Mechanism of cellular accumulation of an iridium(III) pentamethylcyclopentadienyl anticancer complex containing a C,N-chelating ligand

Abstract

The effect of replacement of the N,N-chelating ligand 1,10-phenanthroline (phen) in the Ir^III pentamethylcyclopentadienyl (Cp*) complex [(η⁵-Cp*)(Ir)(phen)Cl]⁺ (2) with the C,N-chelating ligand 7,8-benzoquinoline (bq) to give [(η⁵-Cp*)(Ir)(bq)Cl] (1) on the cytotoxicity of these Cp*Ir^III complexes toward cancer cell lines was investigated. Complex 2 is inactive, similar to other Cp*Ir^III complexes containing the N,N-chelating ligands. In contrast, a single atom change (C⁻ for N) in the chelating N,N ligand resulted in potency in human ovarian carcinoma cisplatin-sensitive A2780 cells, and, strikingly, 1 is active in the cisplatin-resistant human breast cancer MCF-7 and A2780/cisR cells. Replacement of the N,N-chelating ligand with the C,N-chelating ligand gives rise to increased hydrophobicity, leading to higher cellular accumulation, higher DNA-bound iridium in cells and higher cytotoxicity. The pathways involved in cellular accumulation of 1 have been further explored and compared with conventional cisplatin. The results show that both energy-independent passive diffusion and energy-dependent transport play a role in accumulation of 1. Further results were consistent with involvement of p-glycoprotein, multidrug resistance-associated protein 1 and glutathione metabolism in the efflux of 1. In contrast, the internalization of 1 mediated by the endocytotic uptake pathway(s) seems less likely. Understanding the factors which contribute to the mechanism of cellular accumulation of this Ir^III complex can now lead to the design of structurally similar metal complexes for antitumor chemotherapy.