Resistance to
platinum drugs (used in >50% of
cancer chemotherapies) is a clinical problem. Other precious
metal complexes with distinct mechanisms of action might overcome this. Half-sandwich organometallic complexes containing arene or cyclopentadienyl (Cp)
ligands show promise. We screened two
iridium(iii) complexes [Ir(CpXbiph)(ppy)Cl] (ZL49, 1, ppy = phenylpyridine) and [Ir(CpXph)(azpyNMe2)Cl]PF6 (ZL109, 2, azpyNMe2 = N,N-dimethylphenylazopyridine) in 916
cancer cell lines from 28 tissue types. On average, complex 2 was 78× more potent than 1, 36× more active than
cisplatin (CDDP), and strongly active (nanomolar) in patient-derived
ovarian cancer cell lines.
RNA sequencing of A2780 ovarian cells revealed upregulation of
antioxidant responses (NRF2, AP-1) consistent with observed induction of
reactive oxygen species (ROS).
Protein microarrays, high content imaging and cell cycle analysis showed S/G2 arrest, and late-stage DNA damage response without p53 requirement. The
triple-negative breast cancer cell line OCUB-M was highly sensitive to 2 as were cell lines with KIT mutations. Complex 2 exhibits a markedly different pattern of antiproliferative activity compared to the 253 drugs in the Sanger
Cancer Genome database, but is most similar to
osmium(ii) arene complexes which share the same azopyridine
ligand. Redox modulation and DNA damage can provide a multi-targeting strategy, allowing compounds such
as 2 to overcome cellular resistance to
platinum anticancer drugs.