Design, Method Development, and Synthesis of Novel Galectin-9N Inhibitors
(2020) KEMR10 20192Department of Chemistry
- Abstract
- Introducing an N-sulfonylamidine substituent in galactose increased the selectivity for galectin-9N, a protein involved in functions of the immune system, and is believed to have roles in autoimmune diseases and cancer. In this work, a fast method for regioselective monoalkylation of galactose by microwave irradiation was developed, and eight potential galectin-9N inhibitors were synthesized. Molecular dynamics simulations proposed interactions deep into the binding pocket between the N-sulfonylamidine moiety and Asn48 and Asn137; two residues which are thought to be essential for selective binding to the N terminal of galectin-9. Evaluation of six of the eight novel N-sulfonylamidine galactoside derivatives showed selective, high-affinity... (More)
- Introducing an N-sulfonylamidine substituent in galactose increased the selectivity for galectin-9N, a protein involved in functions of the immune system, and is believed to have roles in autoimmune diseases and cancer. In this work, a fast method for regioselective monoalkylation of galactose by microwave irradiation was developed, and eight potential galectin-9N inhibitors were synthesized. Molecular dynamics simulations proposed interactions deep into the binding pocket between the N-sulfonylamidine moiety and Asn48 and Asn137; two residues which are thought to be essential for selective binding to the N terminal of galectin-9. Evaluation of six of the eight novel N-sulfonylamidine galactoside derivatives showed selective, high-affinity binding to galectin-9N over galectin-1 and galectin-3. One of the N-sulfonylamidine galactoside derivatives were highly selective and stood out in the assays. Due to the molecules' inherent high hydrophobicity, they were poorly soluble in water solutions and precipitated during binding affinity testing, and the correct binding affinity could not be determined. The improved affinity and selectivity of the novel N-sulfonylamidine galactoside derivatives provide important information for the development of novel galectin-9N inhibitors. (Less)
- Popular Abstract
- Carbohydrates are not only used as an energy source in the body. The cell surface is covered in different sugar molecules, and one of these is galactose, to which the proteins called galectins bind with their carbohydrate-binding domain. To this day, fifteen different galectins have been discovered in vertebrates, and they bind to similar, but different galactose containing carbohydrates. The different galectins govern different cellular functions, like cell division and cell death, to name a few. When the galectins bind to their sugar of choice on the cell surface, they can, for example, initiate cell signaling in or between cells or cross-link to other proteins.
The aim of this work was to synthesize artificial galactose derivatives... (More) - Carbohydrates are not only used as an energy source in the body. The cell surface is covered in different sugar molecules, and one of these is galactose, to which the proteins called galectins bind with their carbohydrate-binding domain. To this day, fifteen different galectins have been discovered in vertebrates, and they bind to similar, but different galactose containing carbohydrates. The different galectins govern different cellular functions, like cell division and cell death, to name a few. When the galectins bind to their sugar of choice on the cell surface, they can, for example, initiate cell signaling in or between cells or cross-link to other proteins.
The aim of this work was to synthesize artificial galactose derivatives that will bind stronger than the naturally occurring carbohydrates and only bind to one type of galectin proteins, galectin-9N. This protein has functions in the immune system, and diseases, such as arthritis and cancer, have been addressed to this protein. By creating inhibitors to galectin-9N, it may be possible to ease or even cure diseases caused by this protein.
In this work, eight different inhibitors were synthesized, and a fast method for alkylation of galactose molecules was developed. This reaction usually takes everything from five to twenty hours to perform, but with the use of heating by a microwave reactor, the reaction time is significantly decreased to less than an hour. The binding to galectin-1, -3, and -9N by six of the eight synthesized inhibitors were evaluated. All inhibitors showed considerable binding to galectin-9N, and weak binding to galectin-1 and -3, and was, therefore, more selective than previously developed inhibitors. This selectivity is important only to affect one type of galectins to minimize side effects. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9008213
- author
- Gunnarsson, Ludvig LU
- supervisor
- organization
- course
- KEMR10 20192
- year
- 2020
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- Organic chemistry, Medicinal chemistry, Galectin-9N, Organisk kemi
- language
- English
- id
- 9008213
- date added to LUP
- 2020-05-14 11:14:19
- date last changed
- 2020-05-14 11:14:19
@misc{9008213,
abstract = {{Introducing an N-sulfonylamidine substituent in galactose increased the selectivity for galectin-9N, a protein involved in functions of the immune system, and is believed to have roles in autoimmune diseases and cancer. In this work, a fast method for regioselective monoalkylation of galactose by microwave irradiation was developed, and eight potential galectin-9N inhibitors were synthesized. Molecular dynamics simulations proposed interactions deep into the binding pocket between the N-sulfonylamidine moiety and Asn48 and Asn137; two residues which are thought to be essential for selective binding to the N terminal of galectin-9. Evaluation of six of the eight novel N-sulfonylamidine galactoside derivatives showed selective, high-affinity binding to galectin-9N over galectin-1 and galectin-3. One of the N-sulfonylamidine galactoside derivatives were highly selective and stood out in the assays. Due to the molecules' inherent high hydrophobicity, they were poorly soluble in water solutions and precipitated during binding affinity testing, and the correct binding affinity could not be determined. The improved affinity and selectivity of the novel N-sulfonylamidine galactoside derivatives provide important information for the development of novel galectin-9N inhibitors.}},
author = {{Gunnarsson, Ludvig}},
language = {{eng}},
note = {{Student Paper}},
title = {{Design, Method Development, and Synthesis of Novel Galectin-9N Inhibitors}},
year = {{2020}},
}