Small-Molecule Galectin Inhibitors - On Tweezers and Talosides
(2008)- Abstract
- Abstract
Work on the design, synthesis, and biological evaluation of galectin inhibitors is presented. The most significant results relate to the development of galactose-based arginine “tweezers” and taloside-based galectin inhibitors.
The galectins are a β-galactoside binding protein family. They are involved in cancer and inflammation, thus comprising interesting pharmaceutical targets.
Galactose-based tweezers were designed to enhance the affinity to galectin-3 by a simultaneous π-cation and polar interaction with an arginine in the extended carbohydrate recognition domain (CRD). First, a range of substituents involved in the polar interaction were synthesized, which afforded inhibitors with an affinity down... (More) - Abstract
Work on the design, synthesis, and biological evaluation of galectin inhibitors is presented. The most significant results relate to the development of galactose-based arginine “tweezers” and taloside-based galectin inhibitors.
The galectins are a β-galactoside binding protein family. They are involved in cancer and inflammation, thus comprising interesting pharmaceutical targets.
Galactose-based tweezers were designed to enhance the affinity to galectin-3 by a simultaneous π-cation and polar interaction with an arginine in the extended carbohydrate recognition domain (CRD). First, a range of substituents involved in the polar interaction were synthesized, which afforded inhibitors with an affinity down to ca 87 μM against galectin-3. Data suggests that the affinity is reversely related to the partial charge of the anionic O2 substituents. We propose that the affinity-enhancing effect of the introduced anion in forming a salt-bridge is attenuated by penalties in obtaining the biologically active conformation, which is supported by NMR. Second, to further clarify the basis of the simultaneous π-cation and polar interaction with arginine, tweezers with a range of aromatic moieties were synthesized, presumably allowing the direct interactions to be subtracted to leave only the contribution from the added anion. The tweezers design was subsequently incorporated into a thio-di-galactoside scaffold to afford an affinity of below 100 nM.
Taloside-based galectin inhibitors offer the potential to introduce substituents that can explore previously inaccessible regions of the galectin CRD. The region accessible with talosides is typically rich in basic amino acid residues (notably arginines), consequently a library of β-talosides with electron-rich substituents were synthesized. Galectin-4C and -8N both prefer methyl taloside to methyl galactoside and taloside-based inhibitors with affinities two orders of magnitude higher, relative to reference methyl β-galactoside, were found against galectin-4. No mammalian taloside-processing enzymes are known, potentially allowing talosides to overcome the enzymatic degradation plaguing carbohydrate-based drugs.
These projects were undertaken with a clear focus towards providing enhanced galectin inhibitors as biological probes and potential pharmaceutical agents. To this end, synthetic methods have also been developed to provide starting material for the inhibitors. The galactose-based tweezers require 3-azido-3-deoxy-galactosides, a starting material that was limited by cumbersome synthesis. Methodology development has provided new routes to both O and S glycosides, providing improved yield and convenience for the studied intermediates. Talosides, notably β-configured, are challenging synthetic targets. A new route to β-talosides via β-idosides has been developed aiming for flexible introduction of C2 and C3 substituents, thus far the O2/O3 β-taloside has been successfully obtained. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1149837
- author
- Öberg, Christopher LU
- supervisor
-
- Ulf Nilsson LU
- opponent
-
- Docent Ramström, Olof, Kungliga Tekniska Högskolan, Stockholm
- organization
- publishing date
- 2008
- type
- Thesis
- publication status
- published
- subject
- pages
- 164 pages
- publisher
- Lund University
- defense location
- Kemicentrum, sal K:C, Getingevägen 60, Lunds Tekniska Högskola
- defense date
- 2008-06-13 10:30:00
- ISBN
- 978-91-628-7536-7
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Organic chemistry (S/LTH) (011001240)
- id
- e466b2d0-1b46-4767-9191-65d9abada256 (old id 1149837)
- date added to LUP
- 2016-04-04 10:05:23
- date last changed
- 2018-11-21 20:56:40
@phdthesis{e466b2d0-1b46-4767-9191-65d9abada256,
abstract = {{Abstract<br/><br>
Work on the design, synthesis, and biological evaluation of galectin inhibitors is presented. The most significant results relate to the development of galactose-based arginine “tweezers” and taloside-based galectin inhibitors. <br/><br>
The galectins are a β-galactoside binding protein family. They are involved in cancer and inflammation, thus comprising interesting pharmaceutical targets.<br/><br>
Galactose-based tweezers were designed to enhance the affinity to galectin-3 by a simultaneous π-cation and polar interaction with an arginine in the extended carbohydrate recognition domain (CRD). First, a range of substituents involved in the polar interaction were synthesized, which afforded inhibitors with an affinity down to ca 87 μM against galectin-3. Data suggests that the affinity is reversely related to the partial charge of the anionic O2 substituents. We propose that the affinity-enhancing effect of the introduced anion in forming a salt-bridge is attenuated by penalties in obtaining the biologically active conformation, which is supported by NMR. Second, to further clarify the basis of the simultaneous π-cation and polar interaction with arginine, tweezers with a range of aromatic moieties were synthesized, presumably allowing the direct interactions to be subtracted to leave only the contribution from the added anion. The tweezers design was subsequently incorporated into a thio-di-galactoside scaffold to afford an affinity of below 100 nM. <br/><br>
Taloside-based galectin inhibitors offer the potential to introduce substituents that can explore previously inaccessible regions of the galectin CRD. The region accessible with talosides is typically rich in basic amino acid residues (notably arginines), consequently a library of β-talosides with electron-rich substituents were synthesized. Galectin-4C and -8N both prefer methyl taloside to methyl galactoside and taloside-based inhibitors with affinities two orders of magnitude higher, relative to reference methyl β-galactoside, were found against galectin-4. No mammalian taloside-processing enzymes are known, potentially allowing talosides to overcome the enzymatic degradation plaguing carbohydrate-based drugs.<br/><br>
These projects were undertaken with a clear focus towards providing enhanced galectin inhibitors as biological probes and potential pharmaceutical agents. To this end, synthetic methods have also been developed to provide starting material for the inhibitors. The galactose-based tweezers require 3-azido-3-deoxy-galactosides, a starting material that was limited by cumbersome synthesis. Methodology development has provided new routes to both O and S glycosides, providing improved yield and convenience for the studied intermediates. Talosides, notably β-configured, are challenging synthetic targets. A new route to β-talosides via β-idosides has been developed aiming for flexible introduction of C2 and C3 substituents, thus far the O2/O3 β-taloside has been successfully obtained.}},
author = {{Öberg, Christopher}},
isbn = {{978-91-628-7536-7}},
language = {{eng}},
publisher = {{Lund University}},
school = {{Lund University}},
title = {{Small-Molecule Galectin Inhibitors - On Tweezers and Talosides}},
year = {{2008}},
}