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Title: Investigations in chemical protein synthesis
Author: Gordon, Carolyn Alexandra
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2001
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The chemical synthesis of the 184aa anti-angiogenic peptide, endostatin, was undertaken. Preparation via the stepwise of two large fragments approximately 90aa in length was attempted but was unsuccessful. A method that would allow the efficient, sequential coupling of several small fragments was required. To this end, the segment coupling of minimally protected fragments via transfer active ester condensation (TAEC), a technique recently developed within this research group, was investigated. The fragments for synthesis were provisionally selected based on hydrophobicity and potential coupling sites. These peptide fragments were then optimised for stepwise solid phase peptide synthesis (SPPS), using the Fmoc strategy. Peptides containing two types of C-terminal functionality - hydrazides and semicarbazides - were prepared. An alternative strategy for the synthesis of the Wang resin-based hydrazide linker, first proposed by Wang and Merrifield in 1969, was developed to facilitate this process. Peptide fragments of up to 20aa in length were successfully coupled using TAEC. A novel approach to the protection of arginine side chains was also investigated. This target was based on the dibenzocycloheptenyl system, a species which was originally deigned for use as a linker in the preparation of peptide amides. Recent work by Noda involved a derivative of this linker, which has proven to be significantly more acid labile than current arginine protection. Concurrent work on an improved design led to an alternative system - the dimethoxy-suberyl compound - being proposed. The synthesis of the target molecule was achieved in seven steps; key steps involved a Perkin reaction and an intramolecular Friedel Krafts acylation. Coupling to arginine was undertaken but proved unsuccessful.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available