Design, Synthesis, and Biological Evaluation of Novel Hydroxytyrosol Derivatives as Protectors for Vascular Endothelium Against Lipid Overload.

Background and Objective: Hydroxytyrosol (HT) is reported to protect endothelial cells against metabolic overload through inhibiting inflammation. However, the hydrophilic nature of HT limits its oral bioavailability and biological efficiency. The aim of the study was to design and synthesize novel hybrid molecules to improve HT's biological efficiency. Materials and Methods: A pharmacophore connection strategy was used to design and synthesize novel hybrid molecules by combining HT or its analogues with adamantane (ADM). Palmitic acid (PA) was used to induce lipid overload in HAEC cells, and P407 was used to induce acute hyperlipidemia in C57 mice. Results: We found that DP-ADM, combining ADM and dopamine (a HT analogues), exhibited potent protective effects against metabolic overload-induced endothelial dysfunction. DP-ADM showed low toxicity and inhibited inflammation in response to PA overload in cultured endothelial cells. Additionally, it (30 mg/kg) decreased circulating lipids to an extent similar to HT in a mouse model of hyperlipidemia and was superior to HT in decreasing circulating inflammatory cytokine. It was also superior to HT in improving vascular endothelial function in mice with hyperlipidemia. Mechanistically, DP-ADM inactivated MAPK signaling, as evidenced by downregulated phosphorylation of p38 and Erk. Inhibition of MAPK or NF-κB abolished the anti-inflammatory effect of DP-ADM. Specifically, DP-ADM activated FoxO1 signaling and increased mitochondrial biogenesis in endothelial cells. Conclusion: Overall, DP-ADM is a superior form of HT, highlighting its potential therapeutic use in improving endothelial function in metabolic diseases.