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. / Doctor of Philosophy (PhD)
| Identifer | oai:union.ndltd.org:ADTP/233051 |
| Date | January 2008 |
| Creators | Taleb, Robin I., University of Western Sydney, College of Health and Science, School of Biomedical and Health Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
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