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Title: The development of novel solid phase methodologies for the synthesis of atypical peptides and non-peptide entities
Author: Kellam, Barrie
ISNI:       0000 0001 2451 8048
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 1996
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Solid phase peptide synthesis (SPPS) of branched/cyclic peptides, multiple antigenic peptides (MAPs), pseudopeptide toxins etc. requires amine protection orthogonal to the established Fmoc/Boc protocols. It was envisaged that progression from Dde to N-1-(4-Nitro-l,3-dioxoindan-2-ylidene)ethyl (Nde) amino acid protection would maintain the stipulated orthogonality, whilst improving the hydrazine mediated deprotection. A selection of Nα-Nde-amino acids were efficiently synthesised and their compatibility with SPPS conditions demonstrated by the synthesis of a number of peptides. The Nde group displayed a faster and more easily monitored deprotection profile and similar orthogonality when compared with the Dde group. The selective primary amine protecting characteristics of the Nde group was illustrated by the synthesis of N¹N⁸-bis Nde-spermidine which was subsequently utilised in the solid phase synthesis of the natural product, dihydrotrypanothione. Large peptides synthesised by SPPS often demand elaborate, expensive and cumbersome purification protocols. Dde based reversible amine protecting groups incorporating hydrophobic and affinity probes have been developed. Their ease of preparation and efficacy in the purification of synthetic peptides has been demonstrated. Intercellular communication in various Gram-negative microorganisms is often mediated by small signalling molecules, e.g. N-(3-oxohexanoyl)-L-homoserine lactone (OHHL). Detection of these molecules is often extremely difficult. To address this, SPPS procedures have been employed to couple N-β-ketoacyl-L-homoserine lactone containing haptens to a dendritic lysine scaffolding, and the resultant macromolecule evaluated for its ability to raise anti-N-β-ketoacyl-L-homoserine lactone antibodies. 1-Carbapen-2-em-3-carboxylic acid is a broad spectrum antibiotic produced by the Gram-negative Erwinia and Serratia microorganisms. Some key intermediates for the putative synthetic precursors have been successfully prepared in order to study the biosynthetic pathways by feeding blocke mutants of the above bacteria, and also to transpose the methodologies to a solid phase to construct carbapenem libraries. NB. This ethesis has been created by scanning the typescript original and may contain inaccuracies. In case of difficulty, please refer to the original text.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD415 Biochemistry Pharmacology Biochemistry Chemistry, Organic