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

Cancer remains a major global health burden despite significant advances in treatmentregimens. Current drug treatments, including those involving platinum drugs, havedrawbacks including dose limiting toxic side effects and either acquired or intrinsicdrug resistance. The development of safer and more effective drug treatments remainsa major research focus. The platinum drugs in clinical use primarily target DNA.Our Group previously developed novel multi-targeted platinum(II) complexes capableof not only binding cancer cell DNA but also possessing the ability to inhibiting histonedeacetylase (HDAC) enzymes. These complexes demonstrated cytotoxicitycomparable to cisplatin but with a significantly reduced level of toxicity towards healthycells. Building on this research, the work herein describes the rational design anddevelopment of novel platinum(IV) and copper(II) complexes incorporating a modifiedpoly(ADP Ribose) polymerase (PARP) inhibitor ligand 6(5H)phenanthridinone (PHE).PARP is a crucial DNA repair enzyme. The rational behind their synthesis will bedescribed. Molecular modelling studies are included which support the designhypothesis behind the ligand and complexes. The synthetic protocols used to developthe modified ligand and the corresponding platinum(IV)-PHE and three copper(II)-phenanthrene-PHE complexes will also be reported. The complexes were analysedby infrared spectroscopy, mass spectrometry and elemental analysis. The X-raycrystal structure of one of the copper(II) complexes, [Cu(phen)2(PHE)]NO3, is alsoreported. Preliminary biological data supporting their use as anti-cancer agents is alsodescribed.The PARP inhibitor ligand, PHE, was also successfully derivatised in such a way soas to incorporate both PARP and HDAC inhibitor moieties, creating a potential hybridPARP/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 whichsupport the design hypothesis. The synthesis and characterization of three novelcopper(II)-phenanthrene complexes incorporating this new hybrid ligand are reported,together with preliminary biological data on their mode of action. Clinically usedhydroxamate-based HDAC inhibitors such as suberoylanilide hydroxamic acid (SAHA,xvivorinostat) and belinostat, while highly successful, are known to undergo rapidmetabolic breakdown of the hydroxamate moiety and, as such, have relatively shorthalf-lives. The copper-hybrid complexes reported may have the added benefit ofextending the half-life of SAHA given that the copper(II) ion is coordinated directly tothe 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 inhibitorvorinostat with a ruthenium(III) NO scavenger clearly demonstrates that vorinostat canlikewise generate NO and this work is described herein. An ex vivo studydemonstrating the NO generating ability of the hybrid PHE/HDAC inhibitor ligand andthe clinically used hydroxamate-based HDAC inhibitors, vorinostat and belinostat isalso reported.Paul Ehrlich (1854–1915), the founding father of chemotherapy, pioneered theconcept of the “magic bullet”. Our endeavors to move a step closer to Ehrlich’s visionare ultimately presented in this thesis.