Colorectal cancer (CRC) is the third most common cancer Worldwide with nearly 1.4 million new cases and 694,000 deaths in 2012. The tumour suppressor protein, p53, is crucial in multicellular organisms and is responsible for halting the cell cycle and allowing time for the repair of damaged DNA. Many cancer types show a high occurrence of p53 mutations, and there is growing evidence that these mutant genes can lead to tumour progression. It has been shown that p53 mutation occurs in approximately 40-50% of irregular CRC, and has since become the most appealing target for mechanism-driven anticancer drug discovery, with some small molecules being investigated for reactivation and restoration of p53. To date, there are very few inorganic complexes being studied for their interactions with p53, however, some researchers have shown metal complexes to be active against natural CRC which have an active p53 function (HCT116 +/+, p53-wt). Herein, we have synthesised a library of iridium(III) complexes (Fig.1) with our previously published β-ketoiminate ligands. The chemosensitivity data has been determined against a range of tumour lines, and we show the first iridium complexes to show preferential activity towards CRC cells which have non-functional p53 (HCT116 -/-, null-p53), suggesting the activity is via a p53-independent pathway. The data presented will discuss the chemosensitivity studies against a range of cancerous cells and the healthy epithelial cells (APRE-19), the interactions of these complexes with DNA via the Comet assay, enzyme inhibition studies and the complexes’ cytotoxicity towards Cancer Stem Cells (CSCs). Since non-functional or mutated p53 is a common cause of chemotherapy resistance, we envision these compounds to be a highly potent class of anti-cancer therapeutics.

Organometallic iridium(III) complexes: Highly cytotoxic and selective towards colorectal cancers

256th National Meeting (2018)

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