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Hydroxypyr(id)ones are a pharmaceutically important class of compounds that have shown potential in diverse areas of drug discovery. We investigated the 3-hydroxy-4-pyridones 1a&ndash, 1c and 3-hydroxy-4-thiopyridones 1d&ndash, 1f as well as their Ru(&eta, 6-p-cymene)Cl complexes 2a&ndash, 2f, and report here the molecular structures of 1b and 1d as determined by X-ray diffraction analysis. Detailed cell biological investigations revealed potent cytotoxic activity, in particular of the 3-hydroxy-4-thiopyridones 1d&ndash, 1f, while the Ru complexes of both compound types were less potent, despite still showing antiproliferative activity in the low &mu, M range. The compounds did not modulate the cell cycle distribution of cancer cells but were cytostatic in A549 and cytotoxic in NCI-H522 non-small lung cancer cells, among other effects on cancer cells.

The small molecule anticancer agent cisplatin and its Pt(II) analogs carboplatin and oxaliplatin are widely used to treat a variety of tumorigenic diseases. Despite their structural simplicity, side effects and disadvantages, they are cornerstones of cancer chemotherapy. Several strategies have been pursued to enhance the activity and reduce the side effects of metal-based drugs, for example, to use bioactive ligands that equip them with novel modes of action, enhance delivery, allow for selective activation, create synergistic effects or improve tumor accumulation. Many of these strategies have been developed for or adapted in the design of half-sandwich organoruthenium compounds. For such compounds decorated with bioactive ligands that coordinate monodentately to the Ru center, we have identified five design concepts (Coord. Chem. Rev. 2021, 439, 213890): (i) the bioactive ligand coordinates directly to the Ru center or (ii) after functionalization with a coordinating group, (iii) the ligand(s) and the Ru center solely define the overall shape of the molecule, (iv) the bioactive ligand is released, and (v) the bioactive ligand acts as a vector to the tumor (cell). Herein, we use these five concepts and explore their application to half-sandwich organoruthenium anticancer compounds in which the bioactive ligand is coordinated to the Ru center through a bidentate chelating motif.

Metallodrugs have a central role in the treatment and diagnosis of diseases. To overcome potential toxicity and equip metal-based anticancer agents with biological activity, the choice of the ligands coordinated to the metal center is essential. A recent strategy to address the shortcomings of current drugs and improve their targeted properties, is to introduce bioactive ligands, which may result in synergistic activity between the metal center and the ligand system. In this review, we discuss such efforts in the development of Ru half-sandwich compounds, a class of promising anticancer agents which have been widely studied. We explore here strategies to introduce monodentately-coordinated bioactive moieties into such metal complexes by a variety of design concepts and review their potential as multimodal anticancer agents.