Discovery of novel salidroside derivatives as potent hypoxia inducible factor 1α (HIF-1α) signaling inhibitors to treat high altitude cerebral edema

Abstract

High altitude cerebral edema (HACE) represents a potentially lethal manifestation of acute mountain sickness, associated with abnormal activation of hypoxia-inducible factor-1α (HIF-1α) and NF-κB inflammation pathway. Based on ortho-fluorophenyl pharmacophore and scaffold-hopping strategy, we designed and synthesized forty-three salidroside derivatives as HIF-1α inhibitors. Dual-luciferase reporter assay demonstrated that compound N41 exhibited the strongest HIF-1α inhibitory activity in HEK293T cells with an IC₅₀ value of 2.02 ± 0.76 μM. Meanwhile, N41 significantly suppressed the expression of inflammation factors of IL-6 and NO, as well as the accumulation of ROS without obvious cytotoxicity in C8-D1A cells. The in vivo study revealed that compound N41 could reduce brain water content and oxidative stress level in MDA/SOD measurements. In immunofluorescence assay, N41 suppressed inflammatory expression of IL-6, TNF-α, and blood-brain barrier permeability protein AQP-4. Furthermore, the western blotting assay and HE staining demonstrated that N41 regulated the inflammation process in a dose-dependent manner to alleviate cerebral edema in the HACE mouse model. These findings highlighted that compound N41 could effectively target HIF-1α/IKKα/NF-κB signaling pathway to mitigate pathological inflammation in vivo, providing a new strategy for anti-HACE drug research.