Pseudonatural Flavonols as Novel Copper Ionophores for NAFLD Intervention via Synergistic Copper Delivery and Flavonoid Activity

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-03-13 DOI:10.1021/acs.jmedchem.4c02927

Jun Jiang, Gang Chen, Weiqin Zhang, Si Qin, Man Li, Shiyi Zhong, Ying Yang, Liuxin Yang, Muqing Shao, Kai Wang, Qin Li, Chen Jiang, Jingfang Yang, Fang Wang, Shuang Qiu, Xiang Li

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引用次数: 0

Abstract

Copper plays crucial roles in fundamental life processes, including proliferation, metabolism, and survival. Copper deficiency is associated with multiple diseases, such as nonalcoholic fatty liver disease (NAFLD) and Wilson’s disease. Therapeutic programs targeting copper supply are prospectively employed for disease intervention. Herein, we developed biofriendly copper ionophores (HQFs) by constructing pseudonatural flavonols, which possess flavonoid bioactivity and enhanced copper transport properties. In cell models and mice, we found that HQF-mediated copper delivery synergistically, safely, and efficiently intervened in the development of fatty liver. Mechanistically, NAFLD remission involves fatty acid metabolism, anti-inflammatory processes, and pentose phosphate pathway (PPP) enhancement. Our work is the first to propose the utilization of synergistic copper loading and flavonoid activity for NAFLD intervention, which may inform the clinical management of liver disease.

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伪天然黄酮醇作为新型铜离子载体通过铜的协同传递和类黄酮活性干预NAFLD

铜在基本的生命过程中起着至关重要的作用，包括增殖、代谢和生存。铜缺乏与多种疾病有关，如非酒精性脂肪性肝病（NAFLD）和威尔逊氏病。针对铜供应的治疗方案有望用于疾病干预。在此，我们通过构建具有类黄酮生物活性和增强铜转运特性的伪天然黄酮醇来开发生物友好型铜离子载体（HQFs）。在细胞模型和小鼠中，我们发现hqf介导的铜递送协同、安全、有效地干预了脂肪肝的发展。机制上，NAFLD的缓解涉及脂肪酸代谢、抗炎过程和戊糖磷酸途径（PPP）的增强。我们的工作首次提出利用协同铜负荷和类黄酮活性干预NAFLD，这可能为肝脏疾病的临床管理提供信息。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.