Department of Chemistry, York Structural Biology Laboratory , University of York , Heslington, York YO10 5DD , United Kingdom.
J Am Chem Soc. 2018 Apr 18;140(15):5045-5048. doi: 10.1021/jacs.8b02399. Epub 2018 Apr 4.
Gluco-azoles competitively inhibit glucosidases by transition-state mimicry and their ability to interact with catalytic acid residues in glucosidase active sites. We noted that no azole-type inhibitors described, to date, possess a protic nitrogen characteristic for 1 H-imidazoles. Here, we present gluco-1 H-imidazole, a gluco-azole bearing a 1 H-imidazole fused to a glucopyranose-configured cyclitol core, and three close analogues as new glucosidase inhibitors. All compounds inhibit human retaining β-glucosidase, GBA1, with the most potent ones inhibiting this enzyme (deficient in Gaucher disease) on a par with glucoimidazole. None inhibit glucosylceramide synthase, cytosolic β-glucosidase GBA2 or α-glucosidase GAA. Structural, physical and computational studies provide first insights into the binding mode of this conceptually new class of retaining β-glucosidase inhibitors.
葡糖唑类通过过渡态模拟物竞争性抑制糖苷酶，并且能够与糖苷酶活性部位的催化酸残基相互作用。我们注意到，迄今为止，没有描述过任何具有 1H-咪唑特征的唑类抑制剂。在这里，我们提出了葡糖-1H-咪唑，这是一种带有 1H-咪唑的葡糖唑，与葡萄糖吡喃糖构型的环糖醇核心融合，以及三个类似物作为新的糖苷酶抑制剂。所有化合物都抑制人保留β-葡萄糖苷酶 GBA1，其中最有效的抑制剂与葡糖咪唑相当，能抑制这种在戈谢病中缺乏的酶。没有一种抑制剂抑制葡糖脑苷脂合酶、胞质β-葡萄糖苷酶 GBA2 或α-葡萄糖苷酶 GAA。结构、物理和计算研究首次提供了对这一概念上新型保留β-葡萄糖苷酶抑制剂的结合模式的深入了解。
