The Antimicrobial Properties of PdII - and RuII -pyta Complexes.

Infections associated with antimicrobial resistance (AMR) are poised to become the leading cause of death in the next few decades, a scenario that can be ascribed to two phenomena: antibiotic over-prescription and a lack of antibiotic drug development. The crowd-sourced initiative Community for Open Antimicrobial Drug Discovery (CO-ADD) has been testing research compounds contributed by researchers around the world to find new antimicrobials to combat AMR, and during this campaign has found that metallodrugs might be a promising, yet untapped source. To this end, we submitted 18 PdII - and RuII -pyridyl-1,2,3-triazolyl complexes that were developed as catalysts to assess their antimicrobial properties. It was found that the Pd complexes, especially Pd1, possessed potent antifungal activity with MICs between 0.06 and 0.125 µg mL-1 against Candida glabrata. The in-vitro studies were extended to in-vivo studies in Galleria mellonella larvae, where it was established that the compounds were nontoxic. Here, we effectively demonstrate the potential of PdII -pyta complexes as antifungal agents.

DNA-binding affinity and molecular docking studies of the PEGylated binuclear palladacycle, BTC2, an efficient metallodrug 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 TNBC 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.

The palladacycle, BTC2, exhibits anti-breast cancer and breast cancer stem cell activity.

In women globally, breast cancer is responsible for most cancer-related deaths and thus, new effective therapeutic strategies are required to treat this malignancy. Platinum-based compounds like cisplatin are widely used to treat breast cancer, however, they come with limitations such as poor solubility, adverse effects, and drug resistance. To overcome these limitations, complexes containing other platinum group metals such as palladium have been studied and some have already entered clinical trials. Here we investigated the anti-cancer activity of a palladium complex, BTC2, in MCF-7 oestrogen receptor positive (ER+) and MDA-MB-231 triple negative (TN) human breast cancer cells as well as in a human breast cancer xenograft chick embryo model. BTC2 exhibited an average IC50 value of 0.54 µM, a desirable selectivity index of >2, inhibited the migration of ER+ and TN breast cancer cells, and displayed anti-cancer stem cell activity. We demonstrate that BTC2 induced DNA double strand breaks (increased levels of γ-H2AX) and activated the p-ATM/p-CHK2 and p-p38/MAPK pathways resulting in S- and G2/M-phase cell cycle arrests. Importantly, BTC2 sensitised breast cancer cells by triggering the intrinsic (cleaved caspase 9) and extrinsic (cleaved caspase 8) apoptotic as well as necroptotic (p-RIP3 and p-MLKL) cell death pathways and inhibiting autophagy and its pro-survival role. Furthermore, in the xenograft in vivo model, BTC2 displayed limited toxicity and arrested the tumour growth of breast cancer cells over a 9-day period in a manner comparable to that of the positive control drug, paclitaxel. BTC2 thus displayed promising anti-breast cancer activity.