Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.806278
Title: Metallodrug-DNA interactions at the single-molecule level
Author: Berrocal-Martin, Raul
ISNI:       0000 0004 9349 7457
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2020
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Abstract:
Ensemble and single-molecule fluorescence techniques are powerful tools for studying the structure, dynamics and interactions of biomolecules. This thesis presents a novel approach to study the metallation of DNA combining ensemble fluorescence, time-resolved spectroscopy and single-molecule total internal reflection fluorescence microscopy. Metal-based drugs are key anticancer therapies and in many cases it is believed that the mechanism of action involves binding to DNA. In order to develop new anticancer treatments, it is important to understand how the drugs interact with DNA and what effect binding has on the DNA. The metallation of nucleic acids is key to a wide range of applications from anticancer medicine to nanomaterials but there is a lack of understanding the effects of metallation on the structural dynamics of DNA at the molecular-level. This thesis focuses on the interaction of an organo-osmium anticancer complex and DNA applying single-molecule fluorescence methods. Individual metallated DNA hairpins are characterized using Förster resonance energy transfer (FRET). Although ensemble measurements suggest a simple two-state system, single-molecule experiments reveal an underlying heterogeneity in the oligonucleotide dynamics, attributable to different degrees of metallation of the GC-rich hairpin stem. These studies show that this single-molecule approach provides new insight into metallation-induced changes in DNA structural dynamics with potential applications in many areas of DNA technology. New metallodrugs with anticancer activity whose mechanism of action differs from cisplatin are needed. Cyclometallated iridium complexes represent a new class of anticancer drug that exert its anticancer activity by mechanisms which include DNA binding, induction of reactive oxygen species (ROS) and catalytic oxidation. Synthesis, characterization and understanding their mechanisms of action is crucial for developing anticancer drugs with higher affinity for cancer cells, and reduction of side effects. Here, the photophysical properties of two cyclometallated iridium(III) complexes were characterized by steady-state absorption and fluorescence spectroscopy. They showed bright luminescence, with long lifetimes (ca. 35–160 ns) which were studied by time-correlated single-photon counting (TCSPC); while one complex displayed monoexponential decay kinetics, the other complex showed a biexponential decays indicated the presence of more than one energetically-accessible conformation supporting previous studies by electron paramagnetic resonance (EPR) and computational studies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.806278  DOI: Not available
Keywords: QD Chemistry
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