Editorial

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3 pages, 163 KiB

Open AccessEditorial

Glycomimetics: Design, Synthesis, and Therapeutic Applications

by Philippe Compain

Molecules 2018, 23(7), 1658; https://doi.org/10.3390/molecules23071658 - 07 Jul 2018

Cited by 17 | Viewed by 3521

Abstract

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(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)

Research

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18 pages, 2327 KiB

Open AccessArticle

Probing the Inhibitor versus Chaperone Properties of sp²-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease

by Teresa Mena-Barragán, M. Isabel García-Moreno, Alen Sevšek, Tetsuya Okazaki, Eiji Nanba, Katsumi Higaki, Nathaniel I. Martin, Roland J. Pieters, José M. García Fernández and Carmen Ortiz Mellet

Molecules 2018, 23(4), 927; https://doi.org/10.3390/molecules23040927 - 17 Apr 2018

Cited by 30 | Viewed by 5245

Abstract

A series of sp²-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (d-gluco or l-ido), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and [...] Read more.

A series of sp²-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (d-gluco or l-ido), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and assayed for their inhibition properties towards commercial glycosidases. On the basis of their affinity and selectivity towards GH1 β-glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with d-glucose and incorporating an N′-octyl-isourea or -isothiourea segment were selected for further evaluation of their inhibitory/chaperoning potential against human glucocerebrosidase (GCase). The 1-deoxynojirimycin (DNJ)-related nonreducing conjugates behaved as stronger GCase inhibitors than the reducing counterparts and exhibited potent chaperoning capabilities in Gaucher fibroblasts hosting the neuronopathic G188S/G183W mutation, the isothiourea derivative being indeed one of the most efficient chaperone candidates reported up to date (70% activity enhancement at 20 pM). At their optimal concentration, the four selected compounds promoted mutant GCase activity enhancements over 3-fold; yet, the inhibitor/chaperoning balance became unfavorable at much lower concentration for nonreducing as compared to reducing derivatives. Full article

(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)

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11 pages, 1157 KiB

Open AccessFeature PaperCommunication

One-Pot, Highly Stereoselective Synthesis of Dithioacetal-α,α-Diglycosides

by Maria F. Céspedes Dávila, Jérémy P. Schneider, Amélie Godard, Damien Hazelard and Philippe Compain

Molecules 2018, 23(4), 914; https://doi.org/10.3390/molecules23040914 - 15 Apr 2018

Cited by 10 | Viewed by 4760

Abstract

A one-step access to dithioacetal-α,α-diglycosides is reported. The synthetic strategy is based on the thioacetalization of aldehydes or ketones via highly stereoselective ring-opening of 1,6 anhydrosugars with bis(trimethylsilyl)sulfide. Full article

(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)

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11 pages, 2403 KiB

Open AccessFeature PaperArticle

Potent GH20 N-Acetyl-β-d-hexosaminidase Inhibitors: N-Substituted 3-acetamido-4-amino-5-hydroxymethyl-cyclopentanediols

by Patrick Weber, Seyed A. Nasseri, Bettina M. Pabst, Ana Torvisco, Philipp Müller, Eduard Paschke, Marion Tschernutter, Werner Windischhofer, Stephen G. Withers, Tanja M. Wrodnigg and Arnold E. Stütz

Molecules 2018, 23(3), 708; https://doi.org/10.3390/molecules23030708 - 20 Mar 2018

Cited by 8 | Viewed by 4791

Abstract

From 1,2;3,4-di-O-isopropylidene-d-galactopyranose, a preliminary series of highly functionalized amino(hydroxymethyl)cyclopentanes was easily available. These amine-containing basic carbasugars featuring the d-galacto configuration are potent inhibitors of the GH20 β-d-hexosaminidases probed and may bear potential as regulators of [...] Read more.

