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Design and Synthesi...
Design and Synthesis of Galectin Inhibitors
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- Sörme, Pernilla (författare)
- Lund University,Lunds universitet,Centrum för analys och syntes,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Centre for Analysis and Synthesis,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH
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- Kahl Knutson, Barbro (författare)
- Lund University,Lunds universitet,Avdelningen för mikrobiologi, immunologi och glykobiologi - MIG,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Microbiology, Immunology and Glycobiology - MIG,Department of Laboratory Medicine,Faculty of Medicine
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Wellmar, U (författare)
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Magnusson, B-G (författare)
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- Leffler, Hakon (författare)
- Lund University,Lunds universitet,Avdelningen för mikrobiologi, immunologi och glykobiologi - MIG,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Microbiology, Immunology and Glycobiology - MIG,Department of Laboratory Medicine,Faculty of Medicine
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- Nilsson, Ulf (författare)
- Lund University,Lunds universitet,Centrum för analys och syntes,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Centre for Analysis and Synthesis,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH
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Lee, Yuan C. (redaktör/utgivare)
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Lee, Reiko T. (redaktör/utgivare)
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(creator_code:org_t)
- ISBN 9162858653
- 2003
- Engelska 120 s.
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Ingår i: Recognition of Carbohydrates in Biological Systems, Part B: Specific Applications (Methods in Enzymology; 263). - 0121822664 ; 363, s. 157-169
- Relaterad länk:
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http://dx.doi.org/10...
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https://lup.lub.lu.s...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Mikrobiologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Microbiology in the medical area (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
Nyckelord
- Parallel Synthesis
- Inhibitors
- Biomedicinska vetenskaper (allmänt)
- General biomedical sciences
- Carbohydrates
- Galectins
Publikations- och innehållstyp
- dok (ämneskategori)
- vet (ämneskategori)
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