Binding of Metal Complexes to DNA

The ability of metal complexes to form more than one bond to the polynucleotide, especially in Form HI, results in various forms of cross link between the complementary strands of the helix. The coordination number, geometry, and types of ligand all dictate a remarkable range of conformational changes and interactions with DNA, including base pair specificity. 

The concept of intercalation was originally proposed by Lerman [48] to explain the binding of aromatic planar molecules such as aminoacridines, exemplified by proflavine (la), and later phenanthridines, such as homidium bromide (ethidium 2b)  

The basic, classical interaction involves the insertion of the planar molecule between two neighboring base pairs of DNA to which it is held by Van der Waals forces [49]. A further weak interaction of an electrostatic type between the phosphate anions and charged groups of the molecule may also be present. A nonclassical intercalation model involving bending of the helix has also been proposed [50]. The models are outlined schematically  

The classical view of intercalation requires that the helix be extended and locally unwound by the binding reaction. The hydrodynamic properties are affected with an increase in viscosity, resulting from an extension and stiffening of the double helix, as well as a decrease in sedimentation coefficient. The transition melting temperature, is also increased and this can be understood by considering that the intercalator—base pair stacking interaction stabilizes the helical over the unwound form. 

Many intercalators have biological activity and, in fact, the remarkable preponderance of planar aromatic cations with activity was noted even before the intercalation concept was fully formulated. The DNA binding and molecular pharmacology of these species have been reviewed in comprehensive articles [4,52]. 

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Jaquet L, Kelly JM, Kirsch-De Mesmaeker A (1995) Photoadduct between tris(1,4,5,8-tetraazaphena nthrene)ruthenium(ll) and guanosine monophosphate - a model for a new covalent binding of metal complexes to DNA. J Chem Soc Chem Commun 913-914 Jay-Gerin J-P, Ferradini C (2000) A new estimate of the OFI radical yield at early times in the radiolysis of liquid water. Chem Phys Lett 317 388-391... 

The coordination properties of the nucleobases have been reviewed by Houlton (40) and by Lippert (2). In a recent review, Lippert discussed the influence of the metal coordination on the piSTa of the nucleobases (41), which correlates with their coordination properties. While the coordination properties of nucleobases, nucleosides, and nucleotides have been extensively studied and reviewed, the number of articles dedicated to the coordination properties of nucleic acids is signihcantly smaller. DeRose et al. (42) recently published a systematic review of the site-specific interactions between both main group and transition metal ions with a broad range of nucleic acids from 10 bp DNA duplexes to 300 00 nucleotide RNA molecules as well as with some nucleobases, nucleosides, and nucleotides. They focused on results obtained primarily from X-ray crystallographic studies. Egli also presented information on the metal ion coordination to DNA in reviews dedicated to X-ray studies of nucleic acids (43, 44). Sletten and Fr0ystein (45) reviewed NMR studies of the interaction between nucleic acids and several late transition metal ions and Zn. Binding of metal complexes to DNA by n interactions has been reviewed by Dupureur and Barton (46). 

Photolytic Covalent Binding of Metal Complexes to DNA Mark A. Billadeau and Harry Morrison... 

When Pt2(pop)44- is irradiated at 450 nm in the presence of DNA, strand scission occurs, and scavenger studies show that no diffusible intermediates are involved (22). Thus, scission must involve abstraction of hydrogen atoms from the sugar functionalities by the metal complex itself. Because Pt2(pop)44- is an anion, binding of the complex to DNA does not occur. This presents the possibility that Pt2(pop)44- may be a particularly sensitive probe of solvent accessibility and hence nucleic acid structure. 

With the ability to measure high and low binding constants accurately, it is possible to assess carefully the effects of ionic strength on the binding constants of metal complexes to DNA. This analysis is of interest in cases where the binding constant is high, as with octahedral metallointercalators 40, 152). For example, the binding affinity of... 

Due to the numerous applications that have stimulated studies of interactions and reactions of metal complexes with DNA, we cannot cover all the aspects in this review. We will focus our attention on photoreactions of metal complexes with DNA. Although, obviously for carrying out photochemical reactions, it is essential to discuss the binding of these compounds to DNA. Dark reactions, on the other hand, will not be described. 

The ability of metal complexes to unwind DNA has been put forth as an important criterion for proving an intercalative binding mode and has been observed with other complexes of phen, dppz, and phi (21, 28,30,33). The enzyme topoisomerase can be used to determine if small molecules unwind DNA, according to published procedures (28). We find that by using this assay, Ru(tpy)(dppz)OH22+ unwinds DNA by 17°, which is consistent with intercalative binding. 

The confirmation that the binding of these metal complexes to DNA is governed by equation 12 provides insight into the interplay of electrostatic and other forces in controlling the binding affinities. In general, the Z -1[ln (y 5)] term is small compared to the other two, so the binding affinity is basically a sum of the electrostatic Z F term and the K°t term. For complexes that bind solely by electrostatics, In Kohs should be essentially the same as the Z F term. If Z F-1.3, as it is in Ru(phen)32+... 

Fig. 18. Cyclic voltammograms of Ru(bpy>3 with and without calf thymus DNA. The dashed lines show theoretical voltammograms calculated using DigiSim for an EC mechanism. Data were taken at high ionic strength so that binding of the metal complex to DNA did not complicate the kinetic analysis. From Johnston et al. (200). Copyright 1995 American Chemical Society.

The synthetic variation of molecular shape and functionality, coupled to spectroscopic studies, can be useful in probing the parameters that drive binding to B-form DNA. In the transition metal complexes examined, the most important factor driving overall binding of these molecules to DNA appeared to be the match of shape and overlap between metal complex and the B-DNA helix. 

The nature of the target to be attacked by any drug obviously depends on the specific application. Many cytotoxic metal complexes target DNA because of its importance in replication and cell viability. Coordination compounds offer many binding modes to polynucleotides, including outer-sphere noncovalent binding, metal coordination to nucleobase and phosphate backbone... 

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