Chapter Six - Merging Metal–Nucleobase Chemistry With Supramolecular Chemistry
Introduction
The merging of structural nucleic acid chemistry with metal coordination chemistry actually started before the term “Supramolecular Chemistry” had been introduced by Lehn.1 In fact, it was during the 1950s and 1960s that reversible interactions between transition metal ions and polynucleotide strands or DNA began to fascinate chemists.2, 3, 4, 5, 6, 7, 8 By binding soft metal ions to donor sites of the heterocyclic nucleobases rather than the hard phosphate oxygen atoms of the polynucleotide backbone, effects on fundamental physicochemical properties, e.g., melting temperature, viscosity, UV, and CD spectra, were noticed. These effects were clearly different from those of the natural metal counter ions K+, Na+, and Mg2 +, which form a rather diffuse cloud of positive charges around the polynucleotide strands,9 unless they have specific structural functions as is the case, e.g., in guanine quartets,10 in RNA folds,11 or tRNA structures. Representative examples of this new chemistry involving transition metal ions were, among others, findings according to which Ag+ ions could convert largely unstructured poly(U) strands (poly(U) = polyuridylic acid) into an ordered double helix as a consequence of metal cross-linking with substitution of the protons at N3 of uracil bases, and similarly that poly(I) (poly(I) = polyinosinic acid) strands associate into a tetrastranded superstructure, as concluded from X-ray fiber diffraction patterns and spectroscopic techniques (Fig. 1).12 In the latter four hypoxanthine anions and four linear coordinated Ag+ ions form planar base quartets. The present hype on “M-DNA”13, 14, 15, 16 with its many applications in analytical and material sciences is based on relevant early work in this area.
These developments coincided with the discovery of the antitumor activity of Cisplatin (cis-Pt(NH3)2Cl2) by Rosenberg17 and subsequent findings that DNA is the likely target of this drug.18 There were questions regarding the intracellular activation of this drug, its preferred DNA binding sites, in addition to the resulting distortion of DNA by the feasible cross-links, which were asked in the early days of Cisplatin.19 Subsequently, more subtle effects of coordinated Pt or transition metals in general on electronic properties of nucleobases and their base-pairing properties became a major focus. It soon became clear that the isolated nucleobases (nucleotides, nucleosides, and model nucleobases with sites normally carrying the sugar moieties blocked by alkyl groups) rather than polynucleotides with their phosphodiester backbones could be utilized to provide answers to these questions.
Originally our interest in Pt–nucleic acid interactions focused on trying to understand details on a molecular level by applying model nucleobases and by studying the products observed mainly by single crystal X-ray analysis, NMR spectroscopy, and potentiometric titration experiments. However, over the years this work gradually evolved into the realm of Supramolecular Chemistry.
Our first own finding in this context was an unprecedented pair between two 9-ethylguanine model nucleobases carrying PtII entities at N7 of both purines.20 One of the two guanine bases had become deprotonated at N1 under the polarizing effect of the coordinated metal, and the two bases formed three hydrogen bonds in a reverse-Watson–Crick-type manner with each other (Fig. 2). This pairing pattern was later found by us to also occur between a N7 platinated guanine and a free guanine base, thus making it a real mispair with potential relevance to biology (see Section 3.4).21 Interestingly, an analogous pair is formed between the zwitterionic form of neutral 7-methylguanosine22 (or 7,9-dimethylguanine23) and its protonated form(s) which, due to the pKa value of close to 7 and its function as the 5′-cap in eukaryotic mRNAs, as well as the main product of DNA methylation caused by DNA damaging agents, may very well be biologically competent.
Another early report from our laboratory,24 later confirmed and extended in numerous variations, referred to the observation that kinetically inert Pt–nucleobase complexes could be used as “platforms” for the construction of larger or even polymeric heterometallic nucleobase aggregates with either main group or transition metal ions acting as “glue” between the Pt moieties (Fig. 3). This concept (metal complex as ligand) is an important contemporary strategy also for the synthesis of heterometallacyclic assemblies (see 4.8 Heteronuclear Adducts of Nucleobases, 5 Cyclic Complexes and Metallacalix[).25
We have, over the years, summarized these as well as other aspects relating to supramolecular chemistry in a number of review articles, among others with regard to hydrogen bonding interactions involving platinated nucleobases,26 and in particular on molecular architectures derived from the combination of metal ions and nucleobases, again with a focus on Pt-containing constructs.27, 28, 29, 30 In this chapter, we shall only repeat essential aspects from this earlier work and rather add more recent findings. Excellent articles on similar topics have been written also by other authors and shall explicitly be referred to Ref. 31, 32, 33, 34, 35, 36.
Section snippets
Supramolecular Chemistry: Nucleic Acids and Metal Ions
The phenomena of polynucleotide association into di- and polystranded DNA or highly folded RNA structures represent outstanding examples of supramolecular chemistry in that the basic secondary and tertiary interactions between individual strands encompass all the weak noncovalent interactions typical of supramolecular chemistry, namely, hydrogen bonding, π–π stacking, hydrophobic interactions, dipole–dipole contacts, metal ion–ligand bonding, etc.37 The sheer fact that the heterocyclic
Metal Coordination and Base Pairing
As small as they are, hydrogen-bonded base pairs are by definition supramolecular entities, and the same is true for pairs carrying metal ions at their periphery. The biological significance of metalated nucleobases relates to their stabilizing or destabilizing effects on nucleic acid structures as well as mispairing events in DNA leading to mutagenic events if not repaired. Depending on the site of metal binding and the specific metal ion, effects on acid–base equilibria47, 56 or nucleobase
Cross-Linking of Nucleobases
Next to hydrogen-bonded associates of metal-containing nucleobases, species of metal cross-linked nucleobases are most numerous. This is not surprising considering that assembling processes involving metal ions are at the heart of Supramolecular Chemistry and that nucleobases represent versatile ligands for metal ions (see above).
Cyclic Complexes and Metallacalix[n]arenes
To a large extent, the compounds discussed in the context of hydrogen bonding interactions between metalated nucleobases have dealt with metal entities displaying linear coordination geometries. In the following, we shall concentrate on compounds in which the metal entity provides bonds at an angle of 90 degrees. As a consequence, the nucleobases are no longer (close to) coplanar, but rather inclined, up to being perpendicular to each other. This situation applies to cyclic tri-,126 tetra-,31,
Stacking Interactions Involving Metalated Nucleobases
Although π–π stacking forces are major forces in supramolecular constructs,147 and the N-heterocyclic nucleobases are of utmost importance in stacking processes, the number of structurally confirmed cases of a combined action of metal coordination to a particular nucleobase and stacking is relatively rare. In stating this, we explicitly exclude the usual intermolecular packing of nucleobases seen within solid-state structures, unless reinforced by metal–metal interactions (e.g., argentophilic
Conclusions
As small as they are, supramolecular entities derived from model nucleobases and metal ions, as described in this text, do provide a wealth of insights, which assist the understanding of more complex systems involving nucleic acids. The element platinum, the protagonist among the metals discussed here, is by no means an ideal player in Supramolecular Chemistry and specifically not in the context of “coordination-driven self-assembly” processes. However, the behavior of PtII to frequently act as
Acknowledgments
The authors thank their Ph.D. students and colleagues, as indicated in the references, for their enthusiasm and help in getting the results presented here. Financial support from the Deutsche Forschungsgemeinschaft (DFG), the Technische Universität Dortmund, and the University of Zaragoza is gratefully acknowledged.
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