手性吖啶酮-亚氨基糖杂合二聚体对乙酰胆碱酯酶和丁酰胆碱酯酶抑制的对映选择性研究。
Investigation of the enantioselectivity of acetylcholinesterase and butyrylcholinesterase upon inhibition by tacrine-iminosugar heterodimers.
机构信息
Department of Chemistry, Bioscience and Environmental Engineering, Faculty of Science and Technology, University of Stavanger, Stavanger, Norway.
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Seville, Spain.
出版信息
J Enzyme Inhib Med Chem. 2023 Dec;38(1):349-360. doi: 10.1080/14756366.2022.2150762.
The copper-catalysed azide-alkyne cycloaddition was applied to prepare three enantiomeric pairs of heterodimers containing a tacrine residue and a 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) or 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) moiety held together linkers of variable lengths containing a 1,2,3-triazole ring and 3, 4, or 7 CH groups. The heterodimers were tested as inhibitors of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE). The enantiomeric heterodimers with the longest linkers exhibited the highest inhibition potencies for AChE (IC = 9.7 nM and 11 nM) and BuChE (IC = 8.1 nM and 9.1 nM). AChE exhibited the highest enantioselectivity (. 4-fold). The enantiomeric pairs of the heterodimers were found to be inactive (GI > 100 µM), or to have weak antiproliferative properties (GI = 84-97 µM) against a panel of human cancer cells.
铜催化的叠氮化物-炔烃环加成反应被应用于制备三种包含他克林残基和 1,4-二脱氧-1,4-亚氨基-D-阿拉伯糖醇（DAB）或 1,4-二脱氧-1,4-亚氨基-L-阿拉伯糖醇（LAB）部分的非对映异构杂二聚体，它们通过含有 1,2,3-三唑环和 3、4 或 7 CH 基团的不同长度的连接子连接在一起。这些杂二聚体被测试为丁酰胆碱酯酶（BuChE）和乙酰胆碱酯酶（AChE）的抑制剂。具有最长连接子的非对映异构杂二聚体对 AChE（IC = 9.7 nM 和 11 nM）和 BuChE（IC = 8.1 nM 和 9.1 nM）表现出最高的抑制活性。AChE 表现出最高的对映体选择性（4 倍）。发现这些杂二聚体的非对映异构体对一组人类癌细胞没有活性（GI > 100 μM），或者具有较弱的抗增殖特性（GI = 84-97 μM）。
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