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Design, Organic Synthesis, and Evaluation of New Galactose Based Galectin-8 Inhibitors.

Persson, Stella LU (2015) KOK820 20151
Centre for Analysis and Synthesis
Abstract
Lymphangiogenesis, i.e. novel formation of lymph vessels, is known to be one of the underlying causes to the progression of a number of medical conditions, e.g. cancer, inflammation, graft rejection, and lymphedema. Galectin-8 is a tandem-repeat galectin comprised of two carbohydrate domains (CRDs), defined as the N-terminal (galectin-8N) and C-terminal (galectin-8C) CRDs. Galectin-8 has been observed to have a positive effect on signaling mechanisms inducing lymphangiogenesis. It has been shown that inhibition of galectin-8 antagonizes lymphangiogenesis and thus reduces the progression of the aforementioned disorders. The aspiration of efficiently treating these conditions subsequently motivates the development of high affinity inhibitor... (More)
Lymphangiogenesis, i.e. novel formation of lymph vessels, is known to be one of the underlying causes to the progression of a number of medical conditions, e.g. cancer, inflammation, graft rejection, and lymphedema. Galectin-8 is a tandem-repeat galectin comprised of two carbohydrate domains (CRDs), defined as the N-terminal (galectin-8N) and C-terminal (galectin-8C) CRDs. Galectin-8 has been observed to have a positive effect on signaling mechanisms inducing lymphangiogenesis. It has been shown that inhibition of galectin-8 antagonizes lymphangiogenesis and thus reduces the progression of the aforementioned disorders. The aspiration of efficiently treating these conditions subsequently motivates the development of high affinity inhibitor candidates of galectin-8N. Earlier studies have shown that galectin-8N naturally retains a high affinity to 3-O-sialylated lactose. Our aim was to explore and further develop the favorable binding interactions of galectin-8N and 3-O-sialylated lactose. This approach was carried out by chemically modifying a simplified version of the previously studied inhibitor by implementing carboxylic acid isosteres in order to introduce new functional groups on the 3-O position of galactose. Synthetic procedures were subsequently developed to enable the introduction of hydroxamate and sulfonamide functionalities on a β-D-galactopyranoside derivative. It was found that synthesized inhibitor candidates retaining a hydroxamate functional group possessed similar affinities (down to 520 µm) to galectin-8N compared to the corresponding carboxyl-substituted compound. These findings were interpreted as the combined effect on binding from the substituted arene and the hydroxamate functional group was comparable to the binding strength of the corresponding carboxyl-substituted compound. However, it could not be concluded which of and to what degree these functional groups contributed to the binding. The similar affinities of the synthesized inhibitors suggested a rather superficial structure activity relationship (SAR), which opens up for further optimization of the left-hand side substituents from the hydroxamate linker group (Less)
Popular Abstract (Swedish)
Organisk kemi är läran om kolföreningarnas kemi och är en vetenskap som ligger till grund för att förstå praktiskt taget alla naturvetenskapliga områden. En viktig applikation är att med hjälp av kemisk syntes ta fram nya läkemedel. I takt med att vi blir allt äldre och vår livsstil förändras uppstår likväl alltfler problem med nya sjukdomar i en annan omfattning än tidigare och behovet av nya effektiva läkemedel tycks aldrig upphöra. Genom att framställa småmolekyler med rätt struktur kan dessa föreningar interagera med biologiska system i kroppen, vilket i sin tur kan leda till botande eller förmildrande av olika sjukdomar. Kroppens lymfsystem bidrar i normala fall till att dränera kroppens vävnader på vätska och återföra denna till... (More)
