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Synthetic Galectin Inhibitors Selective O-galactosyl aldoximes, multivalent lactosides and galactose-mimicking mannosides

Tejler, Johan LU (2006)
Abstract
This thesis describes the design, synthesis and evaluation of synthetic inhibitors for the carbohydrate binding proteins called galectins. Potent and selective inhibitors can be used as important research tools in the endeavor to chart the true role of galectins in biological events such as cancer and inflammation and possibly as lead for future galectin targeting drugs.



A panel of O-galactosyl aldoximes was synthesized and inhibitors with high affinity and selectivity for galectin-3 and -7 were identified. The best inhibitor for galectin-3, O-(?-D-galactopyranosyl)-indole-3-carbaldoxime, was combined with previously optimized galectin-3 targeting triazoles, in a fragment based approach, to give... (More)
This thesis describes the design, synthesis and evaluation of synthetic inhibitors for the carbohydrate binding proteins called galectins. Potent and selective inhibitors can be used as important research tools in the endeavor to chart the true role of galectins in biological events such as cancer and inflammation and possibly as lead for future galectin targeting drugs.



A panel of O-galactosyl aldoximes was synthesized and inhibitors with high affinity and selectivity for galectin-3 and -7 were identified. The best inhibitor for galectin-3, O-(?-D-galactopyranosyl)-indole-3-carbaldoxime, was combined with previously optimized galectin-3 targeting triazoles, in a fragment based approach, to give 3C-triazol-1-yl-O-galactopyranosyl aldoximes with high affinity and selectivity for galectin-3 (Kd down to 11 µM).



Furthermore, a glycoside clustering effect was observed for multivalent lactose containing inhibitors and galectin-1. The mechanisms behind this were investigated using mutated galectin-1, lacking the possibility to dimerize.



Finally, 1H-[1,2,3]-triazol-1-yl mannosides, with synthetic advantages over galactose based inhibitors, were synthesized and the 4-benzylaminocarbonyl-1H-[1,2,3]-triazol-1-yl ?-D-mannopyranoside (Kd=540 µM, for galectin-9N) compared favorably with its galactoside counterpart. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Galektin är en proteinfamilj med många funktioner i kroppen, varav en del är kopplade till sjukdomstillstånd, såsom inflammationer samt utvecklandet och fortskridandet av cancer.



Galektiners funktion styrs av en kolhydratbindande domän (CRD) som känner igen och binder till galaktos. Vissa galektiner kan hålla ihop olika celler genom att binda till galaktos på cellytor. Detta sker bland annat då cancerceller sprids och bildar nya tumörer vid metastasering. Det finns även galektiner med funktioner inne i cellen där det till exempel har visats att galektin-3 hindrar cytostatika från att döda cancerceller vilket motverkar cancerbehandling. Mekanismerna bakom dessa och andra... (More)
Popular Abstract in Swedish

Galektin är en proteinfamilj med många funktioner i kroppen, varav en del är kopplade till sjukdomstillstånd, såsom inflammationer samt utvecklandet och fortskridandet av cancer.



Galektiners funktion styrs av en kolhydratbindande domän (CRD) som känner igen och binder till galaktos. Vissa galektiner kan hålla ihop olika celler genom att binda till galaktos på cellytor. Detta sker bland annat då cancerceller sprids och bildar nya tumörer vid metastasering. Det finns även galektiner med funktioner inne i cellen där det till exempel har visats att galektin-3 hindrar cytostatika från att döda cancerceller vilket motverkar cancerbehandling. Mekanismerna bakom dessa och andra galektinfunktioner är till stor del okända.



Syntetiska molekyler, inhibitorer, som hindrar inbindningen av galektin till naturligt förekommande ligander kan användas som kemiska verktyg för att undersöka vilka funktioner galektin har. Det är möjligt att en inhibitor som binder till galektin-3 blockerar proteinet så att cytostatikabehanlingen av cancerceller blir effektivare.



