Cycloadditions as a sweet route to ‘double C-glycosylation’

Kevin Patrick Peter Mahoney; Rosemary Lynch; Rhea Tamar Bown; Sunil Vishnuprasadji Sharma; Piyasiri Chueakwon; G. Richard Stephenson; David Bradford Cordes; Alexandra Martha Zoya Slawin; Rebecca Goss

doi:10.3390/biom15060905

Cycloadditions as a sweet route to ‘double C-glycosylation’

Kevin Patrick Peter Mahoney^*, Rosemary Lynch, Rhea Tamar Bown, Sunil Vishnuprasadji Sharma, Piyasiri Chueakwon, G. Richard Stephenson, David Bradford Cordes, Alexandra Martha Zoya Slawin, Rebecca Goss

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Pharmaceuticals, such as the antibiotic erythromycin, and sodium-dependent glucose transporter (SGLT1 & SGTL2) inhibitors such as Bexagliflozin (diabetes) and Sotagliflozin (heart disease), are often sugar-decorated (glycosylated). Glycosylation is a key component of the binding motif in SGLT inhibitors and in natural products, glycosylation often confers improved bioactivity and bioavailability. Whilst a single C-glycoside link between a sugar moiety and its aglycone core is a common feature in natural products isolated to date, only a small number, including the antibiotics granaticin and sarubicin, are covalently bonded twice to a single sugar moiety. The way in which this “double C-glycosylation” is naturally mediated is not yet known, yet speculated. Here we report the exploration and development of a potentially biomimetic procedure that utilises intermolecular cycloaddition chemistry to access new “double C-glycosylated” products and enables the creation of bridged polycyclic ethers from a common maltol derived oxidopyrylium salt precursor.

Original language	English
Article number	905
Journal	Biomolecules
Volume	15
Issue number	6
DOIs	https://doi.org/10.3390/biom15060905
Publication status	Published - 19 Jun 2025

Keywords

Cycloaddition
Biomimetic
Granaticin
Natural product analogue

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/biom15060905Licence: CC BY

Mahoney_2025_BioM_Cycloadditions-sweet-route_CC
Copyright: © 2025 by the authors. Submitted for possible open access publication under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/license s/by/4.0/).
Final published version, 600 KBLicence: CC BY

1 Active
2 Finished

X-Genix:Translating precision molecular: X-Genix:Translating precision molecular editing as a tool for drug discovery
Goss, R. (PI)
BBSRC
1/12/23 → 30/11/25
Project: Standard
Molecular X-Factor & SynBioFilms: Molecular X-Factor & SynBioFilms
Goss, R. (PI)
BBSRC
1/07/20 → 30/06/22
Project: Standard
EMBRIC: EMBRIC
Goss, R. (PI)
European Commission
1/06/15 → 31/05/19
Project: Standard

Cite this

@article{6259dd97d5c146b5a956df17e62b12af,

title = "Cycloadditions as a sweet route to {\textquoteleft}double C-glycosylation{\textquoteright}",

abstract = "Pharmaceuticals, such as the antibiotic erythromycin, and sodium-dependent glucose transporter (SGLT1 & SGTL2) inhibitors such as Bexagliflozin (diabetes) and Sotagliflozin (heart disease), are often sugar-decorated (glycosylated). Glycosylation is a key component of the binding motif in SGLT inhibitors and in natural products, glycosylation often confers improved bioactivity and bioavailability. Whilst a single C-glycoside link between a sugar moiety and its aglycone core is a common feature in natural products isolated to date, only a small number, including the antibiotics granaticin and sarubicin, are covalently bonded twice to a single sugar moiety. The way in which this “double C-glycosylation” is naturally mediated is not yet known, yet speculated. Here we report the exploration and development of a potentially biomimetic procedure that utilises intermolecular cycloaddition chemistry to access new “double C-glycosylated” products and enables the creation of bridged polycyclic ethers from a common maltol derived oxidopyrylium salt precursor.",

keywords = "Cycloaddition, Biomimetic, Granaticin, Natural product analogue",

author = "Mahoney, {Kevin Patrick Peter} and Rosemary Lynch and Bown, {Rhea Tamar} and Sharma, {Sunil Vishnuprasadji} and Piyasiri Chueakwon and Stephenson, {G. Richard} and Cordes, {David Bradford} and Slawin, {Alexandra Martha Zoya} and Rebecca Goss",

