文献类型：期刊文献

英文题名：Design, Synthesis, and Evaluation of Nitroxide Radical Derivatives Based on Rhein as Potential Anti-Aging Agents Targeting the Keap1-Nrf2 Pathway

作者：Wang, Jie[1];Peng, Xuejing[1,2];Zhang, Xinyue[1];Lin, Jia[3];Zhang, Qili[1,2];Li, Jiaojiao[1];Cui, Longchen[1];Zhao, Lei[1,2,4,5,6]

第一作者：王静

通信作者：Zhao, L[1];Cui, LC[1]

机构：[1]Gansu Univ Chinese Med, Coll Pharm, 35 Dingxi East Rd, Lanzhou 730000, Peoples R China;[2]Gansu Univ Chinese Med, Northwest Collaborat Innovat Ctr Tradit Chinese Med Coconstructed Gansu Prov & MOE PRC, Lanzhou, Peoples R China;[3]Gansu Hlth Vocat Coll, Coll Pharm, Lanzhou, Peoples R China;[4]Gansu Univ Chinese Med, Key Lab Chem & Qual TCM Coll Gansu Prov, Lanzhou, Peoples R China;[5]Gansu Univ Chinese Med, Gansu Prov Engn Lab TCM Standardizat Technol & Popularizat, Lanzhou, Peoples R China;[6]Gansu Pharmaceut Ind Innovat Res Inst, Lanzhou, Peoples R China

第一机构：甘肃中医药大学药学院（西北中藏药协同创新中心办公室）

通信机构：[1]corresponding author), Gansu Univ Chinese Med, Coll Pharm, 35 Dingxi East Rd, Lanzhou 730000, Peoples R China.|[1073501e14fb35863569f]甘肃中医药大学药学院（西北中藏药协同创新中心办公室）;[10735]甘肃中医药大学;

年份：2025

卷号：19

起止页码：5153

外文期刊名：DRUG DESIGN DEVELOPMENT AND THERAPY

收录：;Scopus(收录号：2-s2.0-105008965626);WOS:【SCI-EXPANDED(收录号:WOS:001513426900001)】；

基金：This work was supported by the National Natural Science Foundation of China (no. 82160457, no. 81660577) , the Gansu Provincial Department of Education 2024 University scientific research innovation platform major training project (no. 2024CXPT-18) , the Young Doctor Support Project of Gansu Provincial Department of Education (no. 2025QB-067) , the Open Fund of Gansu Province Engineering Laboratory for TCM Standardization Technology and Popularization (no. ddyc-2022-03) and the College industry support plan project of Gansu Province (no. 2025CYZC-052) .

语种：英文

外文关键词：rhein; nitroxide radical; antioxidant; anti-aging; keap1-Nrf2 pathway

摘要：Purpose: Targeting the crucial Keap1-Nrf2-ARE antioxidant pathway, we selected Rhein-a natural anthraquinone from traditional Chinese medicine with established Keap1-Nrf2 inhibitory activity as our lead compound. Through rational structural modification by incorporating nitroxide radicals at the 3-carboxyl position, we aimed to develop enhanced Keap1-Nrf2 modulators with anti-aging potential. Patients and Methods: A series of rhein nitroxide derivatives were synthesized, and their free radical scavenging activity was assessed in vitro using DPPH and ABTS methods. Compound 4b, demonstrating significant activity, was selected for further evaluation. Its effects on the survival of L02 hepatocytes under oxidative stress and the lifespan and stress tolerance of Caenorhabditis elegans (C. elegans) were investigated. Additionally, the impacts of 4b on antioxidant enzyme activity, malondialdehyde (MDA) levels, and reactive oxygen species (ROS) accumulation under oxidative stress were assessed. Molecular docking was conducted to analyze interactions between 4b and the Kelch domain of Keap1. Results: Compound 4b exhibited potent free radical scavenging activity, with IC50 values of 0.51 +/- 0.09 mM against DPPH radicals and 0.12 +/- 0.03 mM against ABTS radicals. It significantly improved the survival rate of L02 hepatocytes under oxidative stress, maintaining 95.42% viability (p < 0.01). In the C. elegans model, 4b extended the average lifespan and enhanced stress resistance, increasing GSH activity, reducing MDA content, and decreasing ROS accumulation. Molecular docking showed that 4b penetrates deeply into the Kelch domain of Keap1, forming stable interactions with key residues. Conclusion: Compound 4b demonstrates superior antioxidant and anti-aging effects compared to the parent compound rhein, representing a highly promising anti-aging candidate and Keap1-Nrf2 signaling pathway modulator with potential as a novel therapeutic agent for age-related diseases.