D-Galactal C1-modifications in search of Galectin-8N inhibition
(2020) KEMR30 20201Department of Chemistry
- Abstract
- Galectins are a family of proteins that bind β-galactosides. These proteins are involved in plethora of physiological functions, such as signalling, inflammation and immune responses. Because galectins play a key role in human physiology, they are heavily involved in disease pathways. Overexpression of different kinds of galectins has been found to be linked to diseases and syndromes, such epithelial ovarian cancer, insulin resistance and fibrosis, breast cancer and prostate cancer. In this thesis, a variety of synthetic routes employing Stille coupling, molecular dynamics simulations and amide coupling that have led to the successful synthesis of potential galectin-8 inhibitors will be discussed.
A few conclusions can be made from the... (More) - Galectins are a family of proteins that bind β-galactosides. These proteins are involved in plethora of physiological functions, such as signalling, inflammation and immune responses. Because galectins play a key role in human physiology, they are heavily involved in disease pathways. Overexpression of different kinds of galectins has been found to be linked to diseases and syndromes, such epithelial ovarian cancer, insulin resistance and fibrosis, breast cancer and prostate cancer. In this thesis, a variety of synthetic routes employing Stille coupling, molecular dynamics simulations and amide coupling that have led to the successful synthesis of potential galectin-8 inhibitors will be discussed.
A few conclusions can be made from the data obtained from this thesis. Firstly, that C1-modifications on D-galactal are possible, but direct arylation of the anomeric position has proven a challenge. Secondly, of the modified products that have been analysed, the modifications only seem to be either tolerated, like in the case with the synthesised C1-naphthalene glycal, by the binding pocket of galectin-8N or worsened, like in the case with the synthesised C1-carboximidate and C1-amide glycals. Lastly, while direct arylations have proven difficult, the ability to synthesise C1-nitrile glycals allows for many synthetic pathways forward. (Less) - Popular Abstract
- There are many ways one can utilise their knowledge of, and skills in chemistry in their life. Some enjoy the thrill of discovering new uses for different compounds and chemical reactions with academia, others find fulfilment in establishing and optimising processes to make them greener, and much more. All of these different ways of applying chemistry to solve a variety of problems can also be done in different subfields within chemistry.
One of those fields is medicinal chemistry. When thinking about this field, many people immediately get the images of fat cat executives making money from preying on the sick and elderly, and not without cause. However, I strongly believe that there are those who join this industry in order to make the... (More) - There are many ways one can utilise their knowledge of, and skills in chemistry in their life. Some enjoy the thrill of discovering new uses for different compounds and chemical reactions with academia, others find fulfilment in establishing and optimising processes to make them greener, and much more. All of these different ways of applying chemistry to solve a variety of problems can also be done in different subfields within chemistry.
One of those fields is medicinal chemistry. When thinking about this field, many people immediately get the images of fat cat executives making money from preying on the sick and elderly, and not without cause. However, I strongly believe that there are those who join this industry in order to make the world a better place, namely the very chemists who work very hard every day in order to tackle different diseases in the hope of finding cures.
A disease that many people are sadly familiar with is cancer. There exist many different types such as ovarian cancer, breast cancer, prostate cancer and many more. A way that scientists have tried to tackle this problem is by finding out what parts of the human body cancer uses in order to replicate itself at such terrifying speed. The complex machinery of our biological bodies consists of cells. In and around these cells, we can find incredibly large molecular known as proteins. These proteins are made from our own DNA and both are made of molecules called amino acids. There is a wide variety of proteins found in the human body, but one that seems to be used by cancer to spread throughout the body is a specific family called galectins.
There are 15 different proteins that call this family home and one of these proteins, galectin-8, is used for making a system of tubes in the body that helps transport white blood cells and other important components, called lymphatic vessels. It has been found through research that cancer, prostate cancer in particular, highjacks this protein and produces more of it (a.k.a. overexpression) in order to make more lymphatic vessels so that it can spread easily throughout the body. This knowledge gives us the hope that it could be possible to stop some cancers from spreading through the body by blocking (a.k.a. inhibiting) this overexpressed protein with small molecules called ligands or inhibitors.
While there already exist inhibitors for galectin-8, many of these also inhibit the other members of the galectin family. This causes different side-effects to occur in the human body. In order to avoid this, a selective inhibitor must be made that specifically targets galectin-8.
In this thesis, different kinds of inhibitors have been made. While only one so far has been made that is selective for galectin-8 that is not very effective, the results also show that making effective and selective inhibitors is not far off and well within our grasp. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9025445
- author
- Lasisi, Olakunle LU
- supervisor
- organization
- course
- KEMR30 20201
- year
- 2020
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- Organic chemistry, Organisk kemi, Inhibitor, Galectin, Stille coupling, Amide coupling
- language
- English
- id
- 9025445
- date added to LUP
- 2020-09-11 10:58:09
- date last changed
- 2020-09-11 10:58:09
@misc{9025445,
abstract = {{Galectins are a family of proteins that bind β-galactosides. These proteins are involved in plethora of physiological functions, such as signalling, inflammation and immune responses. Because galectins play a key role in human physiology, they are heavily involved in disease pathways. Overexpression of different kinds of galectins has been found to be linked to diseases and syndromes, such epithelial ovarian cancer, insulin resistance and fibrosis, breast cancer and prostate cancer. In this thesis, a variety of synthetic routes employing Stille coupling, molecular dynamics simulations and amide coupling that have led to the successful synthesis of potential galectin-8 inhibitors will be discussed.
A few conclusions can be made from the data obtained from this thesis. Firstly, that C1-modifications on D-galactal are possible, but direct arylation of the anomeric position has proven a challenge. Secondly, of the modified products that have been analysed, the modifications only seem to be either tolerated, like in the case with the synthesised C1-naphthalene glycal, by the binding pocket of galectin-8N or worsened, like in the case with the synthesised C1-carboximidate and C1-amide glycals. Lastly, while direct arylations have proven difficult, the ability to synthesise C1-nitrile glycals allows for many synthetic pathways forward.}},
author = {{Lasisi, Olakunle}},
language = {{eng}},
note = {{Student Paper}},
title = {{D-Galactal C1-modifications in search of Galectin-8N inhibition}},
year = {{2020}},
}