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dc.contributor.advisorHulme, Alison
dc.contributor.advisorCampopiano, Dominic
dc.contributor.authorJohnston, Heather Jennifer
dc.date.accessioned2016-11-08T13:35:29Z
dc.date.available2016-11-08T13:35:29Z
dc.date.issued2014-11-27
dc.identifier.urihttp://hdl.handle.net/1842/17617
dc.description.abstractThe linear peptide bisebromoamide was isolated by the Suenaga group in 2009 from the marine cyanobacterium Lyngbya sp. It exhibits antiproliferative activity at nanomolar levels against a wide range of cell lines. Current SAR data indicates that there is some flexibility in the structure with respect to stereochemistry, but the range of modifications that have been biologically tested is limited, as reviewed in Chapter 1. Bisebromoamide contains a number of non-commercial amino acids and an oxopropyl pyrrolidine moiety which had not been found in a natural product previously. Several new synthetic routes towards the non-commercial amino acid fragments have been developed, as described in Chapter 2, including two ring-closure-based approaches to the substituted proline derivative 4-methyl proline (4-MePro). While the presence of six amide bonds makes solid phase peptide synthesis (SPPS) an appealing approach to the synthesis of bisebromoamide, the 4-MePro moiety is attached to a thiazoline and it is well documented that the α-position of an amino acid will racemise, under both acidic and basic conditions, when attached to a thiazoline or oxazoline. Previous reports indicated that the methyl group of the thiazoline was not essential for biological activity and so to increase stability it was replaced with a thiazole. The total synthesis of a series of novel bisebromoamide analogues, via an SPPS approach which enables facile modification of the final structure, is described in Chapter 3. The simple and adaptable SPPS route developed lends itself to SAR studies and allows modifications such as an alanine scan, truncations and incorporation of modified proline derivatives to be achieved rapidly. The promising anticancer activity of bisebromoamide makes the biological activity of these analogues of particular interest and the results of current biological testing are reported in Chapter 4.en
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversion“A Facile, Inexpensive Scalable Route to α-Methyl Cysteine” Johnston, H. J.; Hulme, A. N., Synlett, 2013, 5, 591-594.en
dc.subjectcyanobacteriumen
dc.subjectbisebromoamideen
dc.subjectdrug developmenten
dc.subjectamino aciden
dc.subjectthiazoleen
dc.titleDevelopment of novel analogues of the anti-proliferative marine natural product bisebromoamide: synthesis and structure activity relationship studiesen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2100-12-31en
dcterms.accessRightsRestricted Accessen


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