Vi har utvecklat en metod för att tillverka små modifierade galaktosmolekyler som binder galektin-3 upp till 20 gånger bättre än laktos (mjölksocker). Laktos är en naturlig galektinligand som innehåller galaktos. Några av dessa syntetiska inhibitorer är selektiva för galektin-3, vilket innebär att de binder galektin-3 men inte andra galektiner. Att bara påverka ett galektin i taget är viktigt för att undersöka just det proteinets funktioner. Detta tillsammans med inhibitorernas fördelaktiga kemiska struktur innebär ett steg mot läkemedel som blockerar galektin-3 vid cancer- och inflammationsrelaterade sjukdomar.



Den syntesmetod vi utvecklat för galektin-3 inhibitorer kan vara möjlig att använda även för att göra selektiva inhibitorer för andra galektin. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Dr. Pieters, Roland, Dept. of Medicinal Chemistry and Chemical Biology, Utrecht University
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Proteiner, enzymology, Proteins, Glycomimetic, Fragment based, Cluster effect, Multivalence, Triazole, Inhibitor, Aldoxime, enzymologi, Organic chemistry, Organisk kemi, Galectin, Lectin
pages
84 pages
publisher
Lund University, The Center for Chemistry and Chemical Engineering, Division of organic chemistry
defense location
Kemicentrum, sal K:C
defense date
2006-12-20 09:30:00
ISBN
91-7422-133-7
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: Department of Chemistry (011001220), Organic chemistry (S/LTH) (011001240)
id
b6ff30e0-edb8-49ed-aa35-690c75bd96e3 (old id 547734)
date added to LUP
2016-04-04 10:59:12
date last changed
2018-11-21 21:01:58
@phdthesis{b6ff30e0-edb8-49ed-aa35-690c75bd96e3,
  abstract     = {{This thesis describes the design, synthesis and evaluation of synthetic inhibitors for the carbohydrate binding proteins called galectins. Potent and selective inhibitors can be used as important research tools in the endeavor to chart the true role of galectins in biological events such as cancer and inflammation and possibly as lead for future galectin targeting drugs.<br/><br>
<br/><br>
A panel of O-galactosyl aldoximes was synthesized and inhibitors with high affinity and selectivity for galectin-3 and -7 were identified. The best inhibitor for galectin-3, O-(?-D-galactopyranosyl)-indole-3-carbaldoxime, was combined with previously optimized galectin-3 targeting triazoles, in a fragment based approach, to give 3C-triazol-1-yl-O-galactopyranosyl aldoximes with high affinity and selectivity for galectin-3 (Kd down to 11 µM).<br/><br>
<br/><br>
Furthermore, a glycoside clustering effect was observed for multivalent lactose containing inhibitors and galectin-1. The mechanisms behind this were investigated using mutated galectin-1, lacking the possibility to dimerize.<br/><br>
<br/><br>
Finally, 1H-[1,2,3]-triazol-1-yl mannosides, with synthetic advantages over galactose based inhibitors, were synthesized and the 4-benzylaminocarbonyl-1H-[1,2,3]-triazol-1-yl ?-D-mannopyranoside (Kd=540 µM, for galectin-9N) compared favorably with its galactoside counterpart.}},
  author       = {{Tejler, Johan}},
  isbn         = {{91-7422-133-7}},
  keywords     = {{Proteiner; enzymology; Proteins; Glycomimetic; Fragment based; Cluster effect; Multivalence; Triazole; Inhibitor; Aldoxime; enzymologi; Organic chemistry; Organisk kemi; Galectin; Lectin}},
  language     = {{eng}},
  publisher    = {{Lund University, The Center for Chemistry and Chemical Engineering, Division of organic chemistry}},
  school       = {{Lund University}},
  title        = {{Synthetic Galectin Inhibitors Selective O-galactosyl aldoximes, multivalent lactosides and galactose-mimicking mannosides}},
  url          = {{https://lup.lub.lu.se/search/files/5667629/547736.pdf}},
  year         = {{2006}},
}