Toward dual-action platinum(IV) complexes with bioactive ligands as potent anticancer agents

Abstract

Platinum agents (cisplatin, carboplatin and oxaliplatin) have a crucial role in the treatment of many cancers for several decades. However, they have severe side effects and a high number of patients have intrinsic or acquired resistance to platinum-based chemotherapy. The need for new platinum agents with better patient tolerability and improved anti-tumoral efficacy is necessary in order to overcome the side effects of those drugs. Platinum(IV) anticancer drugs are prodrugs, which can not only overcome side effects and the resistance to platinum-based chemotherapy but also lead to enhanced tolerability in patients. It is highlighted that only four platinum(IV) complexes have made it into clinical trials, and three out of these four have failed to show clinical efficacy. The efficacy of platinum(IV) agents depends on the stability, reduction rate, degree of cellular accumulation and which enzymes are targeted. Platinum(II) drugs and bioactive ligands (particularly the ones that have epigenetic activity) can act on various targets with various cellular mechanisms and it would be more appropriate to design them as multi-action platinum(IV) prodrugs. This thesis focuses on the synthesis and characterisation of novel platinum(IV) complexes derived from FDA-approved platinum(II) complexes and bioactive, axial carboxylate ligands. Also explored here are the biological activity, cellular effects and reactions with cellular targets. Chapter one provides an overview of platinum(IV) complexes and examples of various dual-action agents with the history of platinum anticancer therapy. Chapter two examines the design and synthetic strategies employed for the development of novel platinum(IV) prodrugs for carboplatin with the histone deacetylase inhibitor (HDACi) 4-phenylbutyrate (PBA) and three different biologically inactive carboxylic acids. Lower accumulation levels and lower cytotoxicity were observed for the carboplatin platinum(IV) complexes compared to cisplatin. The carboplatin platinum(IV) derivative with PBA and benzoate had a higher cytotoxic activity and HDAC inhibition potency than carboplatin. Chapter three investigates platinum(IV) complexes based on the cisplatin scaffold and PBA in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells (A2780 and A2780cis). Three complexes in this study were more cytotoxic in A2780 and A2790cis ovarian cancer cells than cisplatin and induced cell death pathways leading to apoptosis. In Chapter four new platinum(IV) derivatives of oxaliplatin are described which induced oxidative stress and cytotoxicity. Novel platinum(IV) oxaliplatin derivatives with indole propionic acid were synthesised and studied by various techniques. The monocarboxylated complex with an hydroxido ligand in the second axial position was the most cytotoxic and potent ROS inducer compared with cisplatin and oxaliplatin. Chapter five provides overall conclusions and identifies key areas for future work.