{"title":"作为多功能抗AD 配体的香叶木素衍生物:设计、合成和生物学评价","authors":"Aihong Yang, Xiaoyue Yi, Hongwei Zhang, Rui Shen, Xiaodi Kou","doi":"10.1111/cbdd.14529","DOIUrl":null,"url":null,"abstract":"<p>With the increasing aging population, rational design of drugs for Alzheimer's disease (AD) treatment has become an important research area. Based on the multifunctional design strategy, four diosmetin derivatives (<b>1</b>–<b>4</b>) were designed, synthesized, and characterized by <sup>1</sup>H NMR, <sup>13</sup>C NMR, and MS. Docking study was firstly applied to substantiate the design strategies and then the biological activities including cholinesterase inhibition, metal chelation, antioxidation and β-amyloid (Aβ) aggregation inhibition in vitro were evaluated. The results showed that <b>1–4</b> had good acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, metal chelation (selective chelation of Cu<sup>2+</sup> ions), antioxidation, self-induced, Cu<sup>2+</sup>-induced, and AChE-induced Aβ aggregation inhibition activities, and suitable blood–brain barrier (BBB) permeability. Especially, compound <b>3</b> had the strongest inhibitory effect on AChE (10<sup>−8</sup> M magnitude) and BuChE (10<sup>−7</sup> M magnitude) and showed the best inhibition on AChE-induced Aβ aggregation with 66.14% inhibition ratio. Furthermore, compound <b>3</b> could also reduce intracellular reactive oxygen species (ROS) levels in <i>Caenorhabditis elegans</i> and had lower cytotoxicity. In summary, <b>3</b> might be considered as a potential multifunctional anti-AD ligand.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":null,"pages":null},"PeriodicalIF":3.2000,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Diosmetin derivatives as multifunctional anti-AD ligands: Design, synthesis, and biological evaluation\",\"authors\":\"Aihong Yang, Xiaoyue Yi, Hongwei Zhang, Rui Shen, Xiaodi Kou\",\"doi\":\"10.1111/cbdd.14529\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>With the increasing aging population, rational design of drugs for Alzheimer's disease (AD) treatment has become an important research area. Based on the multifunctional design strategy, four diosmetin derivatives (<b>1</b>–<b>4</b>) were designed, synthesized, and characterized by <sup>1</sup>H NMR, <sup>13</sup>C NMR, and MS. Docking study was firstly applied to substantiate the design strategies and then the biological activities including cholinesterase inhibition, metal chelation, antioxidation and β-amyloid (Aβ) aggregation inhibition in vitro were evaluated. The results showed that <b>1–4</b> had good acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, metal chelation (selective chelation of Cu<sup>2+</sup> ions), antioxidation, self-induced, Cu<sup>2+</sup>-induced, and AChE-induced Aβ aggregation inhibition activities, and suitable blood–brain barrier (BBB) permeability. Especially, compound <b>3</b> had the strongest inhibitory effect on AChE (10<sup>−8</sup> M magnitude) and BuChE (10<sup>−7</sup> M magnitude) and showed the best inhibition on AChE-induced Aβ aggregation with 66.14% inhibition ratio. Furthermore, compound <b>3</b> could also reduce intracellular reactive oxygen species (ROS) levels in <i>Caenorhabditis elegans</i> and had lower cytotoxicity. In summary, <b>3</b> might be considered as a potential multifunctional anti-AD ligand.</p>\",\"PeriodicalId\":143,\"journal\":{\"name\":\"Chemical Biology & Drug Design\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.2000,\"publicationDate\":\"2024-04-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Chemical Biology & Drug Design\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/cbdd.14529\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemical Biology & Drug Design","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cbdd.14529","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Diosmetin derivatives as multifunctional anti-AD ligands: Design, synthesis, and biological evaluation
With the increasing aging population, rational design of drugs for Alzheimer's disease (AD) treatment has become an important research area. Based on the multifunctional design strategy, four diosmetin derivatives (1–4) were designed, synthesized, and characterized by 1H NMR, 13C NMR, and MS. Docking study was firstly applied to substantiate the design strategies and then the biological activities including cholinesterase inhibition, metal chelation, antioxidation and β-amyloid (Aβ) aggregation inhibition in vitro were evaluated. The results showed that 1–4 had good acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, metal chelation (selective chelation of Cu2+ ions), antioxidation, self-induced, Cu2+-induced, and AChE-induced Aβ aggregation inhibition activities, and suitable blood–brain barrier (BBB) permeability. Especially, compound 3 had the strongest inhibitory effect on AChE (10−8 M magnitude) and BuChE (10−7 M magnitude) and showed the best inhibition on AChE-induced Aβ aggregation with 66.14% inhibition ratio. Furthermore, compound 3 could also reduce intracellular reactive oxygen species (ROS) levels in Caenorhabditis elegans and had lower cytotoxicity. In summary, 3 might be considered as a potential multifunctional anti-AD ligand.
期刊介绍:
Chemical Biology & Drug Design is a peer-reviewed scientific journal that is dedicated to the advancement of innovative science, technology and medicine with a focus on the multidisciplinary fields of chemical biology and drug design. It is the aim of Chemical Biology & Drug Design to capture significant research and drug discovery that highlights new concepts, insight and new findings within the scope of chemical biology and drug design.