{"title":"Multi-target macrocycles: pyrogallol derivatives to control multiple pathological factors associated with Alzheimer’s disease","authors":"Jimin Kwak, Yelim Yi, Seongmin Park, Mi Hee Lim","doi":"10.1039/d4sc06417h","DOIUrl":null,"url":null,"abstract":"Designing multi-target chemical tools is a vital approach to understanding the pathology of Alzheimer’s disease (AD), which involves a complex network of pathological factors, such as free organic radicals, amyloid-β (Aβ), and metal-bound Aβ (metal–Aβ). The pyrogallol moiety, known for its ability to lower redox potentials and interact with both Aβ and metal ions, presents a promising framework for this molecular design. Here we show how simple structural variations of pyrogallol can be used to enhance its ability to scavenge free organic radicals and regulate the aggregation of both metal-free Aβ and metal–Aβ. By incorporating multiple pyrogllol units into a macrocyclic scaffold via methylene bridges, we achieve synergistic reactivity against several pathological targets. Our structure–reactivity relationship studies also reveal that the macrocyclic structure noticeably improves antioxidant activity as well as interactions with both Aβ and metal ions, leading to oxidation of Aβ peptides and influencing their conformation and aggregation in both the absence and presence of metal ions. This work demonstrates the potential of simple redox-active structural entities in developing multifunctional chemical reagents that effectively manage the pathological components associated with AD.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":"19 1","pages":""},"PeriodicalIF":7.6000,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemical Science","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1039/d4sc06417h","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
Designing multi-target chemical tools is a vital approach to understanding the pathology of Alzheimer’s disease (AD), which involves a complex network of pathological factors, such as free organic radicals, amyloid-β (Aβ), and metal-bound Aβ (metal–Aβ). The pyrogallol moiety, known for its ability to lower redox potentials and interact with both Aβ and metal ions, presents a promising framework for this molecular design. Here we show how simple structural variations of pyrogallol can be used to enhance its ability to scavenge free organic radicals and regulate the aggregation of both metal-free Aβ and metal–Aβ. By incorporating multiple pyrogllol units into a macrocyclic scaffold via methylene bridges, we achieve synergistic reactivity against several pathological targets. Our structure–reactivity relationship studies also reveal that the macrocyclic structure noticeably improves antioxidant activity as well as interactions with both Aβ and metal ions, leading to oxidation of Aβ peptides and influencing their conformation and aggregation in both the absence and presence of metal ions. This work demonstrates the potential of simple redox-active structural entities in developing multifunctional chemical reagents that effectively manage the pathological components associated with AD.
期刊介绍:
Chemical Science is a journal that encompasses various disciplines within the chemical sciences. Its scope includes publishing ground-breaking research with significant implications for its respective field, as well as appealing to a wider audience in related areas. To be considered for publication, articles must showcase innovative and original advances in their field of study and be presented in a manner that is understandable to scientists from diverse backgrounds. However, the journal generally does not publish highly specialized research.