The role of ring D in the antitumour antibiotic streptonigrin: metal complexation, DNA binding and topoisomerase inhibition by ABC ring analogues of streptonigrin.
interaction of 7-amino-2-(6'-carboxy-2'-pyridyl)-6-methoxy-5,8-quinolinedione, an ABC ring analogue of the antitumour antibiotic streptonigrin, with zinc(II), oligonucleotides and DNA in the presence of zinc(II), and on the relaxation of DNA by topoisomerase II, has been studied. This ligand contains the key functional groups present in streptonigrin required for biological activity, but lacks the phenolic ring D which confers optical activity on streptonigrin. Variable temperature NMR experiments showed that in the presence of zinc(II) triflate, the methyl ester of the ligand forms a mixture of 1:1 and 1:2 metal:ligand bipyridyl complexes, whose relative stabilities are temperature dependent. Titrations of the water-soluble ligand with zinc(II) nitrate at room temperature showed that the predominant species present in aqueous solution at physiological pH is the 1:1 bipyridyl complex. The interaction of the ligand with the hexanucleotides d(GCATGC)2 and d(ATGCAT)2 was studied by 1H- and 31P-NMR spectroscopy. In the presence of 1 equiv of zinc(II) nitrate and 1 equiv of the ligand, small changes in chemical shifts of the proton resonances associated with the purine resonances were detected consistent with a weak interaction of the zinc(II) complex of the ligand with the oligonucleotides, possibly via a groove binding mechanism. UV-VIS titrations showed a weak interaction of the ligand with calf thymus DNA and poly(dG-dC)2 in the presence of zinc(II) but negligible interaction with poly(dA-dT)2. Gel electrophoresis experiments showed that, in contrast to streptonigrin, the ligand did not inhibit the relaxation of plasmid DNA by human topoisomerase II. These results show that the interaction of the ABC ligand with zinc(II), oligonucleotides, DNA and topoisomerase II is different to streptonigrin and hence the design of biologically active ABC ring analogues of streptongrin that operate via different mechanisms should be possible.
Anderberg
P I
PI
School of Chemistry, University of Sydney, NSW, Australia.
Harding
M M
MM
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D004587:Electrophoresis, Agar Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008670:Metals / Q000737:chemistry*; D009841:Oligonucleotides / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D013308:Streptonigrin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D015032:Zinc / Q000737:chemistry
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D008670:Metals; D009841:Oligonucleotides; D059005:Topoisomerase II Inhibitors; D013308:Streptonigrin; D004247:DNA; D015032:Zinc