study synthesized and evaluated a series of novel Nrf2 activators derived from the marine natural product phidianidine for their ability to protect human umbilical VECs against oxLDL- and HG-induced injury. The results of in vitro bioassays demonstrated that compound D-36 was the most promising Nrf2 activator, effectively inhibiting the apoptosis of HUVECs induced by oxLDL and HG. Furthermore, Nrf2 knockdown experiments confirmed that compound D-36 protected against oxLDL- and HG-induced apoptosis in HUVECs by activating the Nrf2 pathway. These findings provide important insights into a new chemotype of marine-derived Nrf2 activators that could potentially be optimized to develop effective anti-atherosclerosis agents.

Keywords: High glucose; Nrf2 activator; Phidianidine B; Vascular endothelial cell; oxLDL.