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

Reece Kenny

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

Abstract

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.