Biological Investigations of Ru(II) Complexes with Diverse β‐Diketone Ligands

The β‐diketone scaffold is a commonly used synthetic intermediate, and is a functional group found in natural products such as curcuminoids. This core structure can also act as a chelating ligand for a variety of metals. In order to assess the potential of this scaffold for medicinal inorganic chemistry, seven different κ2‐O,O’‐chelating ligands were used to construct Ru(II) complexes with polypyridyl co‐ligands, and their biological activity was evaluated. The complexes demonstrated promising structure‐dependent cytotoxicity. Three complexes maintained high activity in a tumor spheroid model, and all complexes demonstrated low in vivo toxicity in a zebrafish model. From this series, the best compound exhibited a ∼30‐fold window between cytotoxicity in a 3‐D tumor spheroid model and potential in vivo toxicity. These results suggest that κ2‐O,O’‐ligands can be incorporated into Ru(II)‐polypyridyl complexes to create favorable candidates for future drug development. Diketonate compounds can serve as ligands for metal complexes. Seven new complexes were generated to establish structure‐activity relationships for Ru(II) polypyridyl complexes containing a single diketonate ligand. While there is limited correlation between physiochemical property and biological activity, the series resulted in the identification of a new lead compound with high potency in 2D and 3D cancer models and low toxicity in zebrafish.