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新型3-三唑基-1-硫代半乳糖苷作为半乳糖凝集素-1、-3和-8抑制剂的设计与合成

Design and synthesis of novel 3-triazolyl-1-thiogalactosides as galectin-1, -3 and -8 inhibitors.

作者信息

van Klaveren Sjors, Dernovšek Jaka, Jakopin Žiga, Anderluh Marko, Leffler Hakon, Nilsson Ulf J, Tomašič Tihomir

机构信息

University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Chemistry Aškerčeva cesta 7 1000 Ljubljana Slovenia

Centre for Analysis and Synthesis, Department of Chemistry, Lund University SE-221 00 Lund Sweden

出版信息

RSC Adv. 2022 Jun 30;12(29):18973-18984. doi: 10.1039/d2ra03163a. eCollection 2022 Jun 22.

DOI:10.1039/d2ra03163a
PMID:35873334
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9245910/
Abstract

Galectins are galactoside-binding proteins that play a role in various pathophysiological conditions, making them attractive targets in drug discovery. We have designed and synthesised a focused library of aromatic 3-triazolyl-1-thiogalactosides targeting their core site for binding of galactose and a subsite on its non-reducing side. Evaluation of their binding affinities for galectin-1, -3, and -8N identified acetamide-based compound 36 as a suitable compound for further affinity enhancement by adding groups at the reducing side of the galactose. Synthesis of its dichlorothiophenyl analogue 59 and the thiodigalactoside analogue 62 yielded promising pan-galectin inhibitors.

摘要

半乳糖凝集素是一类半乳糖苷结合蛋白，在多种病理生理过程中发挥作用，这使得它们成为药物研发中颇具吸引力的靶点。我们设计并合成了一个聚焦的芳香族3-三唑基-1-硫代半乳糖苷文库，该文库靶向半乳糖结合的核心位点及其非还原侧的一个亚位点。对它们与半乳糖凝集素-1、-3和-8N的结合亲和力进行评估后，发现基于乙酰胺的化合物36是一种合适的化合物，可通过在半乳糖的还原侧添加基团来进一步增强亲和力。其二氯硫代苯基类似物59和硫代双半乳糖苷类似物62的合成产生了有前景的泛半乳糖凝集素抑制剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08a2/9245910/5b12664c30d7/d2ra03163a-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08a2/9245910/607f12feb008/d2ra03163a-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08a2/9245910/18dc8d9f1815/d2ra03163a-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08a2/9245910/10a30df9912c/d2ra03163a-s1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08a2/9245910/4e3d4210e901/d2ra03163a-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08a2/9245910/5b12664c30d7/d2ra03163a-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08a2/9245910/607f12feb008/d2ra03163a-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08a2/9245910/18dc8d9f1815/d2ra03163a-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08a2/9245910/10a30df9912c/d2ra03163a-s1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08a2/9245910/4e3d4210e901/d2ra03163a-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/08a2/9245910/5b12664c30d7/d2ra03163a-f4.jpg

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RSC Adv. 2018 Jul 11;8(44):24913-24922. doi: 10.1039/c8ra04389b. eCollection 2018 Jul 9.
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Glycopolymers Decorated with 3--Substituted Thiodigalactosides as Potent Multivalent Inhibitors of Galectin-3.以3-取代硫代二半乳糖苷修饰的糖聚合物作为半乳糖凝集素-3的有效多价抑制剂
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