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Design and Development of Multi-Targeted Metallodrugs as Potential Chemotherapeutic Agents

thesis
posted on 29.09.2020 by Reece G. Kenny
Cancer remains a major global health burden despite significant advances in treatment
regimens. Current drug treatments, including those involving platinum drugs, have
drawbacks including dose limiting toxic side effects and either acquired or intrinsic
drug resistance. The development of safer and more effective drug treatments remains
a major research focus. The platinum drugs in clinical use primarily target DNA.
Our Group previously developed novel multi-targeted platinum(II) complexes capable
of not only binding cancer cell DNA but also possessing the ability to inhibiting histone
deacetylase (HDAC) enzymes. These complexes demonstrated cytotoxicity
comparable to cisplatin but with a significantly reduced level of toxicity towards healthy
cells. Building on this research, the work herein describes the rational design and
development of novel platinum(IV) and copper(II) complexes incorporating a modified
poly(ADP Ribose) polymerase (PARP) inhibitor ligand 6(5H)phenanthridinone (PHE).
PARP is a crucial DNA repair enzyme. The rational behind their synthesis will be
described. Molecular modelling studies are included which support the design
hypothesis behind the ligand and complexes. The synthetic protocols used to develop
the modified ligand and the corresponding platinum(IV)-PHE and three copper(II)-
phenanthrene-PHE complexes will also be reported. The complexes were analysed
by infrared spectroscopy, mass spectrometry and elemental analysis. The X-ray
crystal structure of one of the copper(II) complexes, [Cu(phen)2(PHE)]NO3, is also
reported. Preliminary biological data supporting their use as anti-cancer agents is also
described.
The PARP inhibitor ligand, PHE, was also successfully derivatised in such a way so
as to incorporate both PARP and HDAC inhibitor moieties, creating a potential hybrid
PARP/HDAC inhibitor ligand. This hybrid contains suberoylanilide hydroxamic acid
(SAHA, vorinostat) which is a clinically used hydroxamate-based HDAC inhibitor,
together with a PHE fragment. Again, molecular modelling studies are included which
support the design hypothesis. The synthesis and characterization of three novel
copper(II)-phenanthrene complexes incorporating this new hybrid ligand are reported,
together with preliminary biological data on their mode of action. Clinically used
hydroxamate-based HDAC inhibitors such as suberoylanilide hydroxamic acid (SAHA,
xvi
vorinostat) and belinostat, while highly successful, are known to undergo rapid
metabolic breakdown of the hydroxamate moiety and, as such, have relatively short
half-lives. The copper-hybrid complexes reported may have the added benefit of
extending the half-life of SAHA given that the copper(II) ion is coordinated directly to
the hydroxamate, forming a stable five-membered chelate ring.
Our Group has previously reported that simple hydroxamic acids can act as nitric oxide
(NO) donors. A reaction of the clinically used hydroxamate-based HDAC inhibitor
vorinostat with a ruthenium(III) NO scavenger clearly demonstrates that vorinostat can
likewise generate NO and this work is described herein. An ex vivo study
demonstrating the NO generating ability of the hybrid PHE/HDAC inhibitor ligand and
the clinically used hydroxamate-based HDAC inhibitors, vorinostat and belinostat is
also reported.
Paul Ehrlich (1854–1915), the founding father of chemotherapy, pioneered the
concept of the “magic bullet”. Our endeavors to move a step closer to Ehrlich’s vision
are ultimately presented in this thesis.

History

First Supervisor

Professor Celine J. Marmion

Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2019.

Published Citation

Kenny RG. Design and Development of Multi-Targeted Metallodrugs as Potential Chemotherapeutic Agents [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2019.

Degree Name

Doctor of Philosophy (PhD)

Date of award

30/06/2019

Programme

  • Doctor of Philosophy (PhD)

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