Design, synthesis and biological evaluation of marine phidianidine-inspired derivatives against oxidized ldl-induced endothelial injury by activating Nrf2 anti-oxidation pathway

• Published in: Bioorganic chemistry 2022-03, Vol.120, p.105606-105606, Article 105606
• Main Authors: Xie, Hong-Xu, Wang, Yan-Hong, Zhang, Jin-He, Zhang, Juan, Zhong, Ying-Nan, Ge, Yong-Xi, Cheng, Zhi-Qiang, Jiang, Cheng-Shi, Meng, Ning
• Format: Article
• Language: English
• Subjects: Indole-1,2,4-oxadiazole; Nrf2; oxLDL; Phidiandine; Vascular endothelial cell
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.105606

[Display omitted] •A series of novel marine phidianidine-inspired indole-1,2,4-oxadiazoles was designed and synthesized.•These derivatives were evaluated for their effects against oxLDL-induced injury in VECs.•The most potent compound D-6 inhibit oxLDL-induced apoptosis and the expression of ICAM-1 and VCAM-1 in VECs.•Compound D-6 suppressed oxLDL-induced increase of ROS level and nuclear translocation of NF-κB.•Compound D-6 protected against oxLDL-induced endothelial injury by activating Nrf2/HO-1 pathway. Inhibition of oxidized low-density lipoprotein (oxLDL)-induced vascular endothelial cell (VEC) injury is one of the effective strategies for treating atherosclerosis. In the present study, a series of novel marine phidianidine-inspired indole-1,2,4-oxadiazoles was designed, synthesized, and evaluated for their effects against oxLDL-induced injury in VECs. Among them, compound D-6, displaying the most effective protective activity, was found to inhibit oxLDL-induced apoptosis and the expression of ICAM-1 and VCAM-1 in VECs. Mechanistic studies showed that D-6 could trigger Nrf2 nuclear translocation, subsequently resulting in increased expression of Nrf2 target gene HO-1. Meanwhile, D-6 suppressed the increase of ROS level and nuclear translocation of NF-κB induced by oxLDL. Importantly, Nrf2 knockdown attenuated the inhibition effects of D-6 on oxLDL-induced apoptosis, ROS production and NF-κB nuclear translocation. Collectively, our studies demonstrated that compound D-6 protected against oxLDL-induced endothelial injury by activating Nrf2/HO-1 anti-oxidation pathway.