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Design and Synthesis of Galectin Inhibitors

Sörme, Pernilla LU (2003)
Abstract
Galectins, a lectin family, have shown binding affinities towards b-galactosides. Galectins have been proposed to be involved in a wide range of functions like for example, cell growth, adhesion, migration, chemo taxis and apoptosis. They have also been associated with various cancer types. However, the detailed functions of galectins are still very much unknown. High affinity inhibitors towards the galectins would thus be of value as research tools, as well as possible future pharmaceutical agents. Existing inhibitors have undesirable properties, for example high molecular weight and instability. This thesis concerns the synthesis of small high affinity galectin inhibitors. A previously published X-ray structure of galectin-3 together... (More)
Galectins, a lectin family, have shown binding affinities towards b-galactosides. Galectins have been proposed to be involved in a wide range of functions like for example, cell growth, adhesion, migration, chemo taxis and apoptosis. They have also been associated with various cancer types. However, the detailed functions of galectins are still very much unknown. High affinity inhibitors towards the galectins would thus be of value as research tools, as well as possible future pharmaceutical agents. Existing inhibitors have undesirable properties, for example high molecular weight and instability. This thesis concerns the synthesis of small high affinity galectin inhibitors. A previously published X-ray structure of galectin-3 together with LacNAc revealed an extended binding pocket close to 3´-C of the galactoside residue. Filling this pocket with additional chemical entities was hypothesized to allow for further interactions and hence creating higher affinity ligands as compared to the naturally occurring ligand. The hypothesis was probed by substituting the 3´-hydroxyl group on the galactose unit of LacNAc with an amine, which enables the introduction of functional groups under mild reaction conditions. We synthesised a collection of more than 60 LacNAc derivatives with various functional groups at 3´-C of the galactose unit. The measurements of inhibitor potencies towards galectins were made in a novel fluorescence polarisation (FP) assay, which is a solution phase method, as well as a general technique that do not need major re-optimisation to enable the study of other galectins. Hence, it enabled us to study the panel of synthetic inhibitors towards galectin-1, -3 and –4. Selective and high affinity inhibitors were discovered, which is of value as often more than one galectin is present in one and the same system. We found that aromatic amides in particular showed high affinity towards galectin-3. In addition, the X-ray structure of one of the best inhibitors (Kd 0.9 mM) revealed that Arg-144 on galectin-3 had moved 3.5 Å to enable a face-to-face stacking interaction with a 4-methoxy-2,3,5,6-tetrafluorobenzamido substituent. The best inhibitor synthesised as of yet, carried a 2-naphthamido functionality at 3´of the galactose residue. This inhibitor had a Kd of 0.3 mM, which the strongest binding affinity achieved as compared to any monovalent inhibitor. It shows over 200 times higher affinity towards galectin-3 than the unfunctionalised LacNAc. (Less)
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author
opponent
  • Professor Lee, Y.C., Johns Hopkins University
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Parallel Synthesis, Inhibitors, Biomedicinska vetenskaper (allmänt), General biomedical sciences, Carbohydrates, Galectins
pages
120 pages
publisher
Microbiology, Immunology and Glycobiology, MIG, Lund University
defense location
Sölvegatan 25
defense date
2003-12-13 10:15
external identifiers
  • Other:ISRN: LUMEDW/MEMG-0018-SE
  • Scopus:17144447272
ISBN
91-628-5865-3
language
English
LU publication?
yes
id
e21e598d-89c4-400e-9516-ae4fe3a60de2 (old id 466389)
date added to LUP
2007-09-28 12:32:02
date last changed
2016-11-27 04:30:54
@misc{e21e598d-89c4-400e-9516-ae4fe3a60de2,
  abstract     = {Galectins, a lectin family, have shown binding affinities towards b-galactosides. Galectins have been proposed to be involved in a wide range of functions like for example, cell growth, adhesion, migration, chemo taxis and apoptosis. They have also been associated with various cancer types. However, the detailed functions of galectins are still very much unknown. High affinity inhibitors towards the galectins would thus be of value as research tools, as well as possible future pharmaceutical agents. Existing inhibitors have undesirable properties, for example high molecular weight and instability. This thesis concerns the synthesis of small high affinity galectin inhibitors. A previously published X-ray structure of galectin-3 together with LacNAc revealed an extended binding pocket close to 3´-C of the galactoside residue. Filling this pocket with additional chemical entities was hypothesized to allow for further interactions and hence creating higher affinity ligands as compared to the naturally occurring ligand. The hypothesis was probed by substituting the 3´-hydroxyl group on the galactose unit of LacNAc with an amine, which enables the introduction of functional groups under mild reaction conditions. We synthesised a collection of more than 60 LacNAc derivatives with various functional groups at 3´-C of the galactose unit. The measurements of inhibitor potencies towards galectins were made in a novel fluorescence polarisation (FP) assay, which is a solution phase method, as well as a general technique that do not need major re-optimisation to enable the study of other galectins. Hence, it enabled us to study the panel of synthetic inhibitors towards galectin-1, -3 and –4. Selective and high affinity inhibitors were discovered, which is of value as often more than one galectin is present in one and the same system. We found that aromatic amides in particular showed high affinity towards galectin-3. In addition, the X-ray structure of one of the best inhibitors (Kd 0.9 mM) revealed that Arg-144 on galectin-3 had moved 3.5 Å to enable a face-to-face stacking interaction with a 4-methoxy-2,3,5,6-tetrafluorobenzamido substituent. The best inhibitor synthesised as of yet, carried a 2-naphthamido functionality at 3´of the galactose residue. This inhibitor had a Kd of 0.3 mM, which the strongest binding affinity achieved as compared to any monovalent inhibitor. It shows over 200 times higher affinity towards galectin-3 than the unfunctionalised LacNAc.},
  author       = {Sörme, Pernilla},
  isbn         = {91-628-5865-3},
  keyword      = {Parallel Synthesis,Inhibitors,Biomedicinska vetenskaper (allmänt),General biomedical sciences,Carbohydrates,Galectins},
  language     = {eng},
  pages        = {120},
  publisher    = {ARRAY(0x87b28e0)},
  title        = {Design and Synthesis of Galectin Inhibitors},
  year         = {2003},
}