C1-Galactopyranosyl Heterocycle Structure Guides Selectivity : Triazoles Prefer Galectin-1 and Oxazoles Prefer Galectin-3
(2019) In ACS Omega 4(4). p.7047-7053- Abstract
Galectins are carbohydrate-recognizing proteins involved in many different pathological processes, including cancer and immune-related disorders. Inhibitors of galectins have evolved from natural oligosaccharides toward more drug-like truncated galactoside scaffolds that only retain key specific interactions of the galactose scaffolds with the galectin carbohydrate recognition domains. In this context, C1-galactosides are attractive and stable scaffolds, and this work reports that the synthesis of novel C1-galactopyranosyl heteroaryl derivatives as galectin inhibitors, in which galectin selectivity is governed by the composition of the heterocycle and affinity, is driven by the structure of the aryl substituent to give compounds... (More)
Galectins are carbohydrate-recognizing proteins involved in many different pathological processes, including cancer and immune-related disorders. Inhibitors of galectins have evolved from natural oligosaccharides toward more drug-like truncated galactoside scaffolds that only retain key specific interactions of the galactose scaffolds with the galectin carbohydrate recognition domains. In this context, C1-galactosides are attractive and stable scaffolds, and this work reports that the synthesis of novel C1-galactopyranosyl heteroaryl derivatives as galectin inhibitors, in which galectin selectivity is governed by the composition of the heterocycle and affinity, is driven by the structure of the aryl substituent to give compounds selective for either galectin-1 or galectin-3. The affinities are close to or better than those of lactose and other natural galectin-binding disaccharides, selectivities induced by the C1-heteroaryl groups are superior to lactose, and compound hydrolytic stabilities and drug-like properties are potentially better than those of natural saccharides. Hence, C1-galactopyranosyl heteroaryls constitute a class of promising starting scaffolds for galectin inhibition, in which a natural ligand pyranose has been replaced by more than fivefold selectivity-inducing heteroaryl rings leading to affinities of 90 μM toward galectin-3 for a C1-galactopyranosyl naphthyloxazole and 170 μM toward galectin-1 for a C1-galactopyranosyl 2-fluorophenyltriazole.
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- author
- Dahlqvist, Alexander LU ; Leffler, Hakon LU and Nilsson, Ulf J. LU
- organization
- publishing date
- 2019
- type
- Contribution to journal
- publication status
- published
- subject
- in
- ACS Omega
- volume
- 4
- issue
- 4
- pages
- 7 pages
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- scopus:85064817462
- ISSN
- 2470-1343
- DOI
- 10.1021/acsomega.9b00320
- language
- English
- LU publication?
- yes
- id
- 579d8bd7-b07a-4e93-a0aa-fac69de44ccb
- date added to LUP
- 2019-05-08 12:13:56
- date last changed
- 2022-06-13 18:33:30
@article{579d8bd7-b07a-4e93-a0aa-fac69de44ccb,
abstract = {{<p>Galectins are carbohydrate-recognizing proteins involved in many different pathological processes, including cancer and immune-related disorders. Inhibitors of galectins have evolved from natural oligosaccharides toward more drug-like truncated galactoside scaffolds that only retain key specific interactions of the galactose scaffolds with the galectin carbohydrate recognition domains. In this context, C1-galactosides are attractive and stable scaffolds, and this work reports that the synthesis of novel C1-galactopyranosyl heteroaryl derivatives as galectin inhibitors, in which galectin selectivity is governed by the composition of the heterocycle and affinity, is driven by the structure of the aryl substituent to give compounds selective for either galectin-1 or galectin-3. The affinities are close to or better than those of lactose and other natural galectin-binding disaccharides, selectivities induced by the C1-heteroaryl groups are superior to lactose, and compound hydrolytic stabilities and drug-like properties are potentially better than those of natural saccharides. Hence, C1-galactopyranosyl heteroaryls constitute a class of promising starting scaffolds for galectin inhibition, in which a natural ligand pyranose has been replaced by more than fivefold selectivity-inducing heteroaryl rings leading to affinities of 90 μM toward galectin-3 for a C1-galactopyranosyl naphthyloxazole and 170 μM toward galectin-1 for a C1-galactopyranosyl 2-fluorophenyltriazole.</p>}},
author = {{Dahlqvist, Alexander and Leffler, Hakon and Nilsson, Ulf J.}},
issn = {{2470-1343}},
language = {{eng}},
number = {{4}},
pages = {{7047--7053}},
publisher = {{The American Chemical Society (ACS)}},
series = {{ACS Omega}},
title = {{C1-Galactopyranosyl Heterocycle Structure Guides Selectivity : Triazoles Prefer Galectin-1 and Oxazoles Prefer Galectin-3}},
url = {{http://dx.doi.org/10.1021/acsomega.9b00320}},
doi = {{10.1021/acsomega.9b00320}},
volume = {{4}},
year = {{2019}},
}