Platinum-DNA interactions

Over the past 20 years, cis-diamminedichloroplatinum(II), known for more than 145 years, has emerged as the classic compound in the context of antitumor drug therapy. Because it is generally accepted that binding of the compound to DNA is a major requirement for its biological activity, scientists have focused their attention especially on platinum-DNA interactions. In the present review, the latest results... 

Initially these hypotheses directed almost all attention to platinum-DNA interactions in the studies concerning the working mechanism of cis-Pt. However, it cannot be excluded that other cis-Pt-induced processes at the cellular level might attribute to the ultimate cell killing. In this respect the natural immune response should be mentioned. It appears, however, that an ever-increasing amount of research is focused on the interactions of platinum compounds with DNA. 

A very interesting aspect of platinum-DNA interactions concerns the nature of the resulting adducts and their relative quantities. Due to the bifunctional nature of cis-Pt, several types of adducts in the DNA can be expected to be formed, to be distinguished in (1) interstrand chelates (binding of two nucleobases that are each positioned in one of the complementary DNA strands), (2) intrastrand chelates (binding of two nucleobases within the same DNA strands), (3) intrabase chelates (binding to two different atoms in one base), and (4) DNA-protein cross-links. 

Investigations on the working mechanism of cisplatin have been carried out during the last decade by a variety of research groups, involving chemists, biochemists, biologists and medical researchers17. Early studies already made it clear that reaction of platinum compounds with nucleic adds play an important role in the mechanism of action. The present review deals with the status of this field, with special attention to platinum-DNA interactions. 

Platinum—Oligonucleotide Structures and Their Relevance to Platinum—DNA Interaction... 

Natile, G. Coluccia, M. Trans-platinum Compounds in Cancer Therapy A Largely Unexplored Strategy for Identifying Novel Antitumor Platinum Drugs In Metallopharmaceuticals l DNA Interactions, Clarke, M. J. Sadler, P. I, Eds. Springer-Verlag Berlin, 1999 Vol. 1, pp 73-98. 

Rate constants for reaction of cis-[Pt(NH3)2(H20)Cl]+ with phosphate and with S - and 5/ -nucleotide bases are 4.6xl0-3, 0.48, and 0.16 M-1s-1, respectively, with ring closure rate constants of 0.17 x 10 5 and 2.55x10-5s-1 for subsequent reaction in the latter two cases 220). Kinetic aspects of interactions between DNA and platinum(II) complexes such as [Pt(NH3)3(H20)]2+, ds-[Pt(NH3)2(H20)2]2+, and cis-[Pt(NH3)2(H20)Cl]+, of loss of chloride from Pt-DNA-Cl adducts, and of chelate ring formation of cis-[Pt(NH3)2(H20)(oligonucleotide)]"+ intermediates implicate cis-[Pt(NH3)2(H20)2]2+ rather than cis-[Pt(NH3)2 (H20)C1]+, as usually proposed, as the most important Pt-binder 222). The role of aquation in the overall scheme of platinum(II)/DNA interactions has been reviewed 223), and platinum(II)-nucleotide-DNA interactions have been the subject of molecular modeling investigations 178). 

In this section a brief summary of the most important Pt—DNA interactions, including cis-Pt, irans-Pt, and other related platinum compounds, and their relevance for antitumor activity will be presented. For more detailed information the reader is referred to the several reviews that have appeared on this subject during the last 5 years (49-53). 

Molecular mechanics and dynamics studies of metal-nucleotide and metal-DNA interactions to date have been limited almost exclusively to modeling the interactions involving platinum-based anticancer drugs. As with metal-amino-acid complexes, there have been surprisingly few molecular mechanics studies of simple metal-nucleotide complexes that provide a means of deriving reliable force field parameters. A study of bis(purine)diamine-platinum(II) complexes successfully reproduced the structures of such complexes and demonstrated how steric factors influenced the barriers to rotation about the Pt(II)-N(purine) coordinate bonds and interconversion of the head-to-head (HTH) to head-to-tail (HTT) isomers (Fig. 12.4)[2011. In the process, force field parameters for the Pt(II)/nucleotide interactions were developed. A promising new approach involving the use of ab-initio calculations to calculate force constants has been applied to the interaction between Pt(II) and adenine[202]. 

To develop platinum drugs with improved properties compared to cisplatin, a plethora of cisplatin analogs have been designed with appended additional ftmctionalities. The rationale is that these incorporated moieties could lead to a host of favorable pharmacokinetic properties, such as targeting to cancer cells, improved transport into the cell, and increased affinity for DNA. Furthermore, to overcome the problem of resistance, pendant DNA interacting moieties have been... 

During the final comparison of energies, it will be beneficial to have the optimized energy of platinum with its ammonia ligands but without any DNA interactions. To create such a molecule select New under File. 

Amino- or halogeno-platinum complexes interact with DNA in different ways. The interaction with cis-[Pt(NH3)2Cl2] is localized on the N(7) (G) and 0(6) (G) sites, forming a chelate without H liberation, while the K2PtCl4 interaction differs in that there is no H liberation before saturation of the N(7) (G) sites. Solid complexes were characterized as [Pt(DNA)Cl2]. Complexes cis-[PtA2], cis- and trans-[Pt(AH)Cl2],... 

Reaction with DNA of cells in culture. Studies with cultured cells have indicated the relevance of platinum-DNA binding to cytotoxicity. Pascoe and Roberts (, ) studied the interaction of several platinum compounds with macromolecules at measured levels of cell kill. 

Models for the Interaction of cis-platin and its hydrolysis products with DNA are discussed. The models are the interstrand cross-link, intrastrand cross-link, N7-06 clip, platinum dimer interaction, Eichhorn costacking, and N1 pK shift. Interactions observed in model compounds have been observed to occur in DNA for most of the models, but it is not possible to say which, if any, is the important lesion in the anti-cancer action of cis-platin. 

Chaney SG, Campbell SL, Temple B, et al. Protein interactions with platinum-DNA adducts from structure to function. J Inorg Biochem 2004 98 1551-1559. 

The interaction of platinum with DNA has been clearly established both in vitro (8-11) and in vivo (12-14), and most modelling studies indicate that, although platinum can interact with the phosphate group (15), the prime interaction is with the purine and pyrimidine bases. Ultra-violet-visible spectroscopy (16,17) nuclear magnetic resonance (18,19) and x-ray photoelectron spectroscopy ( ) studies have been interpreted to suggest that sites of attack could be... 

MM studies on metal-nueleotide and metal-DNA interactions are dominated by platinum-based anticancer drugs. There have been numerous studies on the interaetion of cisplatin, cis-[PtCl2(NH3)2] with DNA foeusing on the intrastrand adduct between adjaeent guanine bases. 

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