note = "Funding: This research was funded by the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007–2013/ERC grant agreement no. 614779 GenoChemetics to R.J.M.G.), the European Union{\textquoteright}s Horizon 2020 research and innovation programme under grant agreement No 654008 and the BBSRC Follow on Fund BB/Y513738/1, BB/T017058/1 and the EU Interreg IV Trans Manche/Channel cross-border projects IS:CE chem (ref 4061) and AIcc (ref 4196).",

year = "2025",

month = jun,

day = "19",

doi = "10.3390/biom15060905",

language = "English",

volume = "15",

journal = "Biomolecules",

issn = "2218-273X",

publisher = "MDPI",

number = "6",

}

TY - JOUR

T1 - Cycloadditions as a sweet route to ‘double C-glycosylation’

AU - Mahoney, Kevin Patrick Peter

AU - Lynch, Rosemary

AU - Bown, Rhea Tamar

AU - Sharma, Sunil Vishnuprasadji

AU - Chueakwon, Piyasiri

AU - Stephenson, G. Richard

AU - Cordes, David Bradford

AU - Slawin, Alexandra Martha Zoya

AU - Goss, Rebecca

N1 - Funding: This research was funded by the European Union’s Seventh Framework Programme (FP7/2007–2013/ERC grant agreement no. 614779 GenoChemetics to R.J.M.G.), the European Union’s Horizon 2020 research and innovation programme under grant agreement No 654008 and the BBSRC Follow on Fund BB/Y513738/1, BB/T017058/1 and the EU Interreg IV Trans Manche/Channel cross-border projects IS:CE chem (ref 4061) and AIcc (ref 4196).

PY - 2025/6/19

Y1 - 2025/6/19

N2 - Pharmaceuticals, such as the antibiotic erythromycin, and sodium-dependent glucose transporter (SGLT1 & SGTL2) inhibitors such as Bexagliflozin (diabetes) and Sotagliflozin (heart disease), are often sugar-decorated (glycosylated). Glycosylation is a key component of the binding motif in SGLT inhibitors and in natural products, glycosylation often confers improved bioactivity and bioavailability. Whilst a single C-glycoside link between a sugar moiety and its aglycone core is a common feature in natural products isolated to date, only a small number, including the antibiotics granaticin and sarubicin, are covalently bonded twice to a single sugar moiety. The way in which this “double C-glycosylation” is naturally mediated is not yet known, yet speculated. Here we report the exploration and development of a potentially biomimetic procedure that utilises intermolecular cycloaddition chemistry to access new “double C-glycosylated” products and enables the creation of bridged polycyclic ethers from a common maltol derived oxidopyrylium salt precursor.

AB - Pharmaceuticals, such as the antibiotic erythromycin, and sodium-dependent glucose transporter (SGLT1 & SGTL2) inhibitors such as Bexagliflozin (diabetes) and Sotagliflozin (heart disease), are often sugar-decorated (glycosylated). Glycosylation is a key component of the binding motif in SGLT inhibitors and in natural products, glycosylation often confers improved bioactivity and bioavailability. Whilst a single C-glycoside link between a sugar moiety and its aglycone core is a common feature in natural products isolated to date, only a small number, including the antibiotics granaticin and sarubicin, are covalently bonded twice to a single sugar moiety. The way in which this “double C-glycosylation” is naturally mediated is not yet known, yet speculated. Here we report the exploration and development of a potentially biomimetic procedure that utilises intermolecular cycloaddition chemistry to access new “double C-glycosylated” products and enables the creation of bridged polycyclic ethers from a common maltol derived oxidopyrylium salt precursor.

KW - Cycloaddition

KW - Biomimetic

KW - Granaticin

KW - Natural product analogue

U2 - 10.3390/biom15060905

DO - 10.3390/biom15060905

M3 - Article

SN - 2218-273X

VL - 15

JO - Biomolecules

JF - Biomolecules

IS - 6

M1 - 905

ER -

Cycloadditions as a sweet route to ‘double C-glycosylation’

Abstract

Keywords

UN SDGs

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Projects

X-Genix:Translating precision molecular: X-Genix:Translating precision molecular editing as a tool for drug discovery

Molecular X-Factor & SynBioFilms: Molecular X-Factor & SynBioFilms

EMBRIC: EMBRIC

Cite this