The development of novel solid phase methodologies for the synthesis of atypical peptides and non-peptide entities

Kellam, Barrie (1996) The development of novel solid phase methodologies for the synthesis of atypical peptides and non-peptide entities. PhD thesis, University of Nottingham.

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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.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Bycroft, B.W.
Chhabra, S.R.
Subjects: Q Science > QD Chemistry > QD241 Organic chemistry > QD415 Biochemistry
Faculties/Schools: UK Campuses > Faculty of Science > School of Pharmacy
Item ID: 10381
Depositing User: EP, Services
Date Deposited: 12 Nov 2007
Last Modified: 15 Dec 2017 04:39

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