Description:
<jats:title>Abstract</jats:title><jats:p>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 κ<jats:sup>2</jats:sup>‐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 <jats:italic>in vivo</jats:italic> 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 <jats:italic>in vivo</jats:italic> toxicity. These results suggest that κ<jats:sup>2</jats:sup>‐O,O’‐ligands can be incorporated into Ru(II)‐polypyridyl complexes to create favorable candidates for future drug development.</jats:p>