Diastereomeric Effects in DNA Binding – Biological and Biophysical Studies on Ruthenium Complexes
Doctoral thesis, 2018
Organic molecules, such as glucose and amino acids, are most often chiral. This means that their mirror-images are different, in the same way a left and a right hand are different from each other. For example, the DNA double helix in its standard form twists like a right-handed screw. Therefore, when chiral DNA-binding ligands interacts with DNA the effect will depend on their handedness – that is, the interactions will be diastereomeric. Hence, it is essential to always consider the effects chirality may have on ligand-DNA interactions when developing new DNA-targeting drugs. By improving properties such as binding affinity and sequence selectivity, many adverse effects present in currently available treatments could be avoided. Therefore,
to have efficient methods for evaluating ligand-DNA binding properties would greatly simplify the search for potential therapeutic candidates.
The key focus in this thesis is the binding interactions between DNA and a group of DNA-intercalating ruthenium complexes. It is demonstrated using spectroscopic and calorimetric methods that both chirality and small changes in the molecular structure of the complex can have significant impact on the binding properties of the complex. Furthermore, a general algorithm used for thermodynamically characterize the ligand-DNA binding interactions is presented as a simplified method for fitting binding models to complex systems. From both photophysical and calorimetric results it is evident that cooperativity between neighboring bound ligands has a huge impact on the overall binding interactions between ruthenium complexes and DNA and must be taken into account in order to find a satisfactory fit of a theoretical binding model. Finally, ruthenium complexes are shown in vitro to have a high antimicrobial activity comparable to clinically available antibiotics and it is again evident that chirality have a strong influence on the binding properties of the complex. As a continuance to the promising antimicrobial results, an alternative type of antibiotic is presented in the concluding remarks as a possible counteract to the ongoing and growing problem of multi-resistant bacteria.