Conformational and Electronic Variations in 1,2‐ and 1,5a‐Cyclophellitols and their Impact on Retaining α‐Glucosidase Inhibition

作者：Tim P. Ofman, Jurriaan J. A. Heming, Alba Nin‐Hill, Florian Küllmer, E. J. MORAN, Megan Bennett, Roy Steneker, Anne‐Mei Klein, Gijs Ruijgrok, Ken Kok, Zachary Armstrong, Johannes M. F. G. Aerts, Gijsbert A. van der Marel, Carme Rovira, G.J. Davies, Marta Artola, Jeroen D. C. Codée, Herman S. Overkleeft · 发表于：Chemistry - A European Journal · 年份：2024 · DOI：10.1002/chem.202400723 · 被引用次数：4 · 研究领域：Carbohydrate Chemistry and Synthesis、Enzyme Catalysis and Immobilization、Natural Antidiabetic Agents Studies

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.