Metal Complex Binding to DNA

The possible similarity between Ru(phen)2Cl2 and etv-[Pt(NH3)2Cl2] in interactions with 2 -DNA is of much interests, since antitumor activities and toxicities of various ruthenium complexes have been recently reported. 

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A great diversity exists in the design of nucleic acid probes upon transition metal chemistry in part because of the abundance of different binding interactions to nucleic acids that may be exploited. Metal complexes bind to DNA through both covalent and noncovalent modes as illustrated in Fig. 2. 

Ru(TMP)3] A distinctive characteristic of the A conformation is its shallow and wide minor-groove surface. Tris(phenanthroline)metal complexes bind to DNA both through intercalation in the major groove and through a surface-bound interaction in the minor groove (18-20) (see above). It is this surface-bound interaction that has been exploited in the construction of a complex, a derivative of tris(phenanthroline)ruthenium(II) that selectively targets A-form helical structures (30, 75). 

Since many metal complexes bind to DNA, those that show luminescence in fluid media have the potential to act as probes of biological structure. Such a feature is particularly useful if the luminescent probe is site specific on the DNA chain. Complexes that can be chemically modified at the ligand periphery, or whose photophysical properties are sensitive to medium effects, have the best potential for use in biological applications. 

White, J. R. Streptonigrin-Transition Metal Complexes Binding to DNA and Biological Activity. Biochem. Biophys. Res. Comm. 77, 387 (1977). 

Hydrogen bonds are only rarely an issue in the modeling of small metal complexes. There are, however, some cases where hydrogen bonds are particularly important. For example, when diamineplatinum(II) complexes bind to DNA, hydrogen bonds form between the H(amine) atoms and oxygen atoms on the DNA, and these interactions may be very important in determining the sequence specificity of Pt/DNA interactions[140]. Also, interactions between cationic and anionic complexes will inevitably involve hydrogen bonds and these terms will probably determine whether there is substantial stereoselectivity in the interactions. 

When I was still at Columbia I was working on chiral metal complexes bound to DNA and I was also doing some studies in collaboration with Nick Turro, my wonderful colleague at Columbia, on the photophysical properties of ruthenium complexes bound to DNA. The complexes I was using in DNA binding studies could be considered as derivatives of those that had been used by Henry Taube in his classic studies of electron transfer... 

Tris(phenanthroline) complexes of ruthenium(II), cobalt(III), and rhodium(III) are octahedral, substitutionally inert complexes, and as a result of this coordina-tive saturation the complexes bind to double-helical DNA through a mixture of noncovalent interactions. Tris(phenanthroline) metal complexes bind to the double helix both by intercalation in the major groove and through hydrophobic association in the minor groove. " " Intercalation and minor groove-binding are, in fact, the two most common modes of noncovalent association of small molecules with nucleic acids. In addition, as with other small molecules, a nonspecific electrostatic interaction between the cationic complexes and the DNA polyanion serves to stabilize association. Overall binding of the tris(phenanthroline) complexes to DNA is moderate (log K = 4)." ... 

Certain kinds of metal ions bind to the DNA double strands by an electrostatic interaction with the phosphate group(s) or by complex formation with the sugar moiety or the nucleic... 

Of all the known sites for metal-ion binding to the heteroatoms of DNA bases, G-N3 is the most elusive. The adjacent 2-amino group is often considered to offer steric hindrance to binding at this site. However, while this undoubtedly influences the chemistry it does not preclude binding. The tri-metalated [ [Pt(N]3(9-Et G N1,N3,N7)]5 compound has for many years been the only structurally characterized example of an N3-coordinated guanine (66). A second example has now been reported, the tetranuclear octacation 16 (56). In this complex both the N7 and N3 atoms are bound to Pd2+ (Fig. 22). The molecule presents an interesting new architecture for a guanine-tetramer. Such structures are well known in DNA chemistry and are almost inevitably metal-ion stabilized (67,68). 

Another way in which Pt could bind to DNA is through the formation of intercalation compounds. The parallel here is with the hydrocarbon carcinogens and the nucleic acid stains, the acridines. It has been shown that metal chelates will form this same type of jt-complex. For example, palladium oxinate will form exactly the same type of -complexes as anthracene (88). 

Trigonal ML3 metal complexes exist as optically active pairs. The complexes can show enantiomeric selective binding to DNA and in excited state quenching.<34) One of the optically active enantiomers of RuLj complexes binds more strongly to chiral DNA than does the other enantiomer. In luminescence quenching of racemic mixtures of rare earth complexes, resolved ML3 complexes stereoselectively quench one of the rare earth species over the other. 35-39 Such chiral recognition promises to be a useful fundamental and practical tool in spectroscopy and biochemistry. 

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