From 1,2;3,4-di-O-isopropylidene-d-galactopyranose, a preliminary series of highly functionalized amino(hydroxymethyl)cyclopentanes was easily available. These amine-containing basic carbasugars featuring the d-galacto configuration are potent inhibitors of the GH20 β-d-hexosaminidases probed and may bear potential as regulators of N-acetyl-d-hexosaminidase activities in vivo. Full article

(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)

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17 pages, 6665 KiB

Open AccessFeature PaperArticle

Synthesis of New C- and N-β-d-Glucopyranosyl Derivatives of Imidazole, 1,2,3-Triazole and Tetrazole, and Their Evaluation as Inhibitors of Glycogen Phosphorylase

by Sándor Kun, Éva Bokor, Ádám Sipos, Tibor Docsa and László Somsák

Molecules 2018, 23(3), 666; https://doi.org/10.3390/molecules23030666 - 15 Mar 2018

Cited by 14 | Viewed by 4234

Abstract

The aim of the present study was to broaden the structure-activity relationships of C- and N-β-d-glucopyranosyl azole type inhibitors of glycogen phosphorylase. 1-Aryl-4-β-d-gluco-pyranosyl-1,2,3-triazoles were prepared by copper catalyzed azide-alkyne cycloadditions between O-perbenzylated or O-peracetylated β- [...] Read more.

The aim of the present study was to broaden the structure-activity relationships of C- and N-β-d-glucopyranosyl azole type inhibitors of glycogen phosphorylase. 1-Aryl-4-β-d-gluco-pyranosyl-1,2,3-triazoles were prepared by copper catalyzed azide-alkyne cycloadditions between O-perbenzylated or O-peracetylated β-d-glucopyranosyl ethynes and aryl azides. 1-β-d-Gluco-pyranosyl-4-phenyl imidazole was obtained in a glycosylation of 4(5)-phenylimidazole with O-peracetylated α-d-glucopyranosyl bromide. C-β-d-Glucopyranosyl-N-substituted-tetrazoles were synthesized by alkylation/arylation of O-perbenzoylated 5-β-d-glucopyranosyl-tetrazole or from a 2,6-anhydroheptose tosylhydrazone and arenediazonium salts. 5-Substituted tetrazoles were glycosylated by O-peracetylated α-d-glucopyranosyl bromide to give N-β-d-glucopyranosyl-C-substituted-tetrazoles. Standard deprotections gave test compounds which were assayed against rabbit muscle glycogen phosphorylase b. Most of the compounds proved inactive, the best inhibitor was 2-β-d-glucopyranosyl-5-phenyltetrazole (IC₅₀ 600 μM). These studies extended the structure-activity relationships of β-d-glucopyranosyl azole type inhibitors and revealed the extreme sensitivity of such type of inhibitors towards the structure of the azole moiety. Full article

(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)

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14 pages, 1354 KiB

Open AccessFeature PaperCommunication

Convergent Synthesis of N,S-bis Glycosylquinolin-2-ones via a Pd-G3-XantPhos Precatalyst Catalysis

by Wafa Redjdal, Nada Ibrahim, Belkacem Benmerad, Mouad Alami and Samir Messaoudi

Molecules 2018, 23(3), 519; https://doi.org/10.3390/molecules23030519 - 26 Feb 2018

Cited by 8 | Viewed by 4961

Abstract

Buchwald-Hartwig-Migita cross-coupling of 1-thiosugars with α- or β-3-iodo-N-glycosylquinolin-2-ones has been accomplished under mild and operationally simple reaction conditions through the use of a Pd-G3 XantPhos palladacycle precatalyst. This new methodology has been successfully applied to a variety of α- or β-mono-, [...] Read more.

Buchwald-Hartwig-Migita cross-coupling of 1-thiosugars with α- or β-3-iodo-N-glycosylquinolin-2-ones has been accomplished under mild and operationally simple reaction conditions through the use of a Pd-G3 XantPhos palladacycle precatalyst. This new methodology has been successfully applied to a variety of α- or β-mono-, di-, and poly-thiosugar derivatives to efficiently synthesize a series of α- or β-N,S-bis-glycosyl quinolin-2-ones, which are difficult to synthesize by classical methods. Full article

(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)

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18 pages, 3034 KiB

Open AccessFeature PaperArticle

Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors

by Giampiero D’Adamio, Matilde Forcella, Paola Fusi, Paolo Parenti, Camilla Matassini, Xhenti Ferhati, Costanza Vanni and Francesca Cardona

Molecules 2018, 23(2), 436; https://doi.org/10.3390/molecules23020436 - 16 Feb 2018

Cited by 11 | Viewed by 3831

Abstract

This work aims to synthesize new trehalase inhibitors selective towards the insect trehalase versus the porcine trehalase, in view of their application as potentially non-toxic insecticides and fungicides. The synthesis of a new pseudodisaccharide mimetic 8, by means of a stereoselective α-glucosylation [...] Read more.

