A Galactoside-Binding Protein Tricked into Binding Unnatural Pyranose Derivatives: 3-Deoxy-3-Methyl-Gulosides Selectively Inhibit Galectin-1

Galectins are a family of galactoside-recognizing proteins involved in different galectin-subtype-specific inflammatory and tumor-promoting processes, which motivates the development of inhibitors that are more selective galectin inhibitors than natural ligand fragments. Here, we describe the synthe...

Full description

Bibliographic Details
Main Authors:	Kumar Bhaskar Pal, Mukul Mahanti, Hakon Leffler, Ulf J. Nilsson
Format:	Article
Language:	English
Published:	MDPI AG 2019-08-01
Series:	International Journal of Molecular Sciences
Subjects:	galectin-1 gulopyranosides fluorescence polarization benzamide selective
Online Access:	https://www.mdpi.com/1422-0067/20/15/3786

id	doaj-8d1cceabdbe644d2bcaa78a4a49baf67
record_format	Article
spelling	doaj-8d1cceabdbe644d2bcaa78a4a49baf672020-11-24T21:34:29ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-08-012015378610.3390/ijms20153786ijms20153786A Galactoside-Binding Protein Tricked into Binding Unnatural Pyranose Derivatives: 3-Deoxy-3-Methyl-Gulosides Selectively Inhibit Galectin-1Kumar Bhaskar Pal0Mukul Mahanti1Hakon Leffler2Ulf J. Nilsson3Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Box 124, SE-221 00 Lund, SwedenCentre for Analysis and Synthesis, Department of Chemistry, Lund University, Box 124, SE-221 00 Lund, SwedenSection MIG, Department of Laboratory Medicine, Lund University, BMC-C1228b, Klinikgatan 28, SE-221 84 Lund, SwedenCentre for Analysis and Synthesis, Department of Chemistry, Lund University, Box 124, SE-221 00 Lund, SwedenGalectins are a family of galactoside-recognizing proteins involved in different galectin-subtype-specific inflammatory and tumor-promoting processes, which motivates the development of inhibitors that are more selective galectin inhibitors than natural ligand fragments. Here, we describe the synthesis and evaluation of 3-<i>C</i>-methyl-gulopyranoside derivatives and their evaluation as galectin inhibitors. Methyl 3-deoxy-3-<i>C</i>-(hydroxymethyl)-β-<span style="font-variant: small-caps;">d</span>-gulopyranoside showed 7-fold better affinity for galectin-1 than the natural monosaccharide fragment analog methyl β-<span style="font-variant: small-caps;">d</span>-galactopyranoside, as well as a high selectivity over galectin-2, 3, 4, 7, 8, and 9. Derivatization of the 3-<i>C</i>-hydroxymethyl into amides gave gulosides with improved selectivities and affinities; methyl 3-deoxy-3-<i>C</i>-(methyl-2,3,4,5,6-pentafluorobenzamide)-β-<span style="font-variant: small-caps;">d</span>-gulopyranoside had K<sub>d</sub> 700 µM for galectin-1, while not binding any other galectin.https://www.mdpi.com/1422-0067/20/15/3786galectin-1gulopyranosidesfluorescence polarizationbenzamideselective
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Kumar Bhaskar Pal Mukul Mahanti Hakon Leffler Ulf J. Nilsson
spellingShingle	Kumar Bhaskar Pal Mukul Mahanti Hakon Leffler Ulf J. Nilsson A Galactoside-Binding Protein Tricked into Binding Unnatural Pyranose Derivatives: 3-Deoxy-3-Methyl-Gulosides Selectively Inhibit Galectin-1 International Journal of Molecular Sciences galectin-1 gulopyranosides fluorescence polarization benzamide selective
author_facet	Kumar Bhaskar Pal Mukul Mahanti Hakon Leffler Ulf J. Nilsson
author_sort	Kumar Bhaskar Pal
