Design and Synthesis of D-Galactal-Based Benzimidazole and Benzoxazole Derivatives as Inhibitors of Galectin-8 N-Terminal Domain
(2022) KASM20 20221Centre for Analysis and Synthesis
- Abstract
- Galectin-8 is a β-galactoside-binding protein, participating in many homeostatic and pathological functions, such as regulation of cellular adhesion, T-cell homeostasis, apoptosis, as well as playing a major role in tumor development and progression. Galectin-8 has two CRDs, namely galectin-8 N-terminal (galectin-8N) and C-terminal (galectin-8C) domains, that exhibit differential glycan binding specificities. Since galectin-8N recognizes a broader spectrum of glycans compared to galectin-8C, it is an attractive molecular target for inhibitor discovery. In recent research, it was found that chemically modified galactose mimic D-galactal-benzimidazole is the most selective galectin-8N ligand to date. The molecule is C-3 substituted with... (More)
- Galectin-8 is a β-galactoside-binding protein, participating in many homeostatic and pathological functions, such as regulation of cellular adhesion, T-cell homeostasis, apoptosis, as well as playing a major role in tumor development and progression. Galectin-8 has two CRDs, namely galectin-8 N-terminal (galectin-8N) and C-terminal (galectin-8C) domains, that exhibit differential glycan binding specificities. Since galectin-8N recognizes a broader spectrum of glycans compared to galectin-8C, it is an attractive molecular target for inhibitor discovery. In recent research, it was found that chemically modified galactose mimic D-galactal-benzimidazole is the most selective galectin-8N ligand to date. The molecule is C-3 substituted with benzimidazole moiety and can be further functionalized at C-4 of benzimidazole to establish interactions with unique amino acid residues of galectin-8N. In this study, a set of C-3 substituted benzimidazole- and benzoxazole-D-galactal derivatives were designed, synthesized, and tested for the binding affinities to galectin-8N in a competitive fluorescence polarization assay. This has led to the discovery of a D-galactal-benzimidazole derivative functionalized with a phenyl group at C-4 with a Kd value of 5 ± 0.5 µM, which is 9-fold higher affinity compared to the previously reported unsubstituted D-galactal benzimidazole derivative and 41-fold higher affinity than equally substituted D-galactal-benzoxazole analogue. Results imply that future studies should be focused on the design and synthesis of D-galactal-benzimidazole ligands as promising compounds for the development of therapeutics targeting galectin-8N. (Less)
- Popular Abstract
- D-Galactal based benzimidazoles as a kick-off toward the design of sweet drugs
Galectins are a family of proteins that participates in various diseases, such as cancer, atherosclerosis, diabetes, and rheumatoid arthritis. One of the members of the galectin family, namely galectin-8N, plays a major role in cancer development. Galectin-8N helps the tumor to grow by orchestrating the growth of new lymphatic vessels which feeds the tumor with oxygen and nutrients. Due to its involvement in tumor development and progression, the design of drugs that could block the activity of galectin-8N is an important area to focus on.
Like other members of the galectin protein family, galectin-8N contains a groove in its structure that can recognize and... (More) - D-Galactal based benzimidazoles as a kick-off toward the design of sweet drugs
Galectins are a family of proteins that participates in various diseases, such as cancer, atherosclerosis, diabetes, and rheumatoid arthritis. One of the members of the galectin family, namely galectin-8N, plays a major role in cancer development. Galectin-8N helps the tumor to grow by orchestrating the growth of new lymphatic vessels which feeds the tumor with oxygen and nutrients. Due to its involvement in tumor development and progression, the design of drugs that could block the activity of galectin-8N is an important area to focus on.
Like other members of the galectin protein family, galectin-8N contains a groove in its structure that can recognize and bind to sweet sugar molecules - carbohydrates, that are a part of larger molecules such as glycoproteins. Galectins provoke an effect on various diseases by binding to glycoproteins, which decorate the membranes of human cells. Upon binding, galectin influences the glycoprotein activity, which can result in a message to the cell telling it to function in a particular way, and that could be to function in favor of disease development. One approach to disable galectin from acting on healthy and diseased cells is to design a drug that could bind the groove of the protein and prevent the protein from binding to carbohydrates on cells until the drug leaves the groove. For the drug to bind the protein, it should have a carbohydrate-related structure to imitate its mode of action as well as to contain additional chemical structure(s) which would make it superior in the binding to galectin over natural carbohydrates in the human body. In recent research, it was found that a molecule, which is composed of sugar named D-galactal and a chemical structure called benzimidazole, binds to galectin-8N with relatively good strength, meaning that in the groove it can replace natural carbohydrates with lower binding strength more efficiently and block galectin-8N activity. In this project, the aim was to further develop the molecule by adding one more chemical structure to benzimidazole to observe if the binding strength has increased.
The results showed that the addition of chemical structure to benzimidazole resulted in increased binding strength. Although the obtained binding strength was higher than the reference compound, it is still not high enough for the molecule to become a drug. Therefore, the gathered results will be useful in the further development of molecules that could bind galectin-8N even stronger. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9094543
- author
- Juskaite, Radvile LU
- supervisor
- organization
- course
- KASM20 20221
- year
- 2022
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- Galectin-8N, D-Galactal, Benzimidazole, Benzoxazole, Selectivity, Organic Chemistry
- language
- English
- id
- 9094543
- date added to LUP
- 2022-06-30 12:33:41
- date last changed
- 2022-06-30 12:33:41
@misc{9094543,
abstract = {{Galectin-8 is a β-galactoside-binding protein, participating in many homeostatic and pathological functions, such as regulation of cellular adhesion, T-cell homeostasis, apoptosis, as well as playing a major role in tumor development and progression. Galectin-8 has two CRDs, namely galectin-8 N-terminal (galectin-8N) and C-terminal (galectin-8C) domains, that exhibit differential glycan binding specificities. Since galectin-8N recognizes a broader spectrum of glycans compared to galectin-8C, it is an attractive molecular target for inhibitor discovery. In recent research, it was found that chemically modified galactose mimic D-galactal-benzimidazole is the most selective galectin-8N ligand to date. The molecule is C-3 substituted with benzimidazole moiety and can be further functionalized at C-4 of benzimidazole to establish interactions with unique amino acid residues of galectin-8N. In this study, a set of C-3 substituted benzimidazole- and benzoxazole-D-galactal derivatives were designed, synthesized, and tested for the binding affinities to galectin-8N in a competitive fluorescence polarization assay. This has led to the discovery of a D-galactal-benzimidazole derivative functionalized with a phenyl group at C-4 with a Kd value of 5 ± 0.5 µM, which is 9-fold higher affinity compared to the previously reported unsubstituted D-galactal benzimidazole derivative and 41-fold higher affinity than equally substituted D-galactal-benzoxazole analogue. Results imply that future studies should be focused on the design and synthesis of D-galactal-benzimidazole ligands as promising compounds for the development of therapeutics targeting galectin-8N.}},
author = {{Juskaite, Radvile}},
language = {{eng}},
note = {{Student Paper}},
title = {{Design and Synthesis of D-Galactal-Based Benzimidazole and Benzoxazole Derivatives as Inhibitors of Galectin-8 N-Terminal Domain}},
year = {{2022}},
}