Platinum nucleobase binding

Another question related to the dynamics of platinum—nucleobase chemistry is the rotational freedom or otherwise of the metal—purine bonds. This point is relevant to the formation of, for instance, an intrastrand link upon binding of the platinum to the first base. Studies on the cis-[Pt(NH3)2(Guo)2] cation indicated little restriction around the Pt—purine bond [65, 66] but with bulkier ligands (A, A-Me2-en, N,N,N N -Mq - vl) restricted rotation is observed [65,67]. 

The coordinating properties of a zinc 2,2 -bipyridyl unit with adenosine 5 -triphosphate and cytidine 5 -triphosphate were studied in aqueous solution. The binding of zinc to both phosphate and ATP nitrogen donor was observed with the potential for displacement of the ATP nitrogen donor by hydroxide.426 The interaction of zinc with the phosphate groups in a platinum(II) bound 2 -deoxyguanosine 5 -monophosphate has been studied in aqueous solution, with little difference noted in the coordinating properties of the phosphate residue or backbone relative to the free nucleobase.427... 

After this brief introduction, the chapter will focus on solvolysis reactions and acid-base equilibria of various platinum compounds and on species distribution of isomeric [PtCl2(NH3)2] in aqueous solution in Section 2. Binding of platinum compounds to monomeric nucleobase derivatives will be discussed in Section 3, while Section 4 pays attention to the reactions of Pt-nucleobase complexes with different nucleophiles. And finally, the interactions of Pt with DNA and defined oligonucleotides will be discussed in Section 5. 

The availability of different metal ion binding sites in 9-substituted purine and pyrimidine nucleobases and their model compounds has been recently reviewed by Lippert [7]. The distribution of metal ions between various donor atoms depends on the basicity of the donor atom, steric factors, interligand interactions, and on the nature of the metal. Under appropriate reaction conditions most of the heteroatoms in purine and pyrimidine moieties are capable of binding Pt(II) or Pt(IV) [7]. In addition, platinum binding also to the carbon atoms (e.g. to C5 in 1,3-dimethyluracil) has been established [22]. However, the strong preference of platinum coordination to the N7 and N1 sites in purine bases and to the N3 site in pyrimidine bases cannot completely be explained by the negative molecular electrostatic potential associated with these sites [23], Other factors, such as kinetics of various binding modes and steric factors, appear to play an important role in the complexation reactions of platinum compounds. 

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. 

Especially the various studies that made use of NMR techniques have contributed a lot to a better understanding of the manner in which DNA fragments react with metal ions. High-field NMR spectroscopy is a very useful tool to determine the platinum binding sites in nucleic add fragments, since crystal structure determinations have been reported only for a limited number of cases. The NMR evidence for platinum binding to nucleobases can be summarized as follows ... 

The purpose of this chapter is to explore the properties and reactions of various Pt-nucleobase complexes. After a short description of various binding modes, attention will be paid on the effects of coordinated platinum. Topics include, e.g., isomerization, thermodynamic stability, and solvolyt-ic reactions of Pt-nucleobase complexes. Finally, factors affecting the mechanism and kinetics of substitution reactions by various nucleophiles will be discussed. 

Attempts to model the intrastrand d(GpG) crosslink with nucleobases have met with only moderate success. Usually the 06 atoms of the two guanosine rings are on opposite sides of the platinum coordination plane ( head-to-tail isomer). Only for cw-[Pt(NH3)2(9-EtG)2] was the correct isomer obtained. Nucleobase complexes of the ds-diammineplatinum(II) moiety have been valuable for testing the controversial proposal of N7,06 chelate formation, which to date has not been observed. Several interesting discoveries of metal-nucleobase chemistry are that metal binding can stabilize rare tautomers, for example, the... 

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