Synthesis of sialic acid 4-C derivatives in development of new antibacterial drugs
(2021) KEMR30 20201Department of Chemistry
- Abstract
- Sialic acids are a large family of acidic sugars. One of the most abundant is N-acetylneuraminic acid. Sialic acids are found at the terminal position of glycan chains of all cell types. Their wide distribution makes them have a broad set of biological functions, for example cell to cell interaction and communication.
Bacteria can utilize sialic acid for two purposes; 1) as a source of carbon, nitrogen and energy, and 2) for immune evasion to avoid the host’s immune response. Only a few bacteria have developed biosynthetic pathways to independently produce sialic acid, while the majority of them relies on host-derived sialic acid.
Bacteria have developed different transport systems to import sialic acid. One of them is the sialic acid... (More) - Sialic acids are a large family of acidic sugars. One of the most abundant is N-acetylneuraminic acid. Sialic acids are found at the terminal position of glycan chains of all cell types. Their wide distribution makes them have a broad set of biological functions, for example cell to cell interaction and communication.
Bacteria can utilize sialic acid for two purposes; 1) as a source of carbon, nitrogen and energy, and 2) for immune evasion to avoid the host’s immune response. Only a few bacteria have developed biosynthetic pathways to independently produce sialic acid, while the majority of them relies on host-derived sialic acid.
Bacteria have developed different transport systems to import sialic acid. One of them is the sialic acid transporter (SiaT) which belongs to the sodium solute symporter (SSS) family. The members of the SSS family cotransport sialic acid with sodium, using the sodium gradient as driving force.
Inside bacteria, sialic acid undergoes two different paths: catabolism or being involved in immune evasion mechanisms. Bacteria using molecular mimicry, utilizes sialic acid to escape the host immune system, since sialic acids are common for mediating a large set of recognition functions. Bacteria sialylate their lipopolysaccharides to avoid recognition, they are mistaken for being the host’s own cells and thereby escaping the host’s immune response.
Despite some synthetic and pharmacokinetic challenges, for example instability of some derivatives and side reactions, sialic acid is an interesting starting point in the development of new antibacterial drug leads since it is involved in several functions.
There has already been some work done with sialic acid on this topic. My objective was to continue that research by modifying the 4 th position of sialic acid by building a large linker onto it that would have a large fluorescent molecule at the end. The aim of the linker is to prevent sialic acid to enter the bacteria, thereby preventing molecular mimicry and immune evasion. This might be helpful in the research for new antibacterial drugs that are based on inhibition of sialic acid uptake.
In my project work, I designed and carried out a pathway towards a compound that potentially would have the properties desired for inhibition of the SiaT protein. The pathway consisted of selective 4-OH alkylation of sialic acid to 3-nitrobenzyl and 3-bromobenzyl ethers. Then exchange of bromine to alkyne and eventually 1,3-dipolar cycloaddition with azide. Many of the steps were optimized during the time and finally, two potential compounds were generated whose binding affinity are ready for being tested. (Less) - Popular Abstract (Swedish)
- Kolhydrater kan användas som en energikälla i kroppen, men de kan även användas för mycket mer än så. I alla organismer finns celler vars ytor är täckta av olika sockermolekyler vilka är avgörande för cellernas överlevnad samt kommunikation med andra celler. Ett exempel på ett sådant socker är sialinsyra; en syrlig kolhydrat med en nio kol lång kolkedja.
Patogener, exempelvis en del bakterier, kan utnyttja vissa sockermolekyler som är vanliga på cellytor för att maskera sig så att de smälter in bland värdens egna celler. Genom att använda speciella transportproteiner kan de importera sockermolekyler från sin omgivning så att de sedan kan dekorera sin egen cellyta med dessa. På detta sätt kan bakterier undvika värdens immunrespons,... (More) - Kolhydrater kan användas som en energikälla i kroppen, men de kan även användas för mycket mer än så. I alla organismer finns celler vars ytor är täckta av olika sockermolekyler vilka är avgörande för cellernas överlevnad samt kommunikation med andra celler. Ett exempel på ett sådant socker är sialinsyra; en syrlig kolhydrat med en nio kol lång kolkedja.
