Design, synthesis, and evaluation of 1-phenylethanol and C2 threitol derivatives as non-pyranose galactose-mimicking inhibitors of Galectin-3
(2023) KASM05 20231Centre for Analysis and Synthesis
- Abstract
- Galectins are cytosolic protein family involved in several biological functions such as cell differentiation, cell migration and apoptosis amongst many others. Their presence is also substantial in diseases including acute inflammation, fibrosis, allergies, and cancer. This protein family consists of 15 members where the majority of them are found in humans and they are divided into three subgroups: prototype, chimera and tandem-repeat. Being the only member of the chimera group, Galectin-3 is an interesting protein to study since it has also been shown to for example promote tumor immune evasion.
LacNAc is a fragment, consisting of galactose and glucose, which has been shown to bind to Galectin-3 effectively. By considering and... (More) - Galectins are cytosolic protein family involved in several biological functions such as cell differentiation, cell migration and apoptosis amongst many others. Their presence is also substantial in diseases including acute inflammation, fibrosis, allergies, and cancer. This protein family consists of 15 members where the majority of them are found in humans and they are divided into three subgroups: prototype, chimera and tandem-repeat. Being the only member of the chimera group, Galectin-3 is an interesting protein to study since it has also been shown to for example promote tumor immune evasion.
LacNAc is a fragment, consisting of galactose and glucose, which has been shown to bind to Galectin-3 effectively. By considering and retaining the essential bindings of LacNAc leading to interactions with the amino acid residues in the binding site, synthetic molecules can be developed. By synthesizing small and relatively nonpolar potential inhibitors of Galectin-3, it is predicted that they would be able to pass through the blood-brain barrier and suppress the protein’s function in cell differentiation of cancer cells positioned in the central nervous system.
In this project, the derivatives of 1-phenylethanol and their respective enantiomers with S and R configuration, were studied with styrene compounds as starting materials. The reason behind it is to investigate whether a specific enantiomer will interact better with the active binding site of Galectin-3. Analyses of the compounds’ configuration were performed and it was concluded that the OH-group could have adapt its conformation to fit into the binding site. Thus, no significant difference was seen in the binding affinity of S and R-enantiomers. Meanwhile, it was also investigated if C2 threitol derivatives would enhance the affinity of other earlier studied threitol derivatives by interacting with Tryptophan 181. Starting from a D-galactose, a threitol compound can be obtained through a series of reactions where modifications can be further made on C2. In this case, it was concluded that converting the hydroxyl group of C2 to a ketone could have caused possible repulsion when interaction with Trp 181. (Less) - Popular Abstract
- Galectins are proteins involved in several biological functions such as cell division, cell migration and cell death amongst many others. Their presence is also substantial in diseases including acute inflammation, scar formation, allergies, and cancer. The galectin family consists of 15 members where the majority of them are found in humans. Especially, galectin-3 is an interesting protein to study since it has been shown to be mainly active in cell division of cancer cells.
LacNAc is a sugar-containing fragment which has been shown to bind the best and inhibit Galectin-3. By considering and retaining the essential bindings of LacNAc leading to excellent interactions with the amino acids in the binding site, synthetic molecules can be... (More) - Galectins are proteins involved in several biological functions such as cell division, cell migration and cell death amongst many others. Their presence is also substantial in diseases including acute inflammation, scar formation, allergies, and cancer. The galectin family consists of 15 members where the majority of them are found in humans. Especially, galectin-3 is an interesting protein to study since it has been shown to be mainly active in cell division of cancer cells.
LacNAc is a sugar-containing fragment which has been shown to bind the best and inhibit Galectin-3. By considering and retaining the essential bindings of LacNAc leading to excellent interactions with the amino acids in the binding site, synthetic molecules can be developed. In this project, small and relatively hydrophobic molecules have been synthesized serving as potential inhibitors of Galectin-3. It is predicted that they would be able to enter the central nervous system and suppress the protein’s function in cell division of cancer cells. (Less) - Popular Abstract (Swedish)
- Galektiner är proteiner som är involverade i många biologiska funktioner så som celldelning, cellvandring och celldöd bland många fler. Deras närvaro är betydande i sjukdomar som akut inflammation, ärrbildning, allergier och cancer. Galektinfamiljen består av 15 medlemmar där majoriteten av dem finns i människor. Speciellt galektin-3 är ett intressant protein att studera eftersom det har visats vara mestadels aktiv i celldelning av cancerceller.
