Potent Half-Sandwich Iridium(III) Anticancer Complexes Containing C ∧ N-Chelated and Pyridine Ligands.

We report the synthesis and characterization of eight half-sandwich cyclopentadienyl Ir ^III pyridine complexes of the type [(η ⁵ -Cp ^xph )Ir(phpy)Z]PF ₆ , in which Cp ^xph = C ₅ Me ₄ C ₆ H ₅ (tetramethyl(phenyl)cyclopentadienyl), phpy = 2-phenylpyridine as C ^∧ N-chelating ligand, and Z = pyridine (py) or a pyridine derivative. Three X-ray crystal structures have been determined. The monodentate py ligands blocked hydrolysis; however, antiproliferative studies showed that all the Ir compounds are highly active toward A2780, A549, and MCF-7 human cancer cells. In general the introduction of an electron-donating group (e.g., Me, NMe ₂ ) at specific positions on the pyridine ring resulted in increased antiproliferative activity, whereas electron-withdrawing groups (e.g., COMe, COOMe, CONEt ₂ ) decreased anticancer activity. Complex 5 displayed the highest anticancer activity, exhibiting submicromolar potency toward a range of cancer cell lines in the National Cancer Institute NCI-60 screen, ca. 5 times more potent than the clinical platinum(II) drug cisplatin. DNA binding appears not to be the major mechanism of action. Although complexes [(η ⁵ -Cp ^xph )Ir(phpy)(py)] ⁺ ( 1 ) and [(η ⁵ -Cp ^xph )Ir(phpy)(4-NMe ₂ -py)] ⁺ ( 5 ) did not cause cell apoptosis or cell cycle arrest after 24 h drug exposure in A2780 human ovarian cancer cells at IC ₅₀ concentrations, they increased the level of reactive oxygen species (ROS) dramatically and led to a loss of mitochondrial membrane potential (ΔΨm), which appears to contribute to the anticancer activity. This class of organometallic Ir complexes has unusual features worthy of further exploration in the design of novel anticancer drugs.