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(NH3)2Cl]2-mu-dpzm]Cl2 (di-Pt) and trans-[trans-[Pt(NH3)2Cl]2[trans-[Pt(NH3)2(mu-dpzm)2]]]Cl4 (tri-Pt), have been synthesized. Both complexes show activity in the murine leukaemia cell line L1210 (IC50 = 3.8 and 2.5 microm, respectively) and the cisplatin-resistant subline L1210/DDP (8.8 and 3.6 microM), and in the human ovarian carcinoma 2008 (2.5 and 17.8 microM) and its cisplatin-resistant subline C13*5 (20.9 and 37.7 microM). Both complexes show high levels of uptake into 2008 cells, when administered at 100 microM, 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.
Wheate
N J
NJ
School of Chemistry, University College, University of New South Wales, Australian Defence Force Academy, Canberra.
Cullinane
C
C
Webster
L K
LK
Collins
J G
JG
D000818:Animals; D003432:Cross-Linking Reagents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D004247:DNA / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D010957:Plasmids / Q000235:genetics; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C453489:((chlorodiammineplatinum(II))(diammineplatinum(II)(mu-4,4'-dipyrazolylmethane))); C453488:(bis(chlorodiammineplatinum(II))mu-4,4'-dipyrazolylmethane); D003432:Cross-Linking Reagents; D009944:Organoplatinum Compounds; D011720:Pyrazoles; D004247:DNA