In the mid-sixties, platinum-based organometallic drugs were among the first compounds used to treat cancer, and they are still widely used today. ‘Over time, they have been adapted to reduce side effects’, says Steve Nolan, Professor of Chemistry at Ghent University.

Recently, however, there has been a move away from platinum, mainly because certain cancers show resistance to the noble metal. ‘You can see a big push towards ruthenium-based drugs, some of which are already in clinical use’, Nolan continues. ‘But one of the latest discoveries concerns palladium, platinum’s metal next door.’

When coupled to N-heterocyclic carbenes (NHCs) and allyl fragments, these compounds, known as palladates, behave in a highly interesting manner. They induce immunogenic cell death (ICD), ‘a form of programmed cell death that triggers an immune response against dying cancer cells. Unlike regular cell death, ICD releases damage-associated molecular patterns that activate the immune system, promoting the recognition and elimination of cancer cells’, write Nolan, Belgian and Italian colleagues in the introduction to a paper in EurJIC about the allyl palladates.

Mortar and Pestle

‘This work builds on earlier studies in which we wanted to see how to make specific NHC-metal complexes’, says Nolan. ‘We used palladium sources in the synthesis of neutral compounds and found that the palladates were intermediates, some of which we could isolate.’

One ‘cool’ aspect of synthesising the palladates is that these compounds can be produced simply by grinding the palladium precursor and the imidazolium salt (the NHC precursor) together in a mortar and pestle, eliminating the need for solvents. ‘Another fascinating property of these compounds is that these palladates are biologically active’, says Nolan.

While it’s still ‘early days’ for these compounds, they have passed the ‘petri dish stage’. ‘In this paper, we created some new palladate variants and tested them in 2D and 3D tumour models’, Nolan explains. ‘We found that some of them are more effective than cisplatin, showing activity against platinum-resistant tumours while having little effect on healthy cells. Our Italian colleagues will explore the biological side further.’

Nolan wants to emphasise the meritorious collaboration. ‘We really made the right connections; it was a classic case of “the whole being greater than the sum of its parts”.’ His group synthesises the compounds and the Italian groups, headed by Flavio Rizzolio and Thomas Scattolin, looked at the biological characterisation. ‘They then give us the results, and we redesign accordingly. Then the whole cycle starts again.’ There is still a lot of work to be done. ‘We will explore more palladate options to see if we can achieve even better activity and selectivity, and establish whether some of these compounds could eventually be used in clinical practice.’

Schiavo, A. et al. (2025) EurJIC, DOI: 10.1002/ejic.202500146