The development of mononuclear platinum hybrid biomaterials for antigene therapeutic application

Since the serendipitous discovery of cisplatin by Rosenberg platinum agents based on the traditional cis chemotype are still the cornerstone of platinum therapeutic application with cisplatin, carboplatin and oxaliplatin as the only agents approved globally for use. Past research has focused mainly on elucidating the mechanistic action of these traditional Pt(II) agents with great success and streamed into efforts centred on trying to reduce the potent toxic side-effects such as nephrotoxicity, ototoxicity and poor target selectivity. Classes of platinum complexes such as trans-substituted platinum(II) agents, platinum(IV) prodrugs, polynuclear platinum(II) complexes and in particular, platinum(II)-DNA hybrids produced for an antigene strategy, have all observed a significant renewal of interest in recent years. This thesis focuses on the development of a library of platinum(II)-triplex forming oligonucleotide hybrids that possess targeted antigene applications. Firstly, the synthesis of azide-functionalised ligands and their complexation with platinum to form azide-functionalised cis-platinum(II) complexes is reported. Thereafter, the design and synthesis of triplex forming oligonucleotides (TFOs) is reported and followed by the utilisation of the copper-catalysed and strain promoted alkyneazide cycloaddition or ‘click chemistry’ to generate gene-directed cis-platinum(II)TFO hybrids. The work reported represents the first example of click chemistry strategies being employed to afford cis-platinum(II)-TFO constructs designed this way. DNA interaction studies identified that the azide-functionalised platinum(II) complexes retain activity against dsDNA targets. The cis-platinum(II)-TFO constructs demonstrated sequence specific triplex recognition with no off-target effects observed in the presence of purine rich sequences. However, in general the crosslink formation on target genes of interest by the platinum(II) ion destabilises triplex formation. The introduction of TO – a known intercalating fluorophore – can remediate this destabilisation and this work demonstrates how TO-modified cis-Pt(II)-TFOs retain their targeting abilities with enhanced stabilising characteristics. Finally, TFO constructs containing a novel alkyne-amine nucleobase were developed and investigated for their ability to incorporate TO and Pt(II). This strategy was developed to enhance site-specific metal ion-DNA target interactions whereby the proximity of the complex to the DNA interface was enhanced under the guidance of the neighbouring TO intercalator. The conjugation of Cu(II)-phenanthrene-type scaffolds with alkyne-modifed TFOs to generate novel Cu(II)-AMN-TFOs has afforded unique stabilising properties and represent an innovative class of gene-targeted system