Organisk kemi är läran om kolföreningarnas kemi och är en vetenskap som ligger till grund för att förstå praktiskt taget alla naturvetenskapliga områden. En viktig applikation är att med hjälp av kemisk syntes ta fram nya läkemedel. I takt med att vi blir allt äldre och vår livsstil förändras uppstår likväl alltfler problem med nya sjukdomar i en annan omfattning än tidigare och behovet av nya effektiva läkemedel tycks aldrig upphöra. Genom att framställa småmolekyler med rätt struktur kan dessa föreningar interagera med biologiska system i kroppen, vilket i sin tur kan leda till botande eller förmildrande av olika sjukdomar. Kroppens lymfsystem bidrar i normala fall till att dränera kroppens vävnader på vätska och återföra denna till blodcirkulationen och har även en viktig roll i immunsystemet. Lymfsystemet utvecklas till största del redan under fosterstadiet och i vuxen ålder sker nybildning av lymfkärl normalt i väldigt liten utsträckning. En onormal lymfkärlsfunktion har visats vara centralt i en rad sjukdomar och tillstånd, t.ex. inflammation, cancer, lymfödem och bortstötande av transplanterade organ. Galektin-8 är ett protein som förekommer naturligt i kroppen och som man har sett kan inducera nybildning av lymfkärl. I denna aktiveringsprocess binder galektin-8 till särskilda receptorer som i sin tur signalerar om att lymfkärl ska bildas. Genom att syntetiskt framställa molekyler som efterliknar delar av dessa receptorer kan man genom inbindning till galektin-8 hämma lymfkärlsbildning. På så vis kan man möjligtvis också förhindra fortskridandet av tidigare nämnda sjukdomar. I det här projektet har målet varit att syntetiskt framställa och utvärdera inbindningen av en ny serie galektin-8-hämmare. För de molekyler som framställdes i det här projektet såg vi att de hade liknande inbindningsstyrka som tidigare testade substanser. Med den information som erhölls kan vi se indikationer på hur särskilda kemiska strukturer korrelerar med hur proteininbindningen sker. Denna information kommer att användas för att förbättra designen av de befintliga kemiska strukturerna. På längre sikt kan detta leda till läkemedelskandidater som hämmar lymfkärlsnybildning genom stark inbindning till galektin-8. (Less)
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author
Persson, Stella LU
supervisor
organization
course
KOK820 20151
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
7373871
date added to LUP
2015-06-25 15:34:37
date last changed
2015-06-25 15:34:37
@misc{7373871,
  abstract     = {Lymphangiogenesis, i.e. novel formation of lymph vessels, is known to be one of the underlying causes to the progression of a number of medical conditions, e.g. cancer, inflammation, graft rejection, and lymphedema. Galectin-8 is a tandem-repeat galectin comprised of two carbohydrate domains (CRDs), defined as the N-terminal (galectin-8N) and C-terminal (galectin-8C) CRDs. Galectin-8 has been observed to have a positive effect on signaling mechanisms inducing lymphangiogenesis. It has been shown that inhibition of galectin-8 antagonizes lymphangiogenesis and thus reduces the progression of the aforementioned disorders. The aspiration of efficiently treating these conditions subsequently motivates the development of high affinity inhibitor candidates of galectin-8N. Earlier studies have shown that galectin-8N naturally retains a high affinity to 3-O-sialylated lactose. Our aim was to explore and further develop the favorable binding interactions of galectin-8N and 3-O-sialylated lactose. This approach was carried out by chemically modifying a simplified version of the previously studied inhibitor by implementing carboxylic acid isosteres in order to introduce new functional groups on the 3-O position of galactose. Synthetic procedures were subsequently developed to enable the introduction of hydroxamate and sulfonamide functionalities on a β-D-galactopyranoside derivative. It was found that synthesized inhibitor candidates retaining a hydroxamate functional group possessed similar affinities (down to 520 µm) to galectin-8N compared to the corresponding carboxyl-substituted compound. These findings were interpreted as the combined effect on binding from the substituted arene and the hydroxamate functional group was comparable to the binding strength of the corresponding carboxyl-substituted compound. However, it could not be concluded which of and to what degree these functional groups contributed to the binding. The similar affinities of the synthesized inhibitors suggested a rather superficial structure activity relationship (SAR), which opens up for further optimization of the left-hand side substituents from the hydroxamate linker group},
  author       = {Persson, Stella},
  language     = {eng},
  note         = {Student Paper},
  title        = {Design, Organic Synthesis, and Evaluation of New Galactose Based Galectin-8 Inhibitors.},
  year         = {2015},
}