Principal Supervisor: Professor Zoe Pikramenou, School of Chemistry
Co-supervisor: Dr. Nik Hodges, School of Biosciences
PhD project title: Luminescent lanthanide probes responsive to DNA targeting
University of Registration: University of Birmingham
Interaction of synthetic supramolecular systems with biologically active molecules has been of particular interest to address recognition features important to biomolecular function. Hairpin-shaped molecules have attracted particular interest for targeting specific DNA sequences. In our approach we use metallohairpin molecules where the metals are luminescent probes responsive to DNA interaction and can also control the hairpin structure.
In previous studies we have introduced the self-assembly of lanthanide luminescent probes with platinum intercalator moieties to yield trimetallic complexes with bis-intercalator units. The complexes showed remarkable DNA stiffening and a preference on d(AT) sequences. The lanthanide luminescence signal acted as a luminescent reporter of the intercalation of the platinum moieties to DNA provide a signal change for monitoring interactions.
In this project we will develop self-assembled hairpin shaped lanthanide probes with DNA recognition units by controlling the hairpin structure with the choice of the ligand and the DNA recognition unit. We will use specific targeting DNA sequences for disease detection (for example for detection of mutational events in cancer cells) and use the lanthanide signal to report the DNA binding event. The lanthanide signal can be Platinum and ruthenium prodrugs will also be attached to the lanthanide scaffold to monitor the photoactivated release of the drug. The interaction of prodrug moieties will be signalled by the lanthanide reporter. Specific cellular uptake will be assessed by confocal microscopy and photoxicity assessed using biochemical assays for viability (MTT, crystal violet), cellular ROS (fluoroscein oxidation), DNA damage (comet assay) and apoptosis (caspase activation).
- Dervan, P. B. Biorg. Med. Chem. 2001, 9, 2215.
- Glover, P. B., Ashton, P. R., Childs, L. J., Rodger, A., Kercher, M., Williams, R. M., De Cola, L. & Pikramenou, Z. 2003, J. Amer. Chem. Soc. 125, 9918.
BBSRC Strategic Research Priority: Molecules, Cells and Systems
Techniques that will be undertaken during the project:
- Steady-state and time-resolved luminescence spectroscopy
- Spectroscopies for molecular identification
- Circular dichroism
- Confocal microscopy
- Comet assay
Contact: Professor Zoe Pikramenou, School of Chemistry