Binuclear palladacycles with ionisable and non-ionisable tethers as anticancer agents

• Published in: Journal of inorganic biochemistry 2024-08, Vol.257, p.112608, Article 112608
• Main Authors: van Niekerk, A., Chakraborty, S., Bellis, C., Chellan, P., Prince, S., Mapolie, S.F.
• Format: Article
• Language: English
• Subjects: Anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; BSA binding; Cell Line, Tumor; Cell Survival - drug effects; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; DNA - chemistry; DNA - metabolism; DNA binding; Female; Humans; MCF-7 Cells; Molecular modeling; Palladacycles; Palladium - chemistry; Palladium - pharmacology; PEGylation; Polyethylene Glycols - chemistry; Polyethylene Glycols - pharmacology
• ISSN: 0162-0134; 1873-3344; 1873-3344
• DOI: 10.1016/j.jinorgbio.2024.112608

The search for novel anticancer agents to replace the current platinum-based treatments remains an ongoing process. Palladacycles have shown excellent promise as demonstrated by our previous work which yielded BTC2, a binuclear palladadycle with a non-ionisable polyethylene glycol (PEG) tether. Here, we explore the importance of the PEG-tether length on the anticancer activity of the binuclear palladacycles by comparing three analogous binuclear palladacycles, BTC2, BTC5 and BTC6, in the oestrogen receptor positive MCF7 and triple-negative MDA-MB-231 breast cancer cell lines. In addition, these are compared to another analogue with an ionisable morpholine tether, BTC7. Potent anticancer activity was revealed through cell viability studies (MTT assays) revealed that while BTC6 showed similar potent anticancer activity as BTC2, it was less toxic towards non-cancerous cell lines. Interestingly, BTC7 and BTCF were less potent than the PEGylated palladacycles but showed significantly improved selectivity towards the triple-negative breast cancer cells. Cell death analysis showed that BTC7 and BTCF significantly induced apoptosis in both the cancer cell lines while the PEGylated complexes induced both apoptosis and secondary necrosis. Furthermore, experimental and computational DNA binding studies indicated partial intercalation and groove binding as the modes of action for the PEGylated palladacycles. Similarly, experimental and computational BSA binding studies indicated and specific binding sites in BSA dependent on the nature of the tethers on the complexes. The nature of the tether controls the activity, selectivity and biomolecular interactions of the palladacycle. [Display omitted] •Developed a series of binuclear palladacycles with ionisable and non-ionisable tethers.•Potent anticancer activity observed via MTT assays.•BTC6 is an improvement on its precursor BTC2 – less toxic and more soluble.•BTC7 shows selectivity towards triple-negative breast cancer cell line MDA-MB-231•Experimental and computational DNA and BSA binding studies show that the nature of the tether determines the type and location of the interaction observed.