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Macrocyclic glycomimetic towards galectin-3 inhibition

Almqvist, Olle LU (2026) KASM05 20261
Centre for Analysis and Synthesis
Abstract
The need for development of novel drugs towards the treatment of neurodegenerative disease such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and cancer is ever-pressing, especially within aging populations. Designing an effective drug towards these normally hard-to-treat conditions requires careful balance between uptake, solubility, and blood-brain-barrier (BBB) permeability, while still retaining high affinity. Upregulation of the carbohydrate-binding protein galectin-3 (gal-3) has a proven correlation to inflammation in the central nervous system (CNS), AD, PD, and cancer, yet no therapeutics have made it past clinical trials. On the current market, macrocycles are a severely underrepresented group of compounds, showing great... (More)
The need for development of novel drugs towards the treatment of neurodegenerative disease such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and cancer is ever-pressing, especially within aging populations. Designing an effective drug towards these normally hard-to-treat conditions requires careful balance between uptake, solubility, and blood-brain-barrier (BBB) permeability, while still retaining high affinity. Upregulation of the carbohydrate-binding protein galectin-3 (gal-3) has a proven correlation to inflammation in the central nervous system (CNS), AD, PD, and cancer, yet no therapeutics have made it past clinical trials. On the current market, macrocycles are a severely underrepresented group of compounds, showing great promise towards fulfilling the outlined criteria.
This work concerns the synthesis of a sulfide-analogue to a target compound previously synthesized and evaluated by the group, a galactose-based macrocycle towards the inhibition of gal-3 for glycomimetic treatment of medical conditions in the CNS.
Following a synthetic route not optimized for the sulfide-analogue, previously established by the group, the formation of the target compound was verified through nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography mass spectrometry (LC-MS) analysis, but full characterization could not be carried out. From the starting point of acetylated 4-azido galactose, this work resulted in the isolation and characterization of 3 novel compounds. However, further optimization is necessary to isolate the target compound and conduct biophysical evaluation to assess its effectiveness in comparison to those previously evaluated by the group. This work outlines a potential synthetic route towards a novel sulfide-analogue of previously isolated gal-3 inhibitors. (Less)
Popular Abstract (Swedish)
I en befolkning med ökande medelålder blir effekterna av neurodegenerativa sjukdomar, cancer, och inflammationsrelaterade diagnoser i det centrala nervsystemet (CNS) påtagliga. En nyckelspelare i dessa sjukdomar är en grupp sockerbindande proteiner vid namn galektiner, vars uppreglering har tydliga kopplingar till bland annat Alzheimers sjukdom, Parkinsons sjukdom, olika cancerformer, samt inflammationssjukdomar i CNS. Galektin-bindning och -blockering är därmed av stor relevans.
Blockering av dessa proteiner har i många fall en positiv effekt på prognosen av det medicinska tillståndet. Trots många framsteg har det varit svårt att ta fram lovande läkemedelskandidater med bra oralt upptag, för såväl sockerbaserade som icke sockerbaserade... (More)
I en befolkning med ökande medelålder blir effekterna av neurodegenerativa sjukdomar, cancer, och inflammationsrelaterade diagnoser i det centrala nervsystemet (CNS) påtagliga. En nyckelspelare i dessa sjukdomar är en grupp sockerbindande proteiner vid namn galektiner, vars uppreglering har tydliga kopplingar till bland annat Alzheimers sjukdom, Parkinsons sjukdom, olika cancerformer, samt inflammationssjukdomar i CNS. Galektin-bindning och -blockering är därmed av stor relevans.
Blockering av dessa proteiner har i många fall en positiv effekt på prognosen av det medicinska tillståndet. Trots många framsteg har det varit svårt att ta fram lovande läkemedelskandidater med bra oralt upptag, för såväl sockerbaserade som icke sockerbaserade molekyler. De tidigare nämnda sjukdomarna brukar ofta kallas ”difficult-to-treat” eller ”difficult-to-drug” – ”svårbehandlade” på svenska – då läkemedlen måste kunna nå CNS. Hjärnan skyddas av den så kallade blod-hjärnbarriären (BBB), som inte bara stoppar smittoämnen, utan också många läkemedel. Att få substanser att ta sig förbi BBB utgör en av de stora utmaningarna i läkemedelskemi, samtidigt som det måste finnas en balans mellan löslighet, stabilitet, och potens.
Makrocykler är cykliska molekyler bestående av 12 eller fler tunga atomer, och är ett förhållandevis outforskat område inom kemi med stor potential när det kommer till att utveckla nytänkande effektiva läkemedel. En fördel med makrocykler är att de kan agera som molekylära kameleonter, vilket innebär att de kan ändra molekylär form beroende på omgivning. Detta är en funktion som är viktig när det kommer till att öka upptag, distribution, och transport av ett läkemedel i kroppen.
Detta projekt syftade till att utvärdera en syntesväg för framställningen av en makrocyklisk molekyl som blockerar galektin-3. Målmolekylen utgör en svavel-variant till en av forskargruppen tidigare framställd och utvärderad substans.
Till följd av tidsbrist kunde målmolekylen inte isoleras och testas. Däremot ledde projektet fram till en stabil syntesväg, med förslag på förbättring, optimering, och fortsatt forskning. (Less)
Please use this url to cite or link to this publication:
author
Almqvist, Olle LU
supervisor
organization
course
KASM05 20261
year
type
H2 - Master's Degree (Two Years)
subject
keywords
galectin-3, macrocycles, organic chemistry, synthesis
language
English
id
9241471
date added to LUP
2026-06-22 09:35:27
date last changed
2026-06-22 09:35:27
@misc{9241471,
  abstract     = {{The need for development of novel drugs towards the treatment of neurodegenerative disease such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and cancer is ever-pressing, especially within aging populations. Designing an effective drug towards these normally hard-to-treat conditions requires careful balance between uptake, solubility, and blood-brain-barrier (BBB) permeability, while still retaining high affinity. Upregulation of the carbohydrate-binding protein galectin-3 (gal-3) has a proven correlation to inflammation in the central nervous system (CNS), AD, PD, and cancer, yet no therapeutics have made it past clinical trials. On the current market, macrocycles are a severely underrepresented group of compounds, showing great promise towards fulfilling the outlined criteria.
	This work concerns the synthesis of a sulfide-analogue to a target compound previously synthesized and evaluated by the group, a galactose-based macrocycle towards the inhibition of gal-3 for glycomimetic treatment of medical conditions in the CNS.
	Following a synthetic route not optimized for the sulfide-analogue, previously established by the group, the formation of the target compound was verified through nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography mass spectrometry (LC-MS) analysis, but full characterization could not be carried out. From the starting point of acetylated 4-azido galactose, this work resulted in the isolation and characterization of 3 novel compounds. However, further optimization is necessary to isolate the target compound and conduct biophysical evaluation to assess its effectiveness in comparison to those previously evaluated by the group. This work outlines a potential synthetic route towards a novel sulfide-analogue of previously isolated gal-3 inhibitors.}},
  author       = {{Almqvist, Olle}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Macrocyclic glycomimetic towards galectin-3 inhibition}},
  year         = {{2026}},
}