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 (ΔΨm) 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.