Synthesis, cytotoxicity, cell uptake and DNA interstrand cross-linking of 4,4'-dipyrazolylmethane-linked multinuclear platinum anti-cancer complexes

Two cationic multinuclear platinum complexes linked with the 4,4'-dipyrazolylmethane (dpzm) ligand, trans-[{Pt(NH 3 ) 2 Cl} 2 -μ-dpzm]Cl 2 (di-Pt) and trans-[trans-{Pt(NH 3 ) 2 Cl} 2 {trans-[Pt(NH 3 ) 2 (μ-dpzm) 2 ]}]Cl 4 (tri-Pt), have been synthesized. Both complexes show activity in the murine leukaemia cell line L1210 (IC 50 = 3.8 and 2.5 μM, respectively) and the cisplatin-resistant subline L1210/DDP (8.8 and 3.6 μM), and in the human ovarian carcinoma 2008 (2.5 and 17.8 μM) and its cisplatin-resistant subline C13 * 5 (20.9 and 37.7 μM). Both complexes show high levels of uptake into 2008 cells, when administered at 100 μM, but significantly reduced uptake in the cisplatin-resistant cell line C13 * 5 (di-Pt, 66% decrease; tri-Pt, 42%; cisplatin, 86%). Both complexes form very high levels of DNA interstrand cross-links in vitro, with 50% interstrand cross-linking observed at far lower concentrations (di-Pt, 12 nM; tri-Pt, 22 nM) than cisplatin (450 nM). It is proposed that the higher extent of interstrand cross-linking may be due to the rigid nature of the dpzm linking ligand, which prevents the complexes from forming short-range intrastrand adducts, like the GpG adduct formed by cisplatin. The results of this study indicate the importance of the flexibility of the linking ligand for the cytotoxicity of di- and trinuclear platinum anti-cancer complexes.