Patogener, exempelvis en del bakterier, kan utnyttja vissa sockermolekyler som är vanliga på cellytor för att maskera sig så att de smälter in bland värdens egna celler. Genom att använda speciella transportproteiner kan de importera sockermolekyler från sin omgivning så att de sedan kan dekorera sin egen cellyta med dessa. På detta sätt kan bakterier undvika värdens immunrespons, fortsätta sprida sig och orsaka infektioner. Detta fenomen kan orsaka antibiotikaresistens, vilket är ett globalt hot.
Genom att blockera de transportproteiner som ansvarar för upptag av sialinsyra, skulle bakterier förlora förmågan att gömma sig för immunresponsen. Därför är det av intresse att designa en molekyl som kan binda till dessa transportproteiner och blockera dem likt en vinkork. Tidigare har det inte gjorts så mycket forskning inom just detta området.
Målet med detta arbete var att skapa en molekyl som potentiellt skulle kunna besitta dessa blockerande förmågor. Utgångspunkten var att bygga på en lång länk på den fjärde positionen i sialinsyra och sedan sätta på en stor molekyl i slutet av den.
I projektet designades en syntesväg mot en molekyl med blockerande egenskaper. Denna innehöll en uppsättning av flera olika reaktionstyper som genomfördes. Många av stegen optimerades under tiden och slutligen genererades två potentiella föreningar som är redo för att bli testade. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9040520
- author
- Andersson, Emelie LU
- supervisor
-
- Ulf Nilsson LU
- organization
- alternative title
- Syntes av 4-C sialinsyraderivat i utvecklingen av nya antibakteriella läkemedel
- course
- KEMR30 20201
- year
- 2021
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- sialic acid, medicinal chemistry, carbohydrate, organic chemistry, antibacterial drugs, organic synthesis, antibiotic resistance
- language
- English
- id
- 9040520
- date added to LUP
- 2021-03-01 08:33:51
- date last changed
- 2021-03-01 08:33:51
@misc{9040520,
abstract = {{Sialic acids are a large family of acidic sugars. One of the most abundant is N-acetylneuraminic acid. Sialic acids are found at the terminal position of glycan chains of all cell types. Their wide distribution makes them have a broad set of biological functions, for example cell to cell interaction and communication.
Bacteria can utilize sialic acid for two purposes; 1) as a source of carbon, nitrogen and energy, and 2) for immune evasion to avoid the host’s immune response. Only a few bacteria have developed biosynthetic pathways to independently produce sialic acid, while the majority of them relies on host-derived sialic acid.
Bacteria have developed different transport systems to import sialic acid. One of them is the sialic acid transporter (SiaT) which belongs to the sodium solute symporter (SSS) family. The members of the SSS family cotransport sialic acid with sodium, using the sodium gradient as driving force.
Inside bacteria, sialic acid undergoes two different paths: catabolism or being involved in immune evasion mechanisms. Bacteria using molecular mimicry, utilizes sialic acid to escape the host immune system, since sialic acids are common for mediating a large set of recognition functions. Bacteria sialylate their lipopolysaccharides to avoid recognition, they are mistaken for being the host’s own cells and thereby escaping the host’s immune response.
Despite some synthetic and pharmacokinetic challenges, for example instability of some derivatives and side reactions, sialic acid is an interesting starting point in the development of new antibacterial drug leads since it is involved in several functions.
There has already been some work done with sialic acid on this topic. My objective was to continue that research by modifying the 4 th position of sialic acid by building a large linker onto it that would have a large fluorescent molecule at the end. The aim of the linker is to prevent sialic acid to enter the bacteria, thereby preventing molecular mimicry and immune evasion. This might be helpful in the research for new antibacterial drugs that are based on inhibition of sialic acid uptake.
In my project work, I designed and carried out a pathway towards a compound that potentially would have the properties desired for inhibition of the SiaT protein. The pathway consisted of selective 4-OH alkylation of sialic acid to 3-nitrobenzyl and 3-bromobenzyl ethers. Then exchange of bromine to alkyne and eventually 1,3-dipolar cycloaddition with azide. Many of the steps were optimized during the time and finally, two potential compounds were generated whose binding affinity are ready for being tested.}},
author = {{Andersson, Emelie}},
language = {{eng}},
note = {{Student Paper}},
title = {{Synthesis of sialic acid 4-C derivatives in development of new antibacterial drugs}},
year = {{2021}},
}