Platinum Anticancer Drug Binding to Oligonucleotide Models of DNA

Marzillï, Luigi G.; Kline, Tammy Page; Live, David; Zon, Gerald

doi:10.1021/bk-1989-0402.ch009

Cited by 8 publications

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“…~* ' ~-~~ Among the various tools which have been used to assess the interactions between platinum complexes and DNA fragments, multinuclear NMR spectroscopy proved to be powerful. 7* 30 The 'P NMR studies of DNA and a variety of oligonucleotides treated with cis-[PtL,Cl,] complexes have pointed in each case to the appearance of a signal downfield of the normal DNA ,'P signal range. 7*30-35 Interestingly the therapeutically inactive trans-[Pt(NH,),Cl,] complex does not produce any abnormal ,'P signal.…”

Section: Interactions With a Tetradeoxyribonucleotide D(t-g-g-t) Andmentioning

confidence: 99%

Platinum(II) complexes of functionalized malonato ligands: unequivocal synthesis, interaction with a tetradeoxyribonucleotide and deoxyribonucleic acid

Laurent¹,

Morvan²

1993

J. Chem. Soc., Dalton Trans.

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Section: Interactions With a Tetradeoxyribonucleotide D(t-g-g-t) Andmentioning

confidence: 99%

Platinum(II) complexes of functionalized malonato ligands: unequivocal synthesis, interaction with a tetradeoxyribonucleotide and deoxyribonucleic acid

Laurent¹,

Morvan²

1993

J. Chem. Soc., Dalton Trans.

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Zinc ion–DNA polymer interactions

Jia¹,

Marzillï²

1991

Biopolymers

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The adjacent GN7-M-GN7 cross-linking and adjacent G-M-G sandwich-complex models for DNA metal ion binding were evaluated both with native DNAs differing in GC content as well as with the synthetic polymers poly [(dGdC)]2, poly[(dAdT)]2, and poly[(dAdC)(dGdT)]. The effect of Zn2+ was studied in depth, and limited studies were also performed with Co2+ and Mg2+. The results were compared to the extensive information available on Cu2+ binding to native DNAs and poly[(dAdT)]2. At high ratios of metal/base (R), Zn2+ caused all native DNAs to denature with the same melting temperature Tm, approximately 61 degrees C. A similar pattern was reported previously for Cu2+, but the typical Tm was approximately 35 degrees C. The extent of renaturation on cooling DNAs denatured in the presence of Zn2+ increased with GC content, as reported previously for Cu2+. These results, together with previously reported similarities, strongly indicate that the DNA binding characteristics of the two cations are similar. By comparison of the Tm values and hyperchromicity changes monitored at 260 and 282 nm, it is clear that, during thermal denaturation in the presence of Zn2+, both AT and GC regions were denatured, even at high R. The Tm vs R profile for the native DNAs was typical. The rise at low R and subsequent decrease at high R were inversely and directly related, respectively, to GC content. Except for poly[(dAdT)]2, where Tm increased with R, the other synthetic polymers exhibited the increase/decrease pattern. Poly[(dAdC)(dGdT)] gave a Tm value at high R of 54 degrees C. In the absence of Zn2+, this polymer exhibited little hypochromicity on cooling of denatured polymer. However, in the presence of Zn2+, nearly complete hypochromicity was observed, although the midpoint of the cooling curve was lower than the Tm value by approximately 15 degrees C at R = 10. These characteristics were similar to those with native DNAs, although viscosity and CD studies suggested that the "renatured" polymer was not identical to the unheated polymer. Furthermore, addition of Zn2+ after denaturation nearly completely reversed the absorption increase. This finding contrasts with those for native DNAs, where the Zn2+ must be present during denaturation in order to reverse the absorption increase nearly completely on cooling. With some caveats, poly[(dAdC)(dGdT)] appears to be a good model for native DNAs since its properties, including CD and uv changes on addition of Zn2+ to premelted and melted polymer, parallel those of the native polymers.(ABSTRACT TRUNCATED AT 400 WORDS)

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Medicinal Applications of Metal Complexes Binding to Biological Macromolecules

Reedijk

2008

Macromolecular Symposia

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Summary: Biological macromolecules present in living organisms, like proteins, DNA, have many metal-binding sites. As a consequence, coordination compounds can react with such cellular components, displaying possible toxic effects, or they also may have beneficial applications. So metal ions and compounds not only are essential for life in e.g. dioxygen transport, or biocatalysis, but they can also be used for controlled toxicity in medicinal applications. Well-known examples are the application of gold compounds in arthritis treatment, bismuth compounds for ulcer healing, and silver compounds for open skin protection. However, only in a few cases details of the mechanist are known, and if so, the biological macromolecules play a key role. Transition-metal coordination compounds that have metal-ligand exchange rates comparable to cell-division processes, i.e. in particular Pt and Ru, often appear to be highly active in killing cancers, as seen from the study of several cancer cell lines. Classical examples, like cisplatin, and new examples of Pt and Ru compounds will be discussed in some detail, with a focus on their binding to the DNA biomacromolecule. The classical compound cis-diamminedichloridoplatinum(II), often abbreviated as cisplatin, and its first-generation derivatives are known to bind to several biomacromolecules in a specific way, and eventually bind at DNA. Four important examples are shown in the figure. However, on its way to DNA other cellular components, like proteins and peptides might be intermediates before the final target is reached. Other metal-containing drugs, like Ru compounds, that show anti-cancer activity have a less well-known mode of action. Molecular-based mechanistic studies may result in improved clinical administration protocols.

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Platinum Anticancer Drug Binding to Oligonucleotide Models of DNA

Cited by 8 publications

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Platinum(II) complexes of functionalized malonato ligands: unequivocal synthesis, interaction with a tetradeoxyribonucleotide and deoxyribonucleic acid

Platinum(II) complexes of functionalized malonato ligands: unequivocal synthesis, interaction with a tetradeoxyribonucleotide and deoxyribonucleic acid

Zinc ion–DNA polymer interactions

Medicinal Applications of Metal Complexes Binding to Biological Macromolecules

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