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Synthesis and Therapeutic Applications of Iminosugars

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 5942

Special Issue Editors


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Guest Editor
Dipartimento di Scienze Chimiche, Università degli Studi di Napoli Federico II, via Cintia, 80126 Naples, Italy
Interests: biomimetic agents; artificial metalloenzymes; organic synthesis; drug discovery; angiogenesis; chronic inflammation
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Guest Editor
Dipartimento di Ingegneria Chimica, dei Materiali e della Produzione Industriale, Università degli Studi di Napoli Federico II, Piazzale V. Tecchio 80, 80125 Napoli, Italy
Interests: iminosugars; drug delivery systems; nucleoside analogues; steroids; antimicrobial agents; stereoselective organic synthesis
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Dipartimento di Chimica “Ugo Schiff”, Università degli Studi di Firenze, Via della Lastruccia 3-13, 50019 Sesto Fiorentino (FI), Italy
Interests: nitrogen-containing glycomimetics; synthesis of natural products and biologically active analogs; multivalency; oxidation reactions; homogeneous catalysis; green chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Iminosugars represent the most important class of glycomimetics (carbohydrate analogues) known to date. Because of their excellent ability to modulate the activity of ubiquitous carbohydrate-processing enzymes, iminosugars have been clinically evaluated in a variety of therapeutic areas, ranging from diabetes to viral infections, from malignancies to genetic disorders. The pharmacological potential of iminosugars has prompted the development of a plethora of synthetic approaches, allowing their preparation from laboratory to industrial scales, while enabling the identification of new bioactive candidates with non-natural structures. This issue aims to collect the most recent advances in the synthesis and biological activity of synthetic iminosugars. Original research works or general reviews are welcome, involving innovative synthetic routes to iminosugars, mechanistic insights into their chemical reactivity and/or biological activity, or highlighting novel therapeutic applications.

Dr. Daniele D'Alonzo
Prof. Dr. Annalisa Guaragna
Prof. Dr. Andrea Goti
Guest Editors

Manuscript Submission Information

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Keywords

  • Iminosugars
  • Glycomimetics
  • Synthesis of iminosugars
  • Carbohydrate processing enzymes
  • Enzyme inhibitors
  • Glycosidase inhibitors
  • Glycosyltransferase inhibitors
  • Pharmacological chaperones
  • Lysosomal storage disorders
  • Antiviral agents
  • Biological activity of iminosugars

Published Papers (3 papers)