LacNAc är ett socker-innehållande fragment som har visat sig binda bäst och hämmar Galektin-3. Genom att ta hänsyn till och bevara de viktiga bindningarna av LacNAc som leder till utmärkta interaktioner med aminosyrorna i bindningsfickan kan man utveckla syntetiska molekyler. I detta projekt har... (More) - Galektiner är proteiner som är involverade i många biologiska funktioner så som celldelning, cellvandring och celldöd bland många fler. Deras närvaro är betydande i sjukdomar som akut inflammation, ärrbildning, allergier och cancer. Galektinfamiljen består av 15 medlemmar där majoriteten av dem finns i människor. Speciellt galektin-3 är ett intressant protein att studera eftersom det har visats vara mestadels aktiv i celldelning av cancerceller.
LacNAc är ett socker-innehållande fragment som har visat sig binda bäst och hämmar Galektin-3. Genom att ta hänsyn till och bevara de viktiga bindningarna av LacNAc som leder till utmärkta interaktioner med aminosyrorna i bindningsfickan kan man utveckla syntetiska molekyler. I detta projekt har små och relativt hydrofobiska molekyler syntetiserats för att möjligen inhibera galektin-3 förutsatt att de ska kunna passera det centrala nervsystemet och dämpa proteinets funktion i celldelning av cancerceller. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9132726
- author
- Cruz Giron, Qrystal LU
- supervisor
- organization
- course
- KASM05 20231
- year
- 2023
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- Galectin-3, Galectin-3 inhibitor, 1-phenylethanol, C2 threitol derivative, galactose-mimicking inhibitor, organic chemistry
- language
- English
- id
- 9132726
- date added to LUP
- 2023-07-10 11:44:35
- date last changed
- 2023-08-08 09:09:49
@misc{9132726,
abstract = {{Galectins are cytosolic protein family involved in several biological functions such as cell differentiation, cell migration and apoptosis amongst many others. Their presence is also substantial in diseases including acute inflammation, fibrosis, allergies, and cancer. This protein family consists of 15 members where the majority of them are found in humans and they are divided into three subgroups: prototype, chimera and tandem-repeat. Being the only member of the chimera group, Galectin-3 is an interesting protein to study since it has also been shown to for example promote tumor immune evasion.
LacNAc is a fragment, consisting of galactose and glucose, which has been shown to bind to Galectin-3 effectively. By considering and retaining the essential bindings of LacNAc leading to interactions with the amino acid residues in the binding site, synthetic molecules can be developed. By synthesizing small and relatively nonpolar potential inhibitors of Galectin-3, it is predicted that they would be able to pass through the blood-brain barrier and suppress the protein’s function in cell differentiation of cancer cells positioned in the central nervous system.
In this project, the derivatives of 1-phenylethanol and their respective enantiomers with S and R configuration, were studied with styrene compounds as starting materials. The reason behind it is to investigate whether a specific enantiomer will interact better with the active binding site of Galectin-3. Analyses of the compounds’ configuration were performed and it was concluded that the OH-group could have adapt its conformation to fit into the binding site. Thus, no significant difference was seen in the binding affinity of S and R-enantiomers. Meanwhile, it was also investigated if C2 threitol derivatives would enhance the affinity of other earlier studied threitol derivatives by interacting with Tryptophan 181. Starting from a D-galactose, a threitol compound can be obtained through a series of reactions where modifications can be further made on C2. In this case, it was concluded that converting the hydroxyl group of C2 to a ketone could have caused possible repulsion when interaction with Trp 181.}},
author = {{Cruz Giron, Qrystal}},
language = {{eng}},
note = {{Student Paper}},
title = {{Design, synthesis, and evaluation of 1-phenylethanol and C2 threitol derivatives as non-pyranose galactose-mimicking inhibitors of Galectin-3}},
year = {{2023}},
}