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A Convenient Approach to Stereoisomeric Iminocyclitols: Generation of Potent Brain-Permeable OGA Inhibitors.

Bergeron-Brlek M, Goodwin-Tindall J, Cekic N, Roth C, Zandberg WF, Shan X, Varghese V, Chan S, Davies GJ, Vocadlo DJ, Britton R
Angew Chem Int Ed Engl 54 15429-33 (2015)
Related entries: 5abe, 5abf, 5abg

Cited: 14 times
EuropePMC logo PMID: 26545827

Abstract

Pyrrolidine-based iminocyclitols are a promising class of glycosidase inhibitors. Reported herein is a convenient epimerization strategy that provides direct access to a range of stereoisomeric iminocyclitol inhibitors of O-GlcNAcase (OGA), the enzyme responsible for catalyzing removal of O-GlcNAc from nucleocytoplasmic proteins. Structural details regarding the binding of these inhibitors to a bacterial homologue of OGA reveal the basis for potency. These compounds are orally available and permeate into rodent brain to increase O-GlcNAc, and should prove useful tools for studying the role of OGA in health and disease.

Reviews citing this publication (6)

  1. Deciphering the Functions of Protein O-GlcNAcylation with Chemistry. Worth M, Li H, Jiang J. ACS Chem Biol 12 326-335 (2017)
  2. Advances in chemical probing of protein O-GlcNAc glycosylation: structural role and molecular mechanisms. Saha A, Bello D, Fernández-Tejada A. Chem Soc Rev 50 10451-10485 (2021)
  3. Glycoside Mimics from Glycosylamines: Recent Progress. Nicolas C, Martin OR. Molecules 23 (2018)
  4. Molecular Interrogation to Crack the Case of O-GlcNAc. Estevez A, Zhu D, Blankenship C, Jiang J. Chemistry 26 12086-12100 (2020)
  5. Multivalent Pyrrolidine Iminosugars: Synthesis and Biological Relevance. Wang Y, Xiao J, Meng A, Liu C. Molecules 27 5420 (2022)
  6. Understanding and exploiting the roles of O-GlcNAc in neurodegenerative diseases. Pratt MR, Vocadlo DJ. J Biol Chem 299 105411 (2023)

Articles citing this publication (8)

  1. Structural and functional insight into human O-GlcNAcase. Roth C, Chan S, Offen WA, Hemsworth GR, Willems LI, King DT, Varghese V, Britton R, Vocadlo DJ, Davies GJ. Nat. Chem. Biol. 13 610-612 (2017)
  2. Expanding the library of divalent fucosidase inhibitors with polyamino and triazole-benzyl bridged bispyrrolidines. Hottin A, Carrión-Jiménez S, Moreno-Clavijo E, Moreno-Vargas AJ, Carmona AT, Robina I, Behr JB. Org. Biomol. Chem. 14 3212-3220 (2016)
  3. Structural Snapshots for Mechanism-Based Inactivation of a Glycoside Hydrolase by Cyclopropyl Carbasugars. Adamson C, Pengelly RJ, Shamsi Kazem Abadi S, Chakladar S, Draper J, Britton R, Gloster TM, Bennet AJ. Angew. Chem. Int. Ed. Engl. 55 14978-14982 (2016)
  4. Diversity-oriented synthesis of glycomimetics. Meanwell M, Fehr G, Ren W, Adluri B, Rose V, Lehmann J, Silverman SM, Rowshanpour R, Adamson C, Bergeron-Brlek M, Foy H, Challa VR, Campeau LC, Dudding T, Britton R. Commun Chem 4 96 (2021)
  5. Design and Optimization of Thioglycosyl-naphthalimides as Efficient Inhibitors Against Human O-GlcNAcase. Shen S, Dong L, Chen W, Wu R, Lu H, Yang Q, Zhang J. Front Chem 7 533 (2019)
  6. Mimics of pramanicin derived from pyroglutamic acid and their antibacterial activity. Tan SW, Chai CL, Moloney MG. Org. Biomol. Chem. 15 1889-1912 (2017)
  7. Study of the β-oxygen effect in the Barton-McCombie reaction for the total synthesis of (4R,5R)-4-hydroxy-γ-decalactone (Japanese orange fly lactone): a carbohydrate based approach. Desireddi JR, Rao MM, Murahari KK, Nimmareddy RR, Mothe T, Lingala AK, Maiti B, Manchal R. RSC Adv 12 25520-25527 (2022)
  8. Thiol-ene "Click" Synthesis and Pharmacological Evaluation of C-Glycoside sp2-Iminosugar Glycolipids. Sánchez-Fernández EM, García-Moreno MI, García-Hernández R, Padrón JM, García Fernández JM, Gamarro F, Ortiz Mellet C. Molecules 24 (2019)


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