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Research

16 pages, 1405 KiB  
Communication
Bambus[4,6]urils as Dual Scaffolds for Multivalent Iminosugar Presentation and Ion Transport: Access to Unprecedented Glycosidase-Directed Anion Caging Agents
by Marine Lafosse, Yan Liang, Jérémy P. Schneider, Elise Cartier, Anne Bodlenner, Philippe Compain and Marie-Pierre Heck
Molecules 2022, 27(15), 4772; https://doi.org/10.3390/molecules27154772 - 26 Jul 2022
Cited by 3 | Viewed by 1565
Abstract
Bambusurils, BU[4] and BU[6], were used for the first time as multivalent scaffolds to link glycosidases inhibitors derived from 1-deoxynojirimycin (DNJ). Two linear DNJ ligands having six or nine carbon alkyl azido linkers or a trivalent DNJ dendron were grafted onto octapropargylated BU[4] [...] Read more.
Bambusurils, BU[4] and BU[6], were used for the first time as multivalent scaffolds to link glycosidases inhibitors derived from 1-deoxynojirimycin (DNJ). Two linear DNJ ligands having six or nine carbon alkyl azido linkers or a trivalent DNJ dendron were grafted onto octapropargylated BU[4] and dodecapropargylated BU[6] using copper-catalyzed cycloaddition (CuAAC) to yield corresponding neoglycobambus[4] and neoglycobambus[6]urils bearing 8 to 24 iminosugars. The inhibition potencies of neoglycoBU[4], neoglycoBU[6] and neoglycoBU[6] caging anions were evaluated against Jack Bean α-mannosidase and compared to monovalent DNJ derivatives. Strong affinity enhancements per inhibitory head were obtained for the clusters holding trivalent dendrons with inhibitory constants in the nanomolar range (Ki = 24 nM for BU[4] with 24 DNJ units). Interestingly, the anion (bromide or iodide) encapsulated inside the cavity of BU[6] does not modify the inhibition potency of neoglycoBU[6], opening the way to water-soluble glycosidase-directed anion caging agents that may find applications in important fields such as bio(in)organic chemistry or oncology. Full article
(This article belongs to the Special Issue Synthesis and Therapeutic Applications of Iminosugars)
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21 pages, 2406 KiB  
Article
Synthesis of a New β-Galactosidase Inhibitor Displaying Pharmacological Chaperone Properties for GM1 Gangliosidosis
by Francesca Clemente, Macarena Martínez-Bailén, Camilla Matassini, Amelia Morrone, Silvia Falliano, Anna Caciotti, Paolo Paoli, Andrea Goti and Francesca Cardona
Molecules 2022, 27(13), 4008; https://doi.org/10.3390/molecules27134008 - 22 Jun 2022
Cited by 2 | Viewed by 1729
Abstract
GM1 gangliosidosis is a rare lysosomal disease caused by the deficiency of the enzyme β-galactosidase (β-Gal; GLB1; E.C. 3.2.1.23), responsible for the hydrolysis of terminal β-galactosyl residues from GM1 ganglioside, glycoproteins, and glycosaminoglycans, such as keratan-sulfate. With the aim of identifying new [...] Read more.
GM1 gangliosidosis is a rare lysosomal disease caused by the deficiency of the enzyme β-galactosidase (β-Gal; GLB1; E.C. 3.2.1.23), responsible for the hydrolysis of terminal β-galactosyl residues from GM1 ganglioside, glycoproteins, and glycosaminoglycans, such as keratan-sulfate. With the aim of identifying new pharmacological chaperones for GM1 gangliosidosis, the synthesis of five new trihydroxypiperidine iminosugars is reported in this work. The target compounds feature a pentyl alkyl chain in different positions of the piperidine ring and different absolute configurations of the alkyl chain at C-2 and the hydroxy group at C-3. The organometallic addition of a Grignard reagent onto a carbohydrate-derived nitrone in the presence or absence of a suitable Lewis Acid was exploited, providing structural diversity at C-2, followed by the ring-closure reductive amination step. An oxidation-reduction process allowed access to a different configuration at C-3. The N-pentyl trihydroxypiperidine iminosugar was also synthesized for the purpose of comparison. The biological evaluation of the newly synthesized compounds was performed on leucocyte extracts from healthy donors and identified two suitable β-Gal inhibitors, namely compounds 10 and 12. Among these, compound 12 showed chaperoning properties since it enhanced β-Gal activity by 40% when tested on GM1 patients bearing the p.Ile51Asn/p.Arg201His mutations. Full article
(This article belongs to the Special Issue Synthesis and Therapeutic Applications of Iminosugars)
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10 pages, 1433 KiB  
Article
Synthesis of Piperidine Nucleosides as Conformationally Restricted Immucillin Mimics
by Maria De Fenza, Anna Esposito, Daniele D’Alonzo and Annalisa Guaragna
Molecules 2021, 26(6), 1652; https://doi.org/10.3390/molecules26061652 - 16 Mar 2021
Cited by 5 | Viewed by 1865
Abstract
The de novo synthesis of piperidine nucleosides from our homologating agent 5,6-dihydro-1,4-dithiin is herein reported. The structure and conformation of nucleosides were conceived to faithfully resemble the well-known nucleoside drugs Immucillins H and A in their bioactive conformation. NMR analysis of the synthesized [...] Read more.
The de novo synthesis of piperidine nucleosides from our homologating agent 5,6-dihydro-1,4-dithiin is herein reported. The structure and conformation of nucleosides were conceived to faithfully resemble the well-known nucleoside drugs Immucillins H and A in their bioactive conformation. NMR analysis of the synthesized compounds confirmed that they adopt an iminosugar conformation bearing the nucleobases and the hydroxyl groups in the appropriate orientation. Full article
(This article belongs to the Special Issue Synthesis and Therapeutic Applications of Iminosugars)
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