Back to (non-)Basics: An Update on Neutral and Charge-Balanced Glycosidase Inhibitors

Simone, Michela I.; Mares, Laura J.; Eveleens, Clothilde A.; McCluskey, Adam; Pappin, Brighid Beatrice; Kiefel, Milton J.; Houston, Todd Ashley

doi:10.2174/1389557517666171002161325

Cited by 14 publications

(7 citation statements)

References 104 publications

(131 reference statements)

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“…lacking a basic nitrogen found in iminosugars/azasugars) glycosidase inhibitors. 15 Here the boron pinacol ester was explored as a pharmacophoric group in the para-, meta-and orthopositions to the unsaturated ester on the aromatic ring. Organic boron continues to emerge as a pharmacophore capable of not only intermolecularly interacting with active sites, but also intramolecularly through the establishment of dative bonds from nucleophilic atoms of the enzyme to the electrophilic boron atom.…”

Section: Glycosidase Assaymentioning

confidence: 99%

“…[4][5][6] Cinnamic acid -with several of its analogues in the clinic, ozagrel, cinromide and piplartine (Figure 1) -represents one such structure possessing wide-ranging biological activity, [7][8][9][10][11][12] inclusive of glycosidase inhibitory capability. [13][14][15] Figure 1. Cinnamic acid analogues in the clinic: ozagrel, cinromide and piplartine.…”

Section: Introductionmentioning

confidence: 99%

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Borylated methyl cinnamates: Expedited synthesis, characterization, crystallographic analysis and biological activities in glycosidase inhibition and in cancer cells lines.

Legge¹,

Shimadate²,

Ghorbani³

et al. 2021

Preprint

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Three cinnamate derivatives bearing a boronate pinacol ester group para, meta and ortho to the a,b-unsaturated ester group have been synthesized via a solventless, expedited Wittig protocol in the best stereoisomeric ratios yet reported, purified by recrystallization, characterized and analyzed by X-ray crystallography. These are valuable building blocks to biologically active derivatives and are themselves biologically active drug leads, displaying excellent selectivities as glycosidase modulators and for future testing as boron neutron capture therapy (BNCT) agents. In a panel of 15 glycosidases, IC50 values of 351 mM and 374 mM were shown for para 2 against almond b-glucosidase and bovine liver b-galactosidase, respectively. For meta 2 the selectivity profile is improved with only inhibition of bovine liver b-galactosidase with an IC50 of 780 mM. These borylated derivatives also possess the capability to be used as BNCT agents. This occurs via irradiation with slow neutrons, thus granting them a switch-on/switch-off toxicity. This is an important new capability imbued into anticancer drugs, too many of which are too toxic in their therapeutic window. BNCT drugs bearing the organic boron pharmacophore have the potential to fine-tune the timing of toxicity delivery.

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Section: Glycosidase Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Borylated methyl cinnamates: Expedited synthesis, characterization, crystallographic analysis and biological activities in glycosidase inhibition and in cancer cells lines.

Legge¹,

Shimadate²,

Ghorbani³

et al. 2021

Preprint

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“…Iminosugars are sugar mimetics that can function as competitive inhibitors of a variety of glycosidase and glycosyltransferase enzymes that interact with sugar substrates. Certain iminosugars are known to inhibit the ER glycosylation pathway by targeting and inhibiting α-glucosidase I and α-glucosidase II and comprise the largest class of α-glucosidase inhibitors currently in development ( Simone et al, 2018 ). Perturbing ER α-glucosidase function can prevent the enzymes from removing terminal glucose residues on N-linked glycans, thereby inhibiting the interaction with the calnexin/calreticulin chaperone proteins and proper folding of some viral glycoproteins.…”

Section: Iminosugarsmentioning

confidence: 99%

Iminosugars: A host-targeted approach to combat Flaviviridae infections

DeWald

Starr

Butters³

et al. 2020

Antiviral Research

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N-linked glycosylation is the most common form of protein glycosylation and is required for the proper folding, trafficking, and/or receptor binding of some host and viral proteins. As viruses lack their own glycosylation machinery, they are dependent on the host’s machinery for these processes. Certain iminosugars are known to interfere with the N-linked glycosylation pathway by targeting and inhibiting α-glucosidases I and II in the endoplasmic reticulum (ER). Perturbing ER α-glucosidase function can prevent these enzymes from removing terminal glucose residues on N-linked glycans, interrupting the interaction between viral glycoproteins and host chaperone proteins that is necessary for proper folding of the viral protein. Iminosugars have demonstrated broad-spectrum antiviral activity in vitro and in vivo against multiple viruses. This review discuses the broad activity of iminosugars against Flaviviridae . Iminosugars have shown favorable activity against multiple members of the Flaviviridae family in vitro and in murine models of disease, although the activity and mechanism of inhibition can be virus specific. While iminosugars are not currently approved for the treatment of viral infections, their potential use as future host-targeted antiviral (HTAV) therapies continues to be investigated.

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“…Furthermore this family of iminosugars is predicted to possess chemical stabilities in vivo akin to those of their 1‐DNJ analogues. While a variety of chemical structures can inhibit glycosidases, iminosugars remain the largest and most important class of glycosidase inhibitors.…”

Section: Conclusion and Future Outlookmentioning

confidence: 99%

Synthetic Routes to 3,4,5‐Trihydroxypiperidines via Stereoselective and Biocatalysed Protocols, and Strategies to N‐ and O‐Derivatisation

et al. 2018

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Stereoselective and biocatalysed synthetic routes to 3,4,5‐trihydroxypiperidines and their N‐ and O‐derivatisations are reviewed. These iminosugars effectively modulate glycosidase enzymes and display biological activities in immunosuppression, as anti‐inflammatory agents and as anti‐viral agents. Syntheses to these building blocks and their N‐ and O‐derivatives are predicted to produce drug leads of high Fsp3 index. This is also crucial in the collection of structure‐activity relationship data, particularly for diseases dependant on glycosidase modulation.

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Back to (non-)Basics: An Update on Neutral and Charge-Balanced Glycosidase Inhibitors

Cited by 14 publications

References 104 publications

Borylated methyl cinnamates: Expedited synthesis, characterization, crystallographic analysis and biological activities in glycosidase inhibition and in cancer cells lines.

Borylated methyl cinnamates: Expedited synthesis, characterization, crystallographic analysis and biological activities in glycosidase inhibition and in cancer cells lines.

Iminosugars: A host-targeted approach to combat Flaviviridae infections

Synthetic Routes to 3,4,5‐Trihydroxypiperidines via Stereoselective and Biocatalysed Protocols, and Strategies to N‐ and O‐Derivatisation

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