Structurally Strained Half-Sandwich Iridium(III) Complexes As Highly Potent Anticancer Agents

Six complexes of formula [Ir­(η⁵:κ¹-C₅Me₄CH₂py)­(C,N)]­PF₆, where C₅Me₄CH₂py is 2-((2,3,4,5-tetramethylcyclopentadienyl)­methyl)­pyridine, and C,N is 2-phenylpyridine (1), 7,8-benzoquinoline (2), 1-phenylisoquinoline (3), 2-(p-tolyl)­pyridine (4), 4-chloro-2-phenylquinoline (5), or 2-(2,4-difluorophenyl)­pyridine (6), have been synthesized. The cyclopentadienyl ligand bears a tethered pyridine that binds to the metal center, resulting in an Ir­(η⁵:κ¹-C₅Me₄CH₂pyN) tether-ring structure, as confirmed by the X-ray crystal structures of 1, 2, 4, 5, and 6. Nontether versions of 1 and 2 were synthesized to aid unambiguous correlation between structure and activity. While nontether complexes are highly potent toward MCF7 cancer cells (similar to cisplatin), complexes bearing the tether-ring structure, 1–6, are exceptionally more potent (1–2 orders of magnitude). Additionally, 1–6 disrupt mitochondrial membrane potential (ΔΨ_m) and induce oxidative stress. Internalization studies strongly correlate intracellular accumulation and anticancer activity in tether and nontether complexes. We present a new class of organo-iridium drug candidates bearing a structural feature that results in a leap in anticancer potency.