Design and Synthesis of Galectin Inhibitors
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/466389
- author
- Sörme, Pernilla LU
- supervisor
- opponent
-
- Professor Lee, Y.C., Johns Hopkins University
- organization
- publishing date
- 2003
- 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 10:15:00
- external identifiers
-
- other:ISRN: LUMEDW/MEMG-0018-SE
- scopus:17144447272
- ISBN
- 91-628-5865-3
- language
- English
- LU publication?
- yes
- additional info
- Article: Low Micromolar Inhibitors of Galectin-3 Based on3-Derivatization of N-AcetyllactosaminePernilla Sˆrme,[a, b] Yuning Qian,[a] Per-Georg Nyholm,[c] Hakon Leffler,*[a] andUlf J. Nilsson*[b] The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Division of Microbiology, Immunology and Glycobiology - MIG (013025200), Organic chemistry (S/LTH) (011001240)
- id
- e21e598d-89c4-400e-9516-ae4fe3a60de2 (old id 466389)
- date added to LUP
- 2016-04-04 10:13:43
- date last changed
- 2022-01-29 19:59:07
@phdthesis{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}},
keywords = {{Parallel Synthesis; Inhibitors; Biomedicinska vetenskaper (allmänt); General biomedical sciences; Carbohydrates; Galectins}},
language = {{eng}},
publisher = {{Microbiology, Immunology and Glycobiology, MIG, Lund University}},
school = {{Lund University}},
title = {{Design and Synthesis of Galectin Inhibitors}},
year = {{2003}},
}