Influence of Side Chain Conformation on the Activity of Glycosidase Inhibitors. Issue 8 (18th January 2023)

• Record Type: Journal Article
• Authors: Tseng, Po‐Sen; Ande, Chennaiah; Moremen, Kelley W.; Crich, David
• Is Part Of: Angewandte Chemie international edition. Volume 62:Issue 8(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-01-18
• Subjects: Glycosidase -- Iminosugar -- Inhibitor -- Methyl Group -- Side Chain Conformation; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202217809
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Substrate side chain conformation impacts reactivity during glycosylation and glycoside hydrolysis and is restricted by many glycosidases and glycosyltransferases during catalysis. We show that the side chains of gluco and manno iminosugars can be restricted to predominant conformations by strategic installation of a methyl group. Glycosidase inhibition studies reveal that iminosugars with the gauche, gauche side chain conformations are 6‐ to 10‐fold more potent than isosteric compounds with the gauche, trans conformation; a manno ‐configured iminosugar with the gauche, gauche conformation is a 27‐fold better inhibitor than 1‐deoxymannojirimycin. The results are discussed in terms of the energetic benefits of preorganization, particularly when in synergy with favorable hydrophobic interactions. The demonstration that inhibitor side chain preorganization can favorably impact glycosidase inhibition paves the way for improved inhibitor design through conformational preorganization. Abstract : The first experimental demonstration that preorganization of inhibitor side chain conformation can favorably impact glycosidase inhibition is reported. By strategic installation of a methyl group at C6, a manno ‐configured iminosugar with the gauche, gauche side chain conformation was found to be a 27‐fold better inhibitor than 1‐deoxymannojirimycin.