Contrasting Anticancer Activity of Half-Sandwich Iridium(III) Complexes Bearing Functionally Diverse 2‑Phenylpyridine Ligands

We
report the synthesis, characterization, and antiproliferative
activity of 15 iridium­(III) half-sandwich complexes of the type [(η5-Cp*)­Ir­(2-(R′-phenyl)-R-pyridine)­Cl] bearing either
an electron-donating (−OH, −CH2OH, −CH3) or electron-withdrawing (−F, −CHO, −NO2) group at various positions on the 2-phenylpyridine (2-PhPy)
chelating ligand giving rise to six sets of structural isomers. The
X-ray crystal structures of [(η5-Cp*)­Ir­(2-(2′-fluorophenyl)­pyridine)­Cl]
(1) and [(η5-Cp*)­Ir­(2-(4′-fluorophenyl)­pyridine)­Cl]
(2) exhibit the expected “piano-stool”
configuration. DFT calculations showed that substituents caused only
localized effects on the electrostatic potential surface of the chelating
2-PhPy ligand of the complexes. Hydrolysis of all complexes is rapid,
but readily reversed by addition of NaCl. The complexes show preferential
binding to 9-ethylguanine over 9-methyladenine and are active catalysts
for the oxidation of NADH to NAD+. Antiproliferative activity
experiments in A2780 ovarian, MCF-7 breast, A549 lung, and HCT116
colon cancer cell lines showed IC50 values ranging from
1 to 89 μM, with the most potent complex, [(η5-Cp*)­Ir­(2-(2′-methylphenyl)­pyridine)­Cl] (13)
(A2780 IC50 = 1.18 μM), being 10× more active
than the parent, [(η5-Cp*)­Ir­(2-phenylpyridine)­Cl],
and 2× more active than [(η5-CpxPh)­Ir­(2-phenylpyridine)­Cl]. Intriguingly, contrasting biological
activities are observed between structural isomers despite exhibiting
similar chemical reactivity. For pairs of structural isomers both
the nature and position of the functional group can affect the hydrophobicity
of the complex. An increase in hydrophobicity resulted in enhanced
cellular-iridium accumulation in A2780 ovarian cells, which generally
gave rise to an increase in potency. The structural isomers [(η5-Cp*)­Ir­(2-(4′-fluorophenyl)­pyridine)­Cl] (2) and [(η5-Cp*)­Ir­(2-phenyl-5-fluoropyridine)­Cl]
(4) preferentially localized in the cytosol > membrane
and particulate > nucleus > cytoskeleton. This work highlights
the
strong dependence of biological behavior on the nature and position
of the substituent on the chelating ligand and shows how this class
of organometallic anticancer complexes can be fine-tuned to increase
their potency without using extended cyclopentadienyl systems.