Synthesis of sialic acid 4-C derivatives in development of new antibacterial drugs
Syntes av 4-C sialinsyraderivat i utvecklingen av nya antibakteriella läkemedel
Author
Summary, in English
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.
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.
Department/s
Publishing year
2021
Language
English
Document type
Student publication for Master's degree (two years)
Topic
- Chemistry
Keywords
- sialic acid
- medicinal chemistry
- carbohydrate
- organic chemistry
- antibacterial drugs
- organic synthesis
- antibiotic resistance
Supervisor
- Ulf Nilsson