文献类型：期刊文献

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

作者：Ni, Shu-Yang[1,2,3];Wang, Nan[4];Luo, De-Yi[5];Hou, Yong-Sheng[1,2];Li, Qiu-Yang[4];Chai, Tian[1,2];Zheng, Yi-Dan[1,2];Bu, Xing-Sheng[4];Zhu, En-Jie[1,2,3];Shi, Xiao-Feng[6];Meng, Xian-Hua[1,2];Wang, Xing-Rong[1,2];Yang, Jun-Li[1,2]

第一作者：Ni, Shu-Yang

通信作者：Wang, XR[1];Yang, JL[1];Wang, XR[2];Yang, JL[2]

机构：[1]Chinese Acad Sci, Lanzhou Inst Chem Phys, CAS Key Lab Chem Northwestern Plant Resources, Lanzhou 730000, Peoples R China;[2]Chinese Acad Sci, Lanzhou Inst Chem Phys, Key Lab Nat Med Gansu Prov, Lanzhou 730000, Peoples R China;[3]Chinese Acad Sci, Univ Chinese Acad Sci, Beijing 100049, Peoples R China;[4]Gansu Univ Tradit Chinese Med, Coll Pharm, Lanzhou 730000, Peoples R China;[5]Lanzhou Univ Technol, Sch Life Sci & Engn, Lanzhou 730000, Peoples R China;[6]Gansu Prov Acad Med Sci & Gansu Prov Canc Hosp, Inst Mat Med, Lanzhou 730000, Peoples R China

第一机构：Chinese Acad Sci, Lanzhou Inst Chem Phys, CAS Key Lab Chem Northwestern Plant Resources, Lanzhou 730000, Peoples R China

通信机构：[1]corresponding author), Chinese Acad Sci, Lanzhou Inst Chem Phys, CAS Key Lab Chem Northwestern Plant Resources, Lanzhou 730000, Peoples R China;[2]corresponding author), Chinese Acad Sci, Lanzhou Inst Chem Phys, Key Lab Nat Med Gansu Prov, Lanzhou 730000, Peoples R China.

年份：2025

卷号：297

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;Scopus(收录号：2-s2.0-105011200261);WOS:【SCI-EXPANDED(收录号:WOS:001540517000001)】；

基金：The work was supported by National Natural Science Foundation of China (32270419) , the Science and Technology Innovation 2030 Major Program (2023ZD0505300) , National Key Research and Development Program (2024YFC3505603) , Lanzhou Youth Science and Technology Talent Innovation Project (2024-QN-52) , Major Program of the Lanzhou Institute of Chemical Physics, CAS (ZYFZFX-6) , and International Partnership Program of Chinese Academy of Sciences, Grant No. 037GJHZ2023043FN.

语种：英文

外文关键词：Hypoxia-inducible factor-1 alpha; Salidroside; High altitude cerebral edema; Anti-inflammation; o rtho -fluorophenyl

摘要：High altitude cerebral edema (HACE) represents a potentially lethal manifestation of acute mountain sickness, associated with abnormal activation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) and NF-kappa B inflammation pathway. Based on ortho-fluorophenyl pharmacophore and scaffold-hopping strategy, we designed and synthesized fortythree salidroside derivatives as HIF-1 alpha inhibitors. Dual-luciferase reporter assay demonstrated that compound N41 exhibited the strongest HIF-1 alpha inhibitory activity in HEK293T cells with an IC50 value of 2.02 +/- 0.76 mu M. 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-alpha, 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-1 alpha/IKK alpha/NF-kappa B signaling pathway to mitigate pathological inflammation in vivo, providing a new strategy for anti-HACE drug research.