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Photoactivatable platinum - iv - anticancer complexes - advanced nmr studies of dna-binding and redox reactions

Objective



Research objectives and content
The aim of this project is the further development of photoactivatable Pt(IV)-prodrugs for the treatment of cancer. To achieve this, it is critical that the pathways and reactive intermediates of the photoreactions and the structures of the final photolysis products be known in detail. For these investigations, (1H, 15N) NMR HSQC methods will be employed to study the photochemistry of photosensitive Pt(IV)-complexes. By using 5N-labeled Pt(IV)-complexes, the identity of the primary photolysis products in the presence and absence of single-and double-stranded GG oligonucleotides will be investigated. This will clarify the role of the nucleotide bases in the photochemical reactions. An important goal of this project will be to determine whether the DNA-platinum adducts resulting from the photolysis products are structurally similar to those caused by the clinical-used platinum-based chemotherapeutic agent, cisplatin. Another objective of this project will be to investigate by means of NMR the mechanism of reaction of selected Pt(IV)-complexes with other biomolecules such as glutathione and proteins (e.g. albumin), and to determine the effects of light on these reactions. Whether photoactivated Pt-species induce protein-DNA cross-linking reactions will also be investigated.
A knowledge of the details concerning the photochemistry of
Pt(IV)-complexes will allow us to improve the design of light-activatable Pt(IV)-prodrugs, which could lead to more effective, less toxic therapies of cancer.
Training content (objective, benefit and expected impact)
This postdoctoral fellowship will allow me to learn and practice state-of-the-art NMR techniques in one of the world's most renowned NMR groups. I will also benefit from the expert knowledge of Pro? Sadler in the field of metal-based drugs. The project will give me the chance to investigate in considerably more depth questions that have arisen from my dissertation thesis. In addition, this project will open up new links between the group in Regensburg and the group of Prof. Sadler in Edinburgh.

Funding Scheme

RGI - Research grants (individual fellowships)

Coordinator

UNIVERSITY OF EDINBURGH
Address
West Mains Road, Kings Buildings
EH 3JJ Edinburgh
United Kingdom

Participants (1)

Not available
Germany