Four ruthenium complexes of clinically used zinc ionophore pyrithione and its oxygen analog 2-hydroxypyridine N-oxide were prepared and evaluated as inhibitors of enzymes of the aldo-keto reductase subfamily 1C (AKR1C). The crystal stucture of the novel compounds was determined by single crystal X-ray diffraction, and stability and reactivity of the compounds in biologically relevant water-dmso systems was studied by NMR. A kinetic study assisted with docking simulations showed a mixed type of inhibition consisting of a fast reversible and a slow irreversible step in the case of two organometallic compounds. Both compounds also showed a remarkable selectivity towards AKR1C1 and AKR1C3 which are targets for breast cancer drug design. The organoruthenium complex of ligand pyrithione as well as pyrithione itself also displayed toxicity on hormone-dependent MCF-7 breast cancer cell line with EC50 values in the low micromolar range. This article follows and evolves our research on the topic of metal-based inhibitors of enzymes of the aldo-keto reductase family AKR1C. A wider screening to investigate the potential of different organometallic and coordination fragments of ruthenium was also published by our group in Traven et al., Chemico-Biological Interactions 2015, 234, 349-359
COBISS.SI-ID: 32724441
Over the past years, the organometalled compounds, including ruthenium, gained a lot of attention as anticancer agents. We report on clioquinol-ruthenium complex [Ru(eta6-p-cymene)(Cq)Cl] as a potent inhibitor of cathepsin B, a lysosomal cysteine peptidase, involved in tumour cell invasion and metastasis. In the low micromolar concentration range, clioquinol-ruthenium complex did not exhibit cytotoxic effects on MCF-10A neoT and U-87 MG cells; it did, however, significantly reduced their ability for extracellular matrix degradation and invasiveness in two independent cell-based models, measuring either electrical impedance in real time or the growth of multicellular tumour spheroids implanted in Matrigel, a model representing the extracellular matrix. These results establish ruthenium based organometallic compounds as promising candidates for further pre-clinical studies as anticancer therapeutics.
COBISS.SI-ID: 4164977