Synthesis and Characterisation of Fluorescent Novel Pt(II) Cyclometallated Complexes with Anticancer Activity

Cancer poses a significant threat to global health and new treatments are required to improve the prognosis for patients. Previously, unconventional platinum complexes designed to incorporate polypyridyl ligands paired with diaminocyclohexane have demonstrated anticancer activity in KRAS mutated cells, previously thought to be undruggable and have cytotoxicity values up to 100 times better than cisplatin. In this work, these complexes were used as inspiration to design six novel cyclometallated examples, whose fluorescence could be exploited to better understand the mechanism of action of these kinds of platinum drugs. The cytotoxicity results revealed that these cyclometallated complexes (CMCs) have significantly different activity compared to the complexes that inspired them; they are as cytotoxic as cisplatin and have much higher selectivity indices in breast cancer cell lines (MCF10A/MCF-7). Complexes 1b, 2a, and 3b all had very high selectivity indexes compared to previous Pt(II) complexes. This prompted further investigation into their DNA binding properties, which revealed that they had good affinity to ctDNA, especially CMCs 1a and 3b. Their inherent fluorescence was successfully utilised in the calculation of their DNA binding affinity and could be useful in future work.

Automated summary

Cancer is a significant global health threat and new treatments are needed to improve patient prognosis. Unconventional platinum complexes, consisting of polypyridyl ligands and diaminocyclohexane, have shown anticancer activity in previously undruggable KRAS mutated cells, with cytotoxicity values up to 100 times better than cisplatin. Inspired by these complexes, six novel cyclometallated examples were designed and their fluorescence was used to study the mechanism of action of platinum drugs. The cytotoxicity results showed that these cyclometallated complexes have different activity compared to the inspiring complexes, but are as cytotoxic as cisplatin and have higher selectivity indices in breast cancer cell lines. Complexes 1b, 2a, and 3b exhibited particularly high selectivity indexes. Further investigation revealed their good affinity to ctDNA, especially CMCs 1a and 3b. The fluorescence of these complexes was successfully utilized in calculating their DNA binding affinity.