Ligand‐Controlled Reactivity and Cytotoxicity of Cyclometalated Rhodium(III) Complexes

We report the synthesis, characterization and cytotoxicity of six cyclometalated rhodium(III) complexes [CpXRh(C^N)Z]0/+, in which CpX = Cp*, Cpph, or Cpbiph, C^N = benzo[h]quinoline, and Z = chloride or pyridine. Three X‐ray crystal structures showing the expected “piano‐stool” configurations have been determined. The chlorido complexes hydrolyzed faster in aqueous solution, and reacted preferentially with 9‐ethyl guanine or glutathione compared to their pyridine analogues. The 1‐biphenyl‐2,3,4,5‐tetramethylcyclopentadienyl complex [CpbiphRh(benzo‐[h]quinoline)Cl] (3a) was the most efficient catalyst in coenzyme reduced nicotinamide adenine dinucleotide (NADH) oxidation to NAD+ and induced an elevated level of reactive oxygen species (ROS) in A549 human lung cancer cells. The pyridine complex [CpbiphRh(benzo[h]quinoline)py]+ (3b) was the most potent against A549 lung and A2780 ovarian cancer cell lines, being 5‐fold more active than cisplatin towards A549 cells, and acted as a ROS scavenger. This work highlights a ligand‐controlled strategy to modulate the reactivity and cytotoxicity of cyclometalated rhodium anticancer complexes. The chemical reactivity and cytotoxicity of half‐sandwich organo‐rhodium complexes can be controlled by the monodentate ligand. Chlorido complexes show faster hydrolysis and higher catalytic efficiency, but pyridine complexes exhibit higher cytotoxicity with lower cellular Rh accumulation. The pyridine complexes act as ROS scavengers, while the chlorido analogues elevate ROS levels in cancer cells.