Synthesis, DNA binding and cytotoxicity of isohelical DNA groove binding platinum complexes.
The two platinum complexes [[Pt(dien)]2mu-dpzm]4+ and trans-[Pt(NH3)2(mu-dpzm)2]2+(dpzm = 4,4'-dipyrazolylmethane) have been synthesized and their DNA binding and cytotoxicity studied in order to evaluate the potential of square-planar platinum complexes as DNA groove binding anti-cancer agents. 1H-NMR spectroscopy was used to study the binding of both metal complexes to the dodecanucleotide d(CGCGAATTCGCG)2. For both platinum complexes, a considerable number of intermolecular NOE contacts were observed in NOESY spectra of the platinum complex bound dodecanucleotide. The NOE data demonstrated that each platinum complex bound in the minor groove at the central AATT region. Neither platinum complex appeared to induce any major DNA conformation change. In vitro cytotoxicity studies in the murine leukaemia cell lines L1210 and L1210/cisR showed that trans-[Pt(NH3)2(mu-dpzm)2]2+ had some activity (IC50: 64 and 32 microM respectively) while the [[Pt(dien)]2mu-dpzm]4+ complex showed no activity at all (>200 microM). The results indicate that it may be possible to synthesize platinum complexes that are useful as groove binding agents in the treatment of cancer.
Wheate
N J
NJ
School of Chemistry, University College, University of New South Wales, Australian Defence Force Academy, Canberra.
Webster
L K
LK
Brodie
C R
CR
Collins
J G
JG
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000737:chemistry / Q000187:drug effects*; D007939:Leukemia L1210 / Q000188:drug therapy; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D009690:Nucleic Acid Conformation; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D008024:Ligands; D009944:Organoplatinum Compounds