Polyaromatic anticancer platinum complexes : synthesis and analysis of DNA binding

Abstract

Chemotherapy is a primary source of treatment for victims of cancer, a globally prominent disease that affects millions. The platinum(II) agents cisplatin, carboplatin and oxaliplatin are used in approximately half of all chemotherapy treatment schemes. These drugs kill cancerous cells by binding covalently to DNA and preventing replication, which leads to apoptosis. Despite the success of these drugs they have many debilitating side effects such as nephrotoxicity, myelotoxicity, nausea and vomiting. Furthermore, many cancers are resistant to treatment from these drugs, often through DNA repair mechanisms. To overcome these issues, researchers are developing platinum complexes (PCs) that kill cancerous cells through different mechanisms of action to cisplatin. A promising series of PCs in this field are those of the type [Pt(PL)(AL)]2+, in which PL is a polyaromatic heterocyclic ligand and AL is a cyclic diamine. Relative to cisplatin, these polyaromatic PCs (PPCs) are more cytotoxic to cancer cells, kill these cells through different mechanisms, and bind to DNA through noncovalent interactions. Due to these characteristics, PPCs have the potential to surpass traditional platinum drugs as chemotherapy candidates. This potential is further amplified when they are oxidised from platinum(II) to platinum(IV), resulting in complexes of the type [Pt(PL)(AL)(X)2]2+, where X is an axial ligand such as hydroxide or succinimide. The PCs can be tuned, through modification of these axial ligands, to target cancer cells selectively, improve bloodstream stability, and to selectively reduce to the active platinum(II) form once inside a cancer cell. In this work, reported in four published journal articles together with some additional experiments, several novel PPCs have been synthesised and tested for their viability as DNA binders and anticancer agents. Several PL and AL combinations were explored, most of which were new to this series of PCs. All PPCs were characterised through nuclear magnetic resonance, elemental microanalysis, ultraviolet (UV) spectroscopy, electrospray ionisation mass spectrometry (ESIMS), and, where applicable, circular dichroism (CD) and X-ray crystallography. Most of the PCs adopted a square-planar coordination geometry, although the geometry of 2-(2?-pyridyl)quinoxaline complexes was distorted, leading to unusual CD, diffusion and crystal packing activity. All PPCs were produced with desirable purity and yield. The anticancer potential of the PPCs was assessed in several human cancer cell lines, revealing high in vitro cytotoxicity across a wide variety of cancers, often higher than that of cisplatin, oxaliplatin and carboplatin. Most of the PCs were particularly active against Du145 prostate cancer, HT29 colon carcinoma and SJ-G2 glioblastoma cells. It was found that while both the choice of PL and AL affected activity, the AL choice was more impactful. Considering that the PL is the component of the PPCs responsible for DNA binding, this is suggestive that DNA interactions are not the primary mechanism of action of these complexes.

Date of Award	2018
Original language	English