Mechanism of cellular accumulation of an iridium(III) pentamethylcyclopentadienyl anticancer complex containing a C,N-chelating ligand
The effect of replacement of the N,N-chelating ligand 1,10-phenanthroline (phen) in the Ir-III pentamethylcyclopentadienyl (Cp-star) complex [(eta(5)-Cp-star)(Ir)(phen) Cl](+) (2) with the C,N-chelating ligand 7,8-benzoquinoline (bq) to give [(eta(5)-Cp-star)(Ir)(bq)Cl] (1) on the cytotoxicity of these (CpIrIII)-Ir-star complexes toward cancer cell lines was investigated. Complex 2 is inactive, similar to other (CpIrIII)-Ir-star 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.