Synthesis of 3-azido-2,4,6-tri-O-(4-methoxybenzyl)-3-deoxy-galactopyranoside
(2019) KASM05 20191Centre for Analysis and Synthesis
- Abstract
- Galectin-3 is a protein that is involved in many physiological processes such as metastasis, T-cell regulation etc. which makes it a good drug target for the medicinal chemist. In a paper made by Doak ete al (2015) macrocyclization emerged as an interesting strategy for new drug design as macrocycles remained orally active in chemical space previously thought of as “unsuitable” as per the classical rules defined by Lipinsky. Previous work done in the Nilsson group at Lund university has explored the binding event of monosaccharide galectin-3 inhibitors based on a galactose scaffold. Based on X-ray crystallography obtained from previous work we predicted that a macrocyclic structure would retain much of the same configuration in the binding... (More)
- Galectin-3 is a protein that is involved in many physiological processes such as metastasis, T-cell regulation etc. which makes it a good drug target for the medicinal chemist. In a paper made by Doak ete al (2015) macrocyclization emerged as an interesting strategy for new drug design as macrocycles remained orally active in chemical space previously thought of as “unsuitable” as per the classical rules defined by Lipinsky. Previous work done in the Nilsson group at Lund university has explored the binding event of monosaccharide galectin-3 inhibitors based on a galactose scaffold. Based on X-ray crystallography obtained from previous work we predicted that a macrocyclic structure would retain much of the same configuration in the binding pocket as the monosaccharides. By comparing the open and cyclised compounds we expect to obtain valuable thermodynamic data of the binding event to aid future drug design. With this goal in mind 3-azido-2,4,6-tri-O-(4-methoxybenzyl)-3-deoxy-galactopyranoside was synthesized and a strategy to obtain the macrocycle has been proposed in this paper. (Less)
- Popular Abstract
- Galectin-3 – a multipurpose protein
And a proposition on how to design drugs to target it
Most people hear quite often about proteins in a lot of different context: from dietists making a balanced meal to daily conversations about what protein-rich bean one might use to supplant meat. To a medicinal chemist, proteins are key players in the search for new drugs; for if the body can be likened to a factory with the cells as workers, then proteins are the tools of said workers.
For the purposes of our work we have chosen galectin-3 as a target-protein as it is involved in several different processes in the body; from making new blood-vessels (angiogenesis) to programmed cell-death (apoptosis) – both of which are functions involved in... (More) - Galectin-3 – a multipurpose protein
And a proposition on how to design drugs to target it
Most people hear quite often about proteins in a lot of different context: from dietists making a balanced meal to daily conversations about what protein-rich bean one might use to supplant meat. To a medicinal chemist, proteins are key players in the search for new drugs; for if the body can be likened to a factory with the cells as workers, then proteins are the tools of said workers.
For the purposes of our work we have chosen galectin-3 as a target-protein as it is involved in several different processes in the body; from making new blood-vessels (angiogenesis) to programmed cell-death (apoptosis) – both of which are functions involved in cancer. These processes are however quite complex and it is difficult at this stage to pinpoint exactly what the role of galectin-3 is in each of the aforementioned bodily functions in detail. Due to its involvement in functions concerning cancer, and metastasis in particular, galectin-3 has been identified as a drug target in hopes that we may understand its role better and possibly use that knowledge to develop better treatments further down the line.
For now, we are exploring the binding site of the protein. A binding site is where a protein receives signals from its surroundings in order to know what to do. Proteins are large molecules and might contain several binding-sites. There might be one part of the protein that recognises certain molecules that the body makes in order to lower its activity and another that makes it increase its activity. When stricken by disease, proteins might be operating at the wrong level. A strategy in drug-design is to make molecules similar to those naturally interacting with the target binding site but with some sort of twist so that we may control the overall activity of the protein as we see fit.
We have looked at previous work done by the Nilsson group that has mapped the binding sites of galectin-3 and tried to build on that knowledge. In particular we have combined those previous finings with an interesting proposal done by Doak (1) who hypothesises that large cyclic molecules might have suitable chemical properties for orally available drugs. With this in mind we have designed a 15-step synthetic strategy to make our drug candidates called compounds ER-13 and ER-15 and successfully completed five of those steps.
We hope that this research can be continued and hopefully yield important information about galectin-3; its binding site and potentially aid in the development of drugs targeting galectin-3.
(1) Doak, B., Zheng, J., Dobritzsch, D., Kihlberg, J. (2016). How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their Targets. Journal of medicinal chemistry. Volume 59 (6), pp 2312-2327. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9053683
- author
- Reistad, Esbjörn LU
- supervisor
-
- Ulf Nilsson LU
- organization
- course
- KASM05 20191
- year
- 2019
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- Medicinal chemistry, Cancer, macrocyclization, Organic chemistry
- language
- English
- id
- 9053683
- date added to LUP
- 2021-06-28 13:34:06
- date last changed
- 2021-06-28 13:34:06
@misc{9053683,
abstract = {{Galectin-3 is a protein that is involved in many physiological processes such as metastasis, T-cell regulation etc. which makes it a good drug target for the medicinal chemist. In a paper made by Doak ete al (2015) macrocyclization emerged as an interesting strategy for new drug design as macrocycles remained orally active in chemical space previously thought of as “unsuitable” as per the classical rules defined by Lipinsky. Previous work done in the Nilsson group at Lund university has explored the binding event of monosaccharide galectin-3 inhibitors based on a galactose scaffold. Based on X-ray crystallography obtained from previous work we predicted that a macrocyclic structure would retain much of the same configuration in the binding pocket as the monosaccharides. By comparing the open and cyclised compounds we expect to obtain valuable thermodynamic data of the binding event to aid future drug design. With this goal in mind 3-azido-2,4,6-tri-O-(4-methoxybenzyl)-3-deoxy-galactopyranoside was synthesized and a strategy to obtain the macrocycle has been proposed in this paper.}},
author = {{Reistad, Esbjörn}},
language = {{eng}},
note = {{Student Paper}},
title = {{Synthesis of 3-azido-2,4,6-tri-O-(4-methoxybenzyl)-3-deoxy-galactopyranoside}},
year = {{2019}},
}