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Small molecule mimics of trans-proline: synthesis and applications

Small molecule mimics of trans-proline: synthesis and applications
Small molecule mimics of trans-proline: synthesis and applications
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.
Aillard, Boris
18da6bd3-4081-40b8-89a7-4aae3f0bc767
Aillard, Boris
18da6bd3-4081-40b8-89a7-4aae3f0bc767
Bloodworth, Sally
943160fc-1b70-4c29-b2e3-b7785cee8a0c

Aillard, Boris (2014) Small molecule mimics of trans-proline: synthesis and applications. University of Southampton, Chemistry, Doctoral Thesis, 307pp.

Record type: Thesis (Doctoral)

Abstract

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.

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Published date: 31 March 2014
Organisations: University of Southampton, Chemistry

Identifiers

Local EPrints ID: 367097
URI: http://eprints.soton.ac.uk/id/eprint/367097
PURE UUID: 82949838-9d21-4cbb-b409-92b1fc111f23
ORCID for Sally Bloodworth: ORCID iD orcid.org/0000-0003-2219-3635

Catalogue record

Date deposited: 22 Oct 2014 12:37
Last modified: 06 Jun 2018 12:49

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Contributors

Author: Boris Aillard
Thesis advisor: Sally Bloodworth ORCID iD

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