Initial studies on the development of a solid phase synthesis of vancomycin and analogues

Al-Shinayyin, Muayyad (2018) Initial studies on the development of a solid phase synthesis of vancomycin and analogues. Doctoral thesis, University of East Anglia.

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Abstract

Vancomycin is a member of an important antibiotic group known as the glycopeptide antibiotics, which mainly act as bactericidal agents against Gram positive bacteria. Vancomycin acts by destroying the integrity of the bacterial cell wall and thereby exerts its detrimental effect on the most virulent gram-positive bacteria such as MRSA. Emergence of resistant strains against vancomycin has drawn scientists’ curiosity to find new analogues to restore its powerful activity or to avoid loss of its efficiency against infectious bacteria. One of the routes that has been followed to find a novel vancomycin analogue is via chemical modification to its structure relying on its well-known mechanism of action. Our approach was to synthesise the constituent amino acids of the backbone of vancomycin in Fmoc-protected form to be suitable for conjugation using solid phase peptide chemistry (SPPS). The SPPS procedure potentially ensures rapid synthesis and modification of a peptide through concise and less demanding chemistry.
The central amino acid of vancomycin was synthesised in Fmoc-protected form at the α-amine terminal with a free carboxylic acid group. The synthesis proceeded through chemistry modification of the route developed by Nicoloau and co-workers and involved a series of reactions such as Sharpless AD reaction, Mitsunobu reaction and a TEMPO oxidation reaction. The Fmoc protected amino acid was successfully obtained and was potentially suitable for the conjugation with other amino acids using Fmoc chemistry and SPPS. Several trials were performed for the conjugation of the central unit on SPPS. Although different coupling reagents and solid supports were used, the results were unsuccessful. To confirm that peptide coupling with this amino acid was possible, it was demonstrated that solution phase coupling led to the successful generation of a tripeptide containing this unit. The suggestion here is that the triazene unit on the central amino acid is too unstable for incorporation into the SPPS protocol.
Finally, the successful synthesis of the Fmoc-protected ethyl ester analogues of the two tyrosine isomers, amino acid 2 and amino acid 6, in the vancomycin structure was completed. Several trials were attempted to hydrolyse the ethyl ester to release the carboxylic acid but were unsuccessful. Due to the time constrains, further efforts for hydrolysis reaction attempts were halted. 1H NMR, 13C NMR, IR, and mass-spectrometry were used throughout for assignments and characterisation of all the products and intermediates of the chemical reactions

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Chris White
Date Deposited: 17 Aug 2018 13:37
Last Modified: 17 Aug 2018 13:37
URI: https://ueaeprints.uea.ac.uk/id/eprint/68080
DOI:

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