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.