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调变亚胺糖的活性：新型烷基化去氧野尻霉素衍生物作为强效 BuChE 抑制剂。

Tuning the activity of iminosugars: novel -alkylated deoxynojirimycin derivatives as strong BuChE inhibitors.

机构信息

Facultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de Puebla, Puebla, México.

BioLab, Instituto Universitario de Bio-Orgánica "Antonio González" (IUBO-AG), Universidad de La Laguna, La Laguna, Spain.

出版信息

J Enzyme Inhib Med Chem. 2021 Dec;36(1):138-146. doi: 10.1080/14756366.2020.1847101.

DOI:10.1080/14756366.2020.1847101
PMID:33228403
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7717699/
Abstract

We have designed unprecedented cholinesterase inhibitors based on 1-deoxynojirimycin as potential anti-Alzheimer's agents. Compounds are comprised of three key structural motifs: the iminosugar, for interaction with cholinesterase catalytic anionic site (CAS); a hydrocarbon tether with variable lengths, and a fragment derived from 2-phenylethanol for promoting interactions with peripheral anionic site (PAS). Title compounds exhibited good selectivity towards BuChE, strongly depending on the substitution pattern and the length of the tether. The lead compounds were found to be strong mixed inhibitors of BuChE (IC = 1.8 and 1.9 µM). The presumptive binding mode of the lead compound was analysed using molecular docking simulations, revealing H-bond interactions with the catalytic subsite (His438) and CAS (Trp82 and Glu197) and van der Waals interactions with PAS (Thr284, Pro285, Asn289). They also lacked significant antiproliferative activity against tumour and non-tumour cells at 100 µM, making them promising new agents for tackling Alzheimer's disease through the cholinergic approach.

摘要

我们设计了前所未有的基于 1-脱氧野尻霉素的胆碱酯酶抑制剂，作为潜在的抗阿尔茨海默病药物。这些化合物由三个关键的结构基序组成：氨基糖，用于与胆碱酯酶催化阴离子部位（CAS）相互作用；具有不同长度的烃链，以及衍生自 2-苯乙醇的片段，用于促进与外周阴离子部位（PAS）的相互作用。标题化合物对 BuChE 表现出良好的选择性，这强烈依赖于取代模式和连接链的长度。发现先导化合物是 BuChE 的强混合抑制剂（IC = 1.8 和 1.9 μM）。使用分子对接模拟分析了先导化合物的假定结合模式，揭示了与催化亚位点（His438）和 CAS（Trp82 和 Glu197）的氢键相互作用以及与 PAS（Thr284、Pro285、Asn289）的范德华相互作用。它们在 100 μM 时对肿瘤和非肿瘤细胞也没有明显的增殖活性，这使它们成为通过胆碱能途径治疗阿尔茨海默病的有前途的新药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfb4/7717699/a476081835c8/IENZ_A_1847101_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfb4/7717699/77502cd56bc0/IENZ_A_1847101_UF0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfb4/7717699/f1edfec9a163/IENZ_A_1847101_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfb4/7717699/d7d9f43f99d4/IENZ_A_1847101_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfb4/7717699/a48e52b6a3ca/IENZ_A_1847101_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfb4/7717699/fbb8099f6882/IENZ_A_1847101_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfb4/7717699/a476081835c8/IENZ_A_1847101_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfb4/7717699/77502cd56bc0/IENZ_A_1847101_UF0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfb4/7717699/f1edfec9a163/IENZ_A_1847101_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfb4/7717699/d7d9f43f99d4/IENZ_A_1847101_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfb4/7717699/a48e52b6a3ca/IENZ_A_1847101_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfb4/7717699/fbb8099f6882/IENZ_A_1847101_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfb4/7717699/a476081835c8/IENZ_A_1847101_F0004_C.jpg

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