Ocotillol Derivatives Mitigate Retinal Ischemia-Reperfusion Injury by Regulating the Keap1/Nrf2/ARE Signaling Pathway,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Ocotillol Derivatives Mitigate Retinal Ischemia-Reperfusion Injury by Regulating the Keap1/Nrf2/ARE Signaling Pathway
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-15 , DOI: 10.1021/acs.jmedchem.4c00867
Xin Zhang ₁ , Wen Zhang ₁ , Laien Zhao ₁ , Gongshan Ma ₁ , Yanmei Huang ₁ , Zhiyuan Geng ₁ , Qian Jiang ₁ , Xiaomei Wen ₁ , Yuqi Lin ₁ , Qingguo Meng ₁ , Zhuhong Zhang ₁ , Yi Bi ₁

Affiliation

Retinal ischemia-reperfusion (RIR) injury can lead to various retinal diseases. Oxidative stress is considered an important pathological event in RIR injury. Here, we designed and synthesized 34 ocotillol derivatives, then examined their antioxidant and anti-inflammatory capacities; we found that compounds 7 (C24-R) and 8 (C24-S) were most active. To enhance their water solubility, sustained release, and biocompatibility, compounds 7 and 8 were encapsulated into liposomes for in vivo activity and mechanistic studies. In vivo studies indicated that compounds 7 and 8 protected normal retinal structure and physiological function after RIR injury, reversed damage to retinal ganglion cells, and the S-configuration exhibited significantly stronger activity compared with the R-configuration. Mechanistic studies showed that compound 8 exerted a therapeutic effect on RIR injury by activating the Keap1/Nrf2/ARE signaling pathway; compound 7 did not influence this pathway. We also demonstrated that differential isomerization at the C-24 position influenced protection against RIR injury.

中文翻译：

Ocotillol 衍生物通过调节 Keap1/Nrf2/ARE 信号通路减轻视网膜缺血再灌注损伤

视网膜缺血再灌注（RIR）损伤可导致多种视网膜疾病。氧化应激被认为是 RIR 损伤的重要病理事件。在这里，我们设计并合成了 34 种奥克替醇衍生物，然后检测了它们的抗氧化和抗炎能力；我们发现化合物7 (C24- R ) 和8 (C24- S ) 活性最强。为了提高其水溶性、缓释性和生物相容性，将化合物7和8封装到脂质体中进行体内活性和机制研究。体内研究表明，化合物7和8可以保护RIR损伤后正常的视网膜结构和生理功能，逆转视网膜神经节细胞的损伤，且S构型较R构型表现出明显更强的活性。机制研究表明，化合物8通过激活Keap1/Nrf2/ARE信号通路对RIR损伤发挥治疗作用；化合物7不影响该途径。我们还证明了 C-24 位点的差异异构化影响了对 RIR 损伤的保护。

更新日期：2024-08-15

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南