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Title: Small molecule mimics of trans-proline : synthesis and applications
Author: Aillard, Boris
ISNI:       0000 0004 5346 9048
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2014
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Herein we detail the synthesis and application of small molecules of trans-proline mimics. A general introduction to the field of peptidomimetics and their uses in specific biological examples is provided; followed by a detailed review of the background and objectives of the project. The synthesis of trans-proline mimics using (–)-cytisine as a building block is disclosed. Its application is demonstrated by incorporation of (–)-cytisine derivatives in a specific anti-cancer peptide PRGPRP and determination of its anti-cancer activity. The synthesis and conformational analysis of a pyroglutamate based mimic, a trans-proline mimic designed to adopt a polyproline type II (PPII) helical conformation, is described. Incorporation of this mimic in the anti-cancer peptide PRGPRP and determination of its anti-cancer activity displays a useful application. To investigate the conformation of the pyroglutamic based mimic, synthesis and conformational analysis of its oligomers is detailed. Using circular dichroism (CD) spectroscopy, NMR and X-ray crystallographic structures, the PPII conformation of these oligomers are compared to the ideal PPII helices and known PPII mimics. A specific protein-ligand interaction (SH3-peptide ligand) is discussed. Incorporation of the pyroglutamic based mimic in the peptide sequence and its binding properties are disclosed. As a result of these studies, a second generation pyroglutamate based mimic is currently under development in the group to further investigate conformational analysis and binding properties with SH3.
Supervisor: Bloodworth, Sally Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry