Preparation, optimisation and characterisation of sequence selective compounds

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dc.contributor.author Taleb, Robin Ishac
dc.date.accessioned 2018-09-06T08:16:04Z
dc.date.available 2018-09-06T08:16:04Z
dc.date.copyright 2008 en_US
dc.date.issued 2018-09-06
dc.identifier.uri http://hdl.handle.net/10725/8424
dc.description.abstract DNA is the pharmacological target for most platinum drugs; however, the majority of these drugs show little or no specificity for particular base pairs. Considerable progress has been made in the design of sequence selective compounds, such that an antiparallel association of a polyamide can have high affinity for selected DNA base pairs. Hairpin polyamides have distinct advantages as they achieve affinities and specificities that are comparable to that of DNA-binding proteins. Platinum(II) hairpin polyamides are expected to display antitumour activity and target specific sequences of DNA. Five DNA-sequence-selective hairpin polyamide platinum(II) complexes, containing pyrrole (Py) and imidazole (Im) heterocyclic rings, have been synthesised using a combination of solid and solution phase chemistry. One mononuclear sequence selective complex, β-Ala-PyPyPy-L4-ImImIm-L4-Pt (HLSP-6) [β-Ala is β-alanine, L4 is 4-(Fmoc-amino)butyric acid and Pt is transplatin], and two dinuclear sequence selective complexes, β-Ala-PyPyPy-L4-ImImIm-L6'-Pt-(Pt) (DNHLSP-6) [L6' is 2,6-Fmoc-Lysine-(Fmoc)-OH] and β-Ala-PyPyImImIm-L4'-PyPyPyPyPy-L6'-Pt-(Pt) (DNHLSP-10) (L4' is 2-Boc-4-Fmoc-L-diaminobutyric acid), were synthesised entirely using solid phase chemistry. Two mononuclear sequence selective complexes, Pt-L6-β-Ala-Py-L4-Im (HSP-2) and Pt-L6-β-Ala-PyPyPy-L4-ImImIm (HSP-6), were synthesised using a combination of solid and solution phase chemistry. The synthesis of a trinuclear sequence selective polyamide was also attempted using a combination of solid and solution phase chemistry. The polyamides were synthesised in a series of reaction steps. Each heterocyclic ring and linker was coupled through solid phase chemistry using 2-(1H-benzotriazole-1-y1)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU). Once the organic components were assembled, the platinum(II) group/s was/were added using either solid or solution phase chemistry. The polyamide sequence of PyPyPy-L4-ImImIm was designed to target the guanine rich telomere region of DNA. The metal complexes reported in this study will span sequences between 2, 5 or 7 DNA base pairs (depending on their length), which include 5'-(A/T)GGG(A/T)-3' and 5'-(A/T)(A/T)(A/T)GGG(A/T)-3'. All complexes were characterised using 1H and 195Pt NMR, high resolution mass spectrometry and elemental analysis. The binding of HLSP-6 and DNHLSP-6 to guanosine was also monitored by 1H NMR. en_US
dc.language.iso en en_US
dc.subject DNA en_US
dc.subject Drugs en_US
dc.subject Polyamides en_US
dc.subject Genetic code en_US
dc.subject Molecular biology en_US
dc.title Preparation, optimisation and characterisation of sequence selective compounds en_US
dc.type Thesis en_US
dc.author.degree PHD en_US
dc.author.school SAS en_US
dc.author.idnumber 200901968 en_US
dc.author.department Natural Sciences en_US
dc.description.embargo N/A en_US
dc.description.physdesc xxix, 246 p. ill en_US
dc.author.advisor A-Wrigh, Janice
dc.description.bibliographiccitations Includes bibliographical references en_US
dc.identifier.ctation Taleb, R. I. (2008). Preparation, optimisation and characterisation of sequence selective compounds. en_US
dc.identifier.tou http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php en_US
dc.identifier.url https://researchdirect.westernsydney.edu.au/islandora/object/uws:6372/ en_US
dc.orcid.id https://orcid.org/0000-0001-8033-6951 en_US
dc.publisher.institution University of Western Sydney en_US
dc.author.affiliation Lebanese American University en_US

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