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Click chemistry-based artificial metallonucleases

Alex, Gibney (2024) Click chemistry-based artificial metallonucleases. PhD thesis, Dublin City University.

Nucleic acids are essential to all life on earth, with the remarkable stability of the phosphodiester backbone providing the integrity required for faithful storage of genetic information. Evolution has, therefore, resulted in a variety of cellular machinery that monitor and maintain this genetic integrity from deleterious processes such as DNA oxidation, which is an inevitable consequence of aerobic respiration and the resulting production of reactive oxygen species (ROS). These DNA repair processes are energetically expensive and prone to error, with both factors contributing to an upper tolerance of DNA oxidation in the cellular environment, exceedance of which ultimately results in triggering of apoptosis or other cell death processes. DNA oxidation and the resulting over-stimulation of the afore mentioned repair processes is therefore a promising approach for the development of novel anticancer agents. The design of inorganic and organometallic complexes that result in DNA-localised ROS production and cleavage of the phosphodiester backbone has proven to be a key strategy in the development in such potential therapeutics, now known as artificial metallonucleases (AMNs). Here, a series of AMNs have been developed using the Nobel prize-winning “Click” chemistry, incorporating the 1,2,3-triazole, resultant of the Cu(I)-catalysed alkyne/azide click reaction as a key structural motif in both DNA recognition and transition metal binding. This method of AMN development has been coined the “Click and Cut” strategy. Clicking a range of commercially available alkynes with proximal N,O and S donors around a C3 -symmetric mesitylene core that has previously been found to facilitate DNA recognition resulted in a series of structurally diverse and potent Cu(II) AMNs. The activity of these Tri-Click (TC) AMNs were investigated using a range of standard and state-of-the-art techniques such as agarose gel electrophoresis, fluorescence quenching, fluorescence melting, microscale thermophoresis and repair-assisted damage detection (RADD). The Cu(II)-TC AMNs were found to selectively bind to and cleave from the minor groove of the DNA duplex, facilitated by a crescent-shape conformation adopted by two arms of the tripodal structures. Cleavage of native DNA was found to occur via a superoxide and peroxide dependant mechanism, with this mechanism being retained in the intracellular environment. Anticancer screening of the most promising ligands revealed broad spectrum activity against a range of cell lines in the national cancer institute’s 60 cell line assay.
Item Type:Thesis (PhD)
Date of Award:March 2024
Supervisor(s):Kellett, Andrew and McKee, Vickie
Uncontrolled Keywords:Bioinorganic Chemistry
Subjects:Physical Sciences > Chemistry
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Chemical Sciences
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 License. View License
Funders:The Science Foundation Ireland Research Centre for Pharmaceuticals (SSPC)
ID Code:29417
Deposited On:25 Mar 2024 15:06 by Andrew Kellett . Last Modified 25 Mar 2024 15:06

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Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0


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