Research objectives and content
Dr. Meunier's group in Toulouse have recently described the synthesis of Cu-bis-phenathroline-spermine bioconjugates as simple synthetic analogues for the antitumour agent Bleomycin. These species have been shown to cause degradation of plasmid DNA at nanomolar concentrations. The specific aims of this proposal are threefold: (1) preparation of a range of derivatives of this molecule in order to fine-tune the reactivity; (2) characterisation of metal complexes (specifically copper' of these ligands; (3) studies of the interaction of these complexes with DNA. Initial work in this project will involve systematic variation of the DNA binding domain of this molecule, through incorporation of minor-groove binders, intercalators and cell-attachment motifs. The pioneering work of Dervan will be used to incorporate oligo-N-methyl carboxamides as minor-groove binders. Modification of the electronic properties of the ligand binding domain are also envisaged, via incorporation of substituents at the 5 and 6 positions of the phenanthroline ligands. After characterisation of metal complexes, work will progress on to studying DNA interactions.
Training content (objective, benefit and expected impact)
The DNA aspect of this work will involve the greatest degree of training: Handling of plasmid DNA and preparation of restriction fragments, followed by reaction with novel bioconjugates is planned. I then plan to use this overall biochemical training in a research environment upon my return to the UK.
Links with industry / industrial relevance (22)