Mechanistic insights into the anti-cancer activity of the PEGylated binuclear palladacycle, BTC2, against triple-negative breast cancer

Triple-negative breast cancer (TNBC) has a low five-year survival rate, especially if the cancer is diagnosed at a late stage and has already metastasized beyond the breast tissue. Current chemotherapeutic options for TNBCs rely on traditional platinum-containing drugs like cisplatin, oxaliplatin and carboplatin. Unfortunately, these drugs are indiscriminately toxic, resulting in severe side effects and the development of drug resistance. Palladium compounds have shown to be viable alternatives to platinum complexes since they are less toxic and have displayed selectivity towards the TNBC cell lines. Here we report the design, synthesis, and characterization of a series of binuclear benzylidene palladacycles with varying phosphine bridging ligands. From this series we have identified BTC2 to be more soluble (28.38–56.77 μg/mL) and less toxic than its predecessor, AJ5, while maintaining its anticancer properties (IC50 (MDA-MB-231) = 0.58 ± 0.012 μM). To complement the previous cell death pathway study of BTC2, we investigated the DNA and BSA binding properties of BTC2 through various spectroscopic and electrophoretic techniques, as well as molecular docking studies. We demonstrate that BTC2 displays multimodal DNA binding properties as both a partial intercalator and groove binder, with the latter being the predominant mode of action. BTC2 was also able to quench the fluorescence of BSA, thereby suggesting that the compound could be transported by albumin in mammalian cells. Molecular docking studies revealed that BTC2 is a major groove binder and binds preferentially to subdomain IIB of BSA. This study provides insight into the influence of the ligands on the activity of the binuclear palladacycles and provides much needed information on the mechanisms through which these complexes elicit their potent anticancer activity.