Potent Anticancer Tethered Organorhodium(III) Complexes Target the Mitochondria

We report a family of tethered rhodium(III) complexes of formula [Rh(η5:κ1-C5Me4(CH2)npyN)(C,N)]+ (n = 1 or 2; C,N = 2-phenylpyridine or benzoquinoline), their nontethered analogues, and their iridium(III) counterparts. The tethered pyridine, κ1-coordinated to the metal, does not dissociate in water, yet the metal-Npy(tether) bond can be cleaved by strong nucleophiles, enabling metal activation. We corroborated that metal-Z bond reactivity correlated with cytotoxicity in breast cancer cells; complexes lacking reactive metal-Z bonds exhibited low anticancer potency, while excessive reactivity impaired efficacy likely through off-target reactions. For the highly potent tethered complexes, we determined the kinetics of pyridine cleavage using DMSO and confirmed that N-acetylcysteine can also promote pyridine dissociation. In tethered complexes, metal-mediated reactivity is crucial to potency, as metal-pyridine bonds with higher activation energy produce complexes less damaging to cells. We confirmed mitochondrial involvement in cell death, demonstrating that the most cytotoxic complexes inhibit OXPHOS more efficiently.