糖苷水解酶(糖苷酶)参与许多生物过程并且是重要的治疗靶标。竞争性和基于机制的抑制剂是剖析其生物学作用的有用工具,并且是药物发现的良好起点。天然产物,环phellitol,基于机制,共价和不可逆保留的β-葡萄糖苷酶抑制剂激发了多种α-和β-葡萄糖苷酶抑制剂和基于活性的探针支架的设计。这里,我们试图加深我们的结构和功能要求的环水糖醇型化合物有效抑制人α-葡萄糖苷酶的理解。我们合成了一套完整的α-配置的1,2-和1,6-环phellitol类似物,带有各种亲电子陷阱。评估了这些化合物对溶酶体和ER保留α-葡糖苷酶的抑制效力。这些研究表明,1,6-环磷醇是最有效的保留α-葡萄糖苷酶抑制剂,具有决定作用的抑制模式(共价或非共价)的亲电子试剂的性质。DFT计算支持1,6-环酚类化合物的能力,但不是1,2-同源物,采用模拟α-葡糖苷酶的米氏复合物或过渡态的构象。
Glycoside hydrolases (glycosidases) take part in myriad biological processes and are important therapeutic targets. Competitive and mechanism-based inhibitors are useful tools to dissect their biological role and comprise a good starting point for drug discovery. The natural product, cyclophellitol, a mechanism-based, covalent and irreversible retaining β-
glucosidase inhibitor has inspired the design of diverse α- and β-glycosidase inhibitor and activity-based probe scaffolds. Here, we sought to deepen our understanding of the structural and functional requirements of cyclophellitol-type compounds for effective human α-
glucosidase inhibition. We synthesized a comprehensive set of α-configured 1,2- and 1,5a-cyclophellitol analogues bearing a variety of electrophilic traps. The inhibitory potency of these compounds was assessed towards both lysosomal and ER retaining α-glucosidases. These studies revealed the 1,5a-cyclophellitols to be the most potent retaining α-
glucosidase inhibitors, with the nature of the electrophile determining inhibitory mode of action (covalent or non-covalent). DFT calculations support the ability of the 1,5a-cyclophellitols, but not the 1,2-congeners, to adopt conformations that mimic either the Michaelis complex or transition state of α-glucosidases.