Department of Organic Chemistry, Faculty of Chemistry, University of Seville, C/ Prof. García González, 1, 41012, Seville, Spain.
Department of Organic Chemistry, Faculty of Chemistry, University of Seville, C/ Prof. García González, 1, 41012, Seville, Spain.
Eur J Med Chem. 2018 May 10;151:765-776. doi: 10.1016/j.ejmech.2018.04.008. Epub 2018 Apr 5.
The synthesis of three libraries (1a-l, 1a'-l' and 2a-l) of dimeric iminosugars through CuAAC reaction between three different alkynyl pyrrolidines and a set of diazides was carried out. The resulting crude dimers were screened in situ against two α-fucosidases (libraries 1a-l and 1a'-l') and one β-galactosidase (2a-l). This method is pioneer in the search of divalent glycosidase inhibitors. It has allowed the rapid identification of dimer 1i as the best inhibitor of α-fucosidases from bovine kidney (K = 0.15 nM) and Homo sapiens (K = 60 nM), and dimer 2e as the best inhibitor of β-galactosidase from bovine liver (K = 5.8 μM). In order to evaluate a possible divalent effect in the inhibition, the synthesis and biological analysis of the reference monomers were also performed. Divalent effect was only detected in the inhibition of bovine liver β-galactosidase by dimer 2e.
通过三炔基吡咯烷与一组叠氮化物之间的 CuAAC 反应，合成了三个二聚亚氨基糖库（1a-l、1a'-l'和 2a-l）。所得粗二聚体就地筛选了两种α-岩藻糖苷酶（库 1a-l 和 1a'-l'）和一种β-半乳糖苷酶（2a-l）。该方法开创了二价糖苷酶抑制剂的研究先河。它能够快速鉴定出二聚体 1i 是牛肾（K=0.15 nM）和人（K=60 nM）α-岩藻糖苷酶的最佳抑制剂，二聚体 2e 是牛肝β-半乳糖苷酶的最佳抑制剂（K=5.8 μM）。为了评估抑制作用中可能存在的二价效应，还进行了参考单体的合成和生物学分析。只有二聚体 2e 对牛肝β-半乳糖苷酶的抑制作用中检测到二价效应。
