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Synthesis of a phenyl thio--D-galactopyranoside library from 1,5-difluoro-2,4-dinitrobenzene: discovery of efficient and selective monosaccharide inhibitors of galectin-7

Cumpstey, Ian LU ; Nordenfelt, Susanne LU ; Leffler, Hakon LU and Nilsson, Ulf LU (2005) In Organic and Biomolecular Chemistry 3(10). p.1922-1932
Abstract
The galectins are a family of -galactoside-binding proteins that have been implicated in cancer and inflammation processes. Herein, we report the synthesis of a library of 28 compounds that was tested for binding to galectins-1, -3, -7, -8N and -9N. An aromatic nucleophilic substitution reaction between 1,5-difluoro-2,4-dinitrobenzene and a galacto thiol gave 5-fluoro-2,4-dinitrophenyl 2,3,4,6-tetra-O-acetyl-1-thio--D-galactopyranoside. This versatile intermediate was then modified in a two dimensional manner: either by further substitution of the second fluoride by amines or thiols, or by reduction of the nitro groups and acylation of the resulting amines, or both. Deacetylation then gave a library of aromatic -galactosides that showed... (More)
The galectins are a family of -galactoside-binding proteins that have been implicated in cancer and inflammation processes. Herein, we report the synthesis of a library of 28 compounds that was tested for binding to galectins-1, -3, -7, -8N and -9N. An aromatic nucleophilic substitution reaction between 1,5-difluoro-2,4-dinitrobenzene and a galacto thiol gave 5-fluoro-2,4-dinitrophenyl 2,3,4,6-tetra-O-acetyl-1-thio--D-galactopyranoside. This versatile intermediate was then modified in a two dimensional manner: either by further substitution of the second fluoride by amines or thiols, or by reduction of the nitro groups and acylation of the resulting amines, or both. Deacetylation then gave a library of aromatic -galactosides that showed variable inhibitory activity against the different galectins, as shown by screening with a fluorescence-polarisation assay. Particularly efficient inhibitors were found against galectin-7, while less impressive enhancements of inhibitor affinity over methyl -D-galactopyranoside were found for galectin-1, -3, -8N and -9N. The best inhibitors against galectin-7 showed significantly higher affinity (Kd as low as 140 µM) than both -methyl galactoside (Kd 4.8 mM) and the unsubstituted -phenyl thiogalactoside (non-inhibitory). The best inhibitors against galectin-7 were poor against the other galectins and thus have potential as structurally simple and selective tools for dissecting biological functions of galectin-7. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Organic and Biomolecular Chemistry
volume
3
issue
10
pages
1922 - 1932
publisher
Royal Society of Chemistry
external identifiers
  • wos:000229067300016
  • pmid:15889175
  • scopus:19944425218
ISSN
1477-0539
DOI
10.1039/b502354h
language
English
LU publication?
yes
id
8bd1799a-8b89-443b-a6a8-64f4d66b4b84 (old id 158687)
date added to LUP
2007-07-10 09:26:50
date last changed
2017-09-03 03:49:50
@article{8bd1799a-8b89-443b-a6a8-64f4d66b4b84,
  abstract     = {The galectins are a family of -galactoside-binding proteins that have been implicated in cancer and inflammation processes. Herein, we report the synthesis of a library of 28 compounds that was tested for binding to galectins-1, -3, -7, -8N and -9N. An aromatic nucleophilic substitution reaction between 1,5-difluoro-2,4-dinitrobenzene and a galacto thiol gave 5-fluoro-2,4-dinitrophenyl 2,3,4,6-tetra-O-acetyl-1-thio--D-galactopyranoside. This versatile intermediate was then modified in a two dimensional manner: either by further substitution of the second fluoride by amines or thiols, or by reduction of the nitro groups and acylation of the resulting amines, or both. Deacetylation then gave a library of aromatic -galactosides that showed variable inhibitory activity against the different galectins, as shown by screening with a fluorescence-polarisation assay. Particularly efficient inhibitors were found against galectin-7, while less impressive enhancements of inhibitor affinity over methyl -D-galactopyranoside were found for galectin-1, -3, -8N and -9N. The best inhibitors against galectin-7 showed significantly higher affinity (Kd as low as 140 µM) than both -methyl galactoside (Kd 4.8 mM) and the unsubstituted -phenyl thiogalactoside (non-inhibitory). The best inhibitors against galectin-7 were poor against the other galectins and thus have potential as structurally simple and selective tools for dissecting biological functions of galectin-7.},
  author       = {Cumpstey, Ian and Nordenfelt, Susanne and Leffler, Hakon and Nilsson, Ulf},
  issn         = {1477-0539},
  language     = {eng},
  number       = {10},
  pages        = {1922--1932},
  publisher    = {Royal Society of Chemistry},
  series       = {Organic and Biomolecular Chemistry},
  title        = {Synthesis of a phenyl thio--D-galactopyranoside library from 1,5-difluoro-2,4-dinitrobenzene: discovery of efficient and selective monosaccharide inhibitors of galectin-7},
  url          = {http://dx.doi.org/10.1039/b502354h},
  volume       = {3},
  year         = {2005},
}