The promising drug candidate indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) is the second Ru-based anticancer agent to enter clinical trials. In this review, which is an update of a paper from 2006 (Hartinger et al., J. Inorg. Biochem. 2006, 100, 891-904), the experimental evidence for the proposed mode of action of this coordination compound is discussed, including transport into the cell via the transferrin cycle and activation by reduction. The results of the early clinical development of KP1019 are summarized in which five out of six evaluated patients experienced disease stabilization with no severe side effects.

Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favourable toxicity and clearance properties. Nonetheless, their molecular targeting and mechanism of action are poorly understood. Here we study two prototypical ruthenium-arene agents—the cytotoxic antiprimary tumour compound [(η6-p-cymene)Ru(ethylene-diamine)Cl]PF6 and the relatively non-cytotoxic antimetastasis compound [(η6-p-cymene)Ru(1,3,5-triaza-7-phosphaadamantane)Cl2]—and discover that the former targets the DNA of chromatin, while the latter preferentially forms adducts on the histone proteins. Using a novel ‘atom-to-cell’ approach, we establish the basis for the surprisingly site-selective adduct formation behaviour and distinct cellular impact of these two chemically similar anticancer agents, which suggests that the cytotoxic effects arise largely from DNA lesions, whereas the protein adducts may be linked to the other therapeutic activities. Our study shows promise for developing new ruthenium drugs, via ligand-based modulation of DNA versus protein binding and thus cytotoxic potential, to target distinguishing epigenetic features of cancer cells.

Lipidomics is a particularly difficult analytical challenge due to the number and importance of isomeric species that are known or postulated in biological samples. Current separation and identification techniques are too often insufficiently powerful, slow or ambiguous. High resolution, low field ion mobility coupled to mass spectrometry is shown here to have sufficient performance to represent a new alternative for lipidomics. For the first time, drift-tube ion mobility separation of lipid isomers that differ only in position of the acyl chain, position of the double bond or double bond geometry is demonstrated. Differences in collision cross sections of less than 1% are sufficient for baseline separation. The same level of performance is maintained in complex biological mixtures. More than 130 high-precision reduced mobility and collision cross section values were also determined for a range of lipids. Such data can be the basis of a new lipidomics workflow, as the appropriate libraries are developed.