Discovery of Novel Marine‐Derived Phidiandine/Lipoic Acid Hybrid as a Potential Anti‐Atherosclerosis Agent: Design, Synthesis and in Vitro/in Vivo Evaluation

Abstract

AbstractIn the present study, a novel derivative, IOP‐LA, was prepared by hybridizing antioxidant lipoic acid (LA) and our recently reported antioxidative marine phidianidine B‐inspired indole/1,2,4‐oxadiazole derivative. Our results demonstrated that IOP‐LA could protect vascular endothelial cells (VECs) from oxidized low‐density lipoprotein (oxLDL)‐induced oxidative stress by activating the Nrf2 pathway, inhibit the production of atherosclerotic plaque, and promote the stability of atherosclerotic plaque in apoE−/− mice. Moreover, the protective effect of IOP‐LA was superior to LA at the same concentration. Mechanistic studies revealed that IOP‐LA significantly inhibited the increase of reactive oxygen species (ROS) levels and the translocation of nuclear factor kappa‐B (NF‐κB) nuclear induced by oxLDL through the nuclear factor erythroid2‐related factor 2 (Nrf2) pathway. In summary, the data demonstrate that IOP‐LA, as a new antioxidant, protects VECs from oxLDL‐induced oxidative stress by activating the Nrf2 pathway. It is worth noting that this study provides a promising lead compound for the prevention and treatment of atherosclerosis.