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

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

  • Eur J Med Chem. 2025 Nov 5:297:117982. doi: 10.1016/j.ejmech.2025.117982.
Shu-Yang Ni 1,  Nan Wang 2,  De-Yi Luo 3,  Yong-Sheng Hou 4,  Qiu-Yang Li 2,  Tian Chai 4,  Yi-Dan Zheng 4,  Xing-Sheng Bu 2,  En-Jie Zhu 1,  Xiao-Feng Shi 5,  Xian-Hua Meng 4,  Xing-Rong Wang 6,  Jun-Li Yang 7
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Chemistry of Northwestern Plant Resources and Key Laboratory for Natural Medicine of Gansu Province, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Lanzhou, 730000, People's Republic of China; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.
  • 2 College of Pharmacy, Gansu University of Traditional Chinese Medicine, Lanzhou, 730000, People's Republic of China.
  • 3 School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou, 730000, People's Republic of China.
  • 4 CAS Key Laboratory of Chemistry of Northwestern Plant Resources and Key Laboratory for Natural Medicine of Gansu Province, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Lanzhou, 730000, People's Republic of China.
  • 5 Institute of Materia Medica, Gansu Provincial Academy of Medical Sciences and Gansu Provincial Cancer Hospital, Lanzhou, 730000, People's Republic of China.
  • 6 CAS Key Laboratory of Chemistry of Northwestern Plant Resources and Key Laboratory for Natural Medicine of Gansu Province, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Lanzhou, 730000, People's Republic of China. Electronic address: wangxr@licp.cas.cn.
  • 7 CAS Key Laboratory of Chemistry of Northwestern Plant Resources and Key Laboratory for Natural Medicine of Gansu Province, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Lanzhou, 730000, People's Republic of China. Electronic address: yangjl@licp.cas.cn.
PMID: 40706447 DOI: 10.1016/j.ejmech.2025.117982
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.

Keywords

Anti-inflammation; High altitude cerebral edema; Hypoxia-inducible factor-1α; Salidroside; ortho-fluorophenyl.

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