Barrett, Stephen (2021) Targeted Copper (II) Compounds with Selective Anti – Cancer and Anti-Microbial Activity. PhD thesis, National University of Ireland Maynooth.
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Abstract
The selectivity for cancer cells has always been one of the major challenges for anticancer
drugs and, in particular, for metal-based agents, such as cisplatin. Despite the great success
of the anticancer drug of cisplatin and of a few other Pt(II) compounds, such as carboplatin
and oxalilplatin, the lack of selectivity, the high toxicity and the resistance mechanisms are
limiting their use. There are several strategies that could be implemented to overcome the
lack of selectivity and one of these is the use of specific vectors whose receptors are
overexpressed in the cancer cells with respect healthy tissues (i.e. sugars and carbohydrates
in general). Two very important vectors whose receptors are overexpressed are estrogens
and biotin.
In this thesis we report the synthesis and characterisation of a plethora of completely novel
Copper (II) based compounds whose coordination sphere has been modified to
accommodate estrogens (Chapter 2) and biotin (Chapter 3), with the aim to enhance the
tumour selectivity. The complexes have been successfully synthesised and characterised and
their application as anticancer agents have been evaluated. The rationale for the use of
Copper instead of Platinum is due to Copper being much less toxic than Platinum, being and
endogenous metal, and for this reason it is more tolerable within the body. There are several
examples of Copper based complexes with anticancer properties and it is interesting to note
that Copper complexes show a different mechanism of action with respect Pt based ones.
Copper, being a redox active metal with two available oxidation states in physiological
conditions (E0
Cu(II)/Cu(I) = + 0.15 V) can interfere with the cellular redox stress and produce ROS
(Reactive Oxygen Species) that can alter the cellular redox environment. In fact,
mitochondria, where the cellular respiration process happens, are considered an important
target for Cu complexes. The new complexes have been tested against a large panel of cancer
cell lines, cells which both overexpress these corresponding receptors (estrogens or biotin)
and ones which do not and very promising and interesting results are obtained. For some
complexes the redox stress, the ROS production and the mechanism of cell death are
reported. While mitochondria are considered the most important target of Copper based
compounds, the mitochondrial and nuclear DNA also play a very important role. Depending
on the nature of the ancillary ligands, Cu species can bind to the DNA forming several
adducts. In Chapter 4 are described a series of novel Cu(II) species, containing different
planar aromatic ligands (derivatives of DPPZ, dipyrido-phenazine), that can act as DNA
intercalators, with the aim to investigate the role of the substituents (electron withdrawing
or electron donating groups) on the biological properties. These complexes are synthesised
and characterised and their interaction with DNA is explored. A detailed and comprehensive
theoretical characterisation is also reported. These complexes show very interesting
antimicrobial properties against MRSA strain and antifungal activity against Candida
Albicans.
Item Type: | Thesis (PhD) |
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Keywords: | Targeted Copper (II) Compounds; Anti–Cancer; Anti-Microbial; |
Academic Unit: | Faculty of Science and Engineering > Chemistry |
Item ID: | 19297 |
Depositing User: | IR eTheses |
Date Deposited: | 09 Jan 2025 11:15 |
URI: | https://mural.maynoothuniversity.ie/id/eprint/19297 |
Use Licence: | This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here |
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