title	A Galactoside-Binding Protein Tricked into Binding Unnatural Pyranose Derivatives: 3-Deoxy-3-Methyl-Gulosides Selectively Inhibit Galectin-1
title_short	A Galactoside-Binding Protein Tricked into Binding Unnatural Pyranose Derivatives: 3-Deoxy-3-Methyl-Gulosides Selectively Inhibit Galectin-1
title_full	A Galactoside-Binding Protein Tricked into Binding Unnatural Pyranose Derivatives: 3-Deoxy-3-Methyl-Gulosides Selectively Inhibit Galectin-1
title_fullStr	A Galactoside-Binding Protein Tricked into Binding Unnatural Pyranose Derivatives: 3-Deoxy-3-Methyl-Gulosides Selectively Inhibit Galectin-1
title_full_unstemmed	A Galactoside-Binding Protein Tricked into Binding Unnatural Pyranose Derivatives: 3-Deoxy-3-Methyl-Gulosides Selectively Inhibit Galectin-1
title_sort	galactoside-binding protein tricked into binding unnatural pyranose derivatives: 3-deoxy-3-methyl-gulosides selectively inhibit galectin-1
publisher	MDPI AG
series	International Journal of Molecular Sciences
issn	1422-0067
publishDate	2019-08-01
description	Galectins are a family of galactoside-recognizing proteins involved in different galectin-subtype-specific inflammatory and tumor-promoting processes, which motivates the development of inhibitors that are more selective galectin inhibitors than natural ligand fragments. Here, we describe the synthesis and evaluation of 3-<i>C</i>-methyl-gulopyranoside derivatives and their evaluation as galectin inhibitors. Methyl 3-deoxy-3-<i>C</i>-(hydroxymethyl)-β-<span style="font-variant: small-caps;">d</span>-gulopyranoside showed 7-fold better affinity for galectin-1 than the natural monosaccharide fragment analog methyl β-<span style="font-variant: small-caps;">d</span>-galactopyranoside, as well as a high selectivity over galectin-2, 3, 4, 7, 8, and 9. Derivatization of the 3-<i>C</i>-hydroxymethyl into amides gave gulosides with improved selectivities and affinities; methyl 3-deoxy-3-<i>C</i>-(methyl-2,3,4,5,6-pentafluorobenzamide)-β-<span style="font-variant: small-caps;">d</span>-gulopyranoside had K<sub>d</sub> 700 µM for galectin-1, while not binding any other galectin.
topic	galectin-1 gulopyranosides fluorescence polarization benzamide selective
url	https://www.mdpi.com/1422-0067/20/15/3786
work_keys_str_mv	AT kumarbhaskarpal agalactosidebindingproteintrickedintobindingunnaturalpyranosederivatives3deoxy3methylgulosidesselectivelyinhibitgalectin1 AT mukulmahanti agalactosidebindingproteintrickedintobindingunnaturalpyranosederivatives3deoxy3methylgulosidesselectivelyinhibitgalectin1 AT hakonleffler agalactosidebindingproteintrickedintobindingunnaturalpyranosederivatives3deoxy3methylgulosidesselectivelyinhibitgalectin1 AT ulfjnilsson agalactosidebindingproteintrickedintobindingunnaturalpyranosederivatives3deoxy3methylgulosidesselectivelyinhibitgalectin1 AT kumarbhaskarpal galactosidebindingproteintrickedintobindingunnaturalpyranosederivatives3deoxy3methylgulosidesselectivelyinhibitgalectin1 AT mukulmahanti galactosidebindingproteintrickedintobindingunnaturalpyranosederivatives3deoxy3methylgulosidesselectivelyinhibitgalectin1 AT hakonleffler galactosidebindingproteintrickedintobindingunnaturalpyranosederivatives3deoxy3methylgulosidesselectivelyinhibitgalectin1 AT ulfjnilsson galactosidebindingproteintrickedintobindingunnaturalpyranosederivatives3deoxy3methylgulosidesselectivelyinhibitgalectin1
_version_	1725949253427134464

A Galactoside-Binding Protein Tricked into Binding Unnatural Pyranose Derivatives: 3-Deoxy-3-Methyl-Gulosides Selectively Inhibit Galectin-1

Similar Items