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。

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-08-25 DOI:10.1002/cmdc.202500299
Yaojia Li, Jiahui Zhou, Xiaoxing Wu, Wei Li, Zhe Wang, Jianchen Yang, Genzoh Tanabe, Osamu Muraoka, Weijia Xie
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引用次数: 0

摘要

设计并合成了一系列具有不同苄基缩醛侧链取代基的磺酸盐、硒盐和铵盐。与以往的研究相反,本研究强调了3'位置的立体化学反转和磺胺阳离子中心的生物等构取代。体外α-葡萄糖苷酶抑制实验鉴定20b、20l和21b为有效抑制剂。在体内,20b (15.0 mg kg-1)使蔗糖负荷小鼠的餐后血糖水平降低了40.6%(15分钟)、49.5%(30分钟)和43.6%(60分钟),超过了阿卡波糖(20.0 mg kg-1)。20b与malase - glucoamylase (ntMGAM) n端亚基的分子对接显示出相同的结合模式,即3'立体倒置诱导苯并二乙基缩醛苯环与Phe450之间的π-π堆积以及邻硝基与Asp203之间的静电相互作用。细胞毒性评估证实了所选化合物在正常细胞系中的良好安全性。酶动力学研究表明,这些磺化盐对α-葡萄糖苷酶具有完全竞争性抑制作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
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. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
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