{"title":"具有3′,5′-邻苯并缩醛侧链的α-葡萄糖苷酶抑制剂磺酸和硒衍生物的设计与合成。","authors":"Yaojia Li, Jiahui Zhou, Xiaoxing Wu, Wei Li, Zhe Wang, Jianchen Yang, Genzoh Tanabe, Osamu Muraoka, Weijia Xie","doi":"10.1002/cmdc.202500299","DOIUrl":null,"url":null,"abstract":"<p><p>A series of sulfonium, selenonium, and ammonium salts featuring diverse benzylidene acetal side chain substituents are designed and synthesized. In contrast to the previous work, this study emphasized stereochemical inversion at the 3'-position and bioisosteric replacements at the sulfonium cationic center. In vitro α-glucosidase inhibition assays identified 20b, 20l, and 21b as potent inhibitors. In vivo, 20b (15.0 mg kg<sup>-1</sup>) reduced postprandial blood glucose levels in sucrose-loaded mice by 40.6% (15 min), 49.5% (30 min), and 43.6% (60 min), surpassing acarbose (20.0 mg kg<sup>-</sup> <sup>1</sup>). Molecular docking of 20b with the N-terminal subunit of Maltase-Glucoamylase (ntMGAM) revealed an identical binding mode, where 3'-stereoinversion induced π-π stacking between the benzylidene acetal phenyl ring and Phe450 and electrostatic interactions between the ortho-nitro group and Asp203. Cytotoxicity assessments confirmed the favorable safety profile of selected compounds in normal cell lines. Enzyme kinetic studies demonstrated fully competitive inhibition of α-glucosidase by these sulfonium salts.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202500299"},"PeriodicalIF":3.4000,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Design and Synthesis of Sulfonium and Selenonium Derivatives Bearing 3',5'-O-Benzylidene Acetal Side Chains as Potent α-Glucosidase Inhibitors.\",\"authors\":\"Yaojia Li, Jiahui Zhou, Xiaoxing Wu, Wei Li, Zhe Wang, Jianchen Yang, Genzoh Tanabe, Osamu Muraoka, Weijia Xie\",\"doi\":\"10.1002/cmdc.202500299\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>A series of sulfonium, selenonium, and ammonium salts featuring diverse benzylidene acetal side chain substituents are designed and synthesized. In contrast to the previous work, this study emphasized stereochemical inversion at the 3'-position and bioisosteric replacements at the sulfonium cationic center. In vitro α-glucosidase inhibition assays identified 20b, 20l, and 21b as potent inhibitors. In vivo, 20b (15.0 mg kg<sup>-1</sup>) reduced postprandial blood glucose levels in sucrose-loaded mice by 40.6% (15 min), 49.5% (30 min), and 43.6% (60 min), surpassing acarbose (20.0 mg kg<sup>-</sup> <sup>1</sup>). Molecular docking of 20b with the N-terminal subunit of Maltase-Glucoamylase (ntMGAM) revealed an identical binding mode, where 3'-stereoinversion induced π-π stacking between the benzylidene acetal phenyl ring and Phe450 and electrostatic interactions between the ortho-nitro group and Asp203. Cytotoxicity assessments confirmed the favorable safety profile of selected compounds in normal cell lines. Enzyme kinetic studies demonstrated fully competitive inhibition of α-glucosidase by these sulfonium salts.</p>\",\"PeriodicalId\":147,\"journal\":{\"name\":\"ChemMedChem\",\"volume\":\" \",\"pages\":\"e202500299\"},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2025-08-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ChemMedChem\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/cmdc.202500299\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ChemMedChem","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/cmdc.202500299","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Design and Synthesis of Sulfonium and Selenonium Derivatives Bearing 3',5'-O-Benzylidene Acetal Side Chains as Potent α-Glucosidase Inhibitors.
A series of sulfonium, selenonium, and ammonium salts featuring diverse benzylidene acetal side chain substituents are designed and synthesized. In contrast to the previous work, this study emphasized stereochemical inversion at the 3'-position and bioisosteric replacements at the sulfonium cationic center. In vitro α-glucosidase inhibition assays identified 20b, 20l, and 21b as potent inhibitors. In vivo, 20b (15.0 mg kg-1) reduced postprandial blood glucose levels in sucrose-loaded mice by 40.6% (15 min), 49.5% (30 min), and 43.6% (60 min), surpassing acarbose (20.0 mg kg-1). Molecular docking of 20b with the N-terminal subunit of Maltase-Glucoamylase (ntMGAM) revealed an identical binding mode, where 3'-stereoinversion induced π-π stacking between the benzylidene acetal phenyl ring and Phe450 and electrostatic interactions between the ortho-nitro group and Asp203. Cytotoxicity assessments confirmed the favorable safety profile of selected compounds in normal cell lines. Enzyme kinetic studies demonstrated fully competitive inhibition of α-glucosidase by these sulfonium salts.
期刊介绍:
Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies.
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