This work aims to synthesize new trehalase inhibitors selective towards the insect trehalase versus the porcine trehalase, in view of their application as potentially non-toxic insecticides and fungicides. The synthesis of a new pseudodisaccharide mimetic 8, by means of a stereoselective α-glucosylation of the key pyrrolizidine intermediate 13, was accomplished. The activity of compound 8 as trehalase inhibitor towards C. riparius trehalase was evaluated and the results showed that 8 was active in the μM range and showed a good selectivity towards the insect trehalase. To reduce the overall number of synthetic steps, simpler and more flexible disaccharide mimetics 9–11 bearing a pyrrolidine nucleus instead of the pyrrolizidine core were synthesized. The biological data showed the key role of the linker chain’s length in inducing inhibitory properties, since only compounds 9 (α,β-mixture), bearing a two-carbon atom linker chain, maintained activity as trehalase inhibitors. A proper change in the glucosyl donor-protecting groups allowed the stereoselective synthesis of the β-glucoside 9β, which was active in the low micromolar range (IC₅₀ = 0.78 μM) and 12-fold more potent (and more selective) than 9α towards the insect trehalase. Full article

(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)

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Review

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30 pages, 13466 KiB

Open AccessFeature PaperReview

Glycoside Mimics from Glycosylamines: Recent Progress

by Cyril Nicolas and Olivier R. Martin

Molecules 2018, 23(7), 1612; https://doi.org/10.3390/molecules23071612 - 02 Jul 2018

Cited by 28 | Viewed by 6081

Abstract

Glycosylamines are valuable sugar derivatives that have attracted much attention as synthetic intermediates en route to iminosugar-C-glycosyl compounds. Iminosugars are among the most important glycomimetics reported to date due to their powerful activities as inhibitors of a wide variety of glycosidases [...] Read more.

Glycosylamines are valuable sugar derivatives that have attracted much attention as synthetic intermediates en route to iminosugar-C-glycosyl compounds. Iminosugars are among the most important glycomimetics reported to date due to their powerful activities as inhibitors of a wide variety of glycosidases and glycosyltransferases, as well as for their use as pharmacological chaperones. As they provide ready access to these important glycoside mimics, we have reviewed the most significant glycosylamine-based methodologies developed to date, with a special emphasis on the literature reported after 2006. The groups of substrates covered include N-alkyl- and N-benzyl-glycosylamines, N-glycosylhydroxylamines, N-(alkoxycarbonyl)-, and N-tert-butanesulfinyl-glycosylamines. Full article

(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)

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15 pages, 3723 KiB

Open AccessReview

Synthesis of O-Amino Sugars and Nucleosides

by Na Chen and Juan Xie

Molecules 2018, 23(3), 641; https://doi.org/10.3390/molecules23030641 - 12 Mar 2018

Cited by 5 | Viewed by 8262

Abstract

Nucleic acids and carbohydrates are essential biomolecules involved in numerous biological and pathological processes. Development of multifunctional building blocks based on nucleosides and sugars is in high demand for the generation of novel oligonucleotide mimics and glycoconjugates for biomedical applications. Recently, aminooxyl-functionalized compounds [...] Read more.

Nucleic acids and carbohydrates are essential biomolecules involved in numerous biological and pathological processes. Development of multifunctional building blocks based on nucleosides and sugars is in high demand for the generation of novel oligonucleotide mimics and glycoconjugates for biomedical applications. Recently, aminooxyl-functionalized compounds have attracted increasing research interest because of their easy derivatization through oxime ligation or N-oxyamide formation reactions. Various biological applications have been reported for O-amino carbohydrate- and nucleoside-derived compounds. Here, we report our efforts in the design and synthesis of glyco-, glycosyl, nucleoside- and nucleo-aminooxy acid derivatives from readily available sugars and amino acids, and their use for the generation of N-oxyamide-linked oligosaccharides, glycopeptides, glycolipids, oligonucleosides and nucleopeptides as novel glycoconjugates or oligonucleotide mimics. Delicate and key points in the synthesis will be emphasized. Full article

(This article belongs to the Special Issue Glycomimetics: Design, Synthesis and Therapeutic Applications)

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