The Renaissance of MetalâPyrimidine Nucleobase Coordination

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The Renaissance of Metal−Pyrimidine Nucleobase Coordination Chemistry Bernhard Lippert*,† and Pablo J. Sanz Miguel*,‡ †

Fakultät für Chemie und Chemische Biologie (CCB), Technische Universität Dortmund, 44221 Dortmund, Germany Departamento de Química Inorgánica, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Universidad de Zaragoza−CSIC, 50009 Zaragoza, Spain

‡

CONSPECTUS: The significance of metal ions for the function and properties of DNA and RNA, long seen primarily under biological aspects and medicinal uses, has recently gained a renewed momentum. This is a consequence of the advent of novel applications in the fields of materials science, biotechnology, and analytical sensor chemistry that relate to the designed incorporation of transition metal ions into nucleic acid base pairs. Ag+ and Hg2+ ions, binding to pyrimidine (pym) nucleobases, represent major players in this development. Interestingly, these metal ions were the ones that some 60 years ago started the field! At the same time, the mentioned metal ions had demonstrated a “special relationship” with the pym nucleobases cytosine, thymine, and uracil! Parallel work conducted with oligonucleotides and model nucleobases fostered numerous significant details of these interactions, in particular when X-ray crystallography was involved, correcting earlier views occasionally. Our own activities during the past three to four decades have focused on, among others, the coordination chemistry of transition and main-group metal ions with pym model nucleobases, with an emphasis on PtII and PdII. It has always been our goal to deduce, if possible, the potential relevance of our findings for biological processes. It is interesting to put our data, in particular for trans-a2PtII (a = NH3 or amine), into perspective with those of other metal ions, notably Ag+ and Hg2+. Irrespective of major differences in kinetics and lability/inertness between d8 and d10 metal ions, there is also a lot of similarity in structural aspects as a result of the preferred linear coordination geometry of these species. Moreover, the apparent clustering of metal ions to the pym nucleobases, which is presumably essential for the formation of nanoclusters on oligonucleotide scaffolds, is impressively reflected in model systems, as are reasons for inter-nucleobase cross-links containing more than a single metal ion. The present understanding of these interrelationships is a consequence of intensive research carried out during the last 60 years by numerous laboratories. For space restrictions in this Account, it was impossible to adequately highlight the valuable contributions of all of the researchers in the field of metal−pym nucleobase interactions. Explicitly this refers to colleagues not cited in the references, e.g., R. Stuart Tobias, Robert Bau, R. Bruce Martin, Colin J. L. Lock, Katsuyuki Aoki, Helmut Sigel, and Michael J. Clarke, among others.

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INTRODUCTION

During the past few years a remarkable renaissance of interest in the reactions of transition metal ions with pym nucleobases has taken place, which is being spurred by a large number of promising new applications in analyte and DNA nanotechnology,8 most of which crucially depend on the formation of T−Hg−T and C−Ag−C cross-links in DNA molecules. For example, numerous ultrasensitive variants to detect Hg2+ in aqueous solutions are available today, the assembly of gold nanoparticles via T−Hg−T bonds or of DNA hydrogels via C−Ag−C bonds can be achieved, and singlenucleotide polymorphism can be probed by taking advantage of the affinity of Hg2+ for T. In regard to possible future applications, the generation of molecular wires, of Ag

When more than half a century ago details of transition metal− nucleic acid interactions began to emerge, reactions of Hg2+, CH3Hg+, and Ag+ with the pyrimidine (pym) nucleobases thymine (T), uracil (U), and cytosine (C) represented a major focus.1−5 In fact, relevant pym model complexes were among the first ones to be characterized by X-ray crystallography in the 1970s.6,7 Unlike the “natural” counterions of the negatively charged nucleic acids (K+, Na+, Mg2+), which, with few exceptions, interact preferentially with oxygen donor atoms of the phosphate groups in the backbone, these transition metal ions bind primarily to donor atoms of the heterocyclic bases. Even at an early stage it was recognized that preferences of individual metal ions exist: thus, Hg2+ ions prefer A,T (A = adenine)-rich DNA over G,C (G = guanine)-rich DNA, while for Ag+ it is the other way around.5 © XXXX American Chemical Society

Received: May 25, 2016

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DOI: 10.1021/acs.accounts.6b00253 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research

amino group cannot be protonated, not even in superacidic media.

nanoclusters of uniform size, and of logic gates are to be mentioned. In this Account, we will provide an overview of fundamental properties of the pym nucleobases T, U, and C relevant to metal coordination and base pairing and put these into perspective with the novel applications mentioned.

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PYM PAIRING PATTERNS In view of the number of endo- and exocyclic groups in the heterocyclic pym bases, it is not surprising that there is a series of possible homopairing patterns, many of which are seen in solid-state crystal structures and on surfaces or indirectly deduced from mass spectrometry data. In DNA usually pairing with the complementary purine (pu) nucleobases occurs, unless there is mispairing, in which case a destabilization of the double helix in the vicinity of the mismatch results. In RNA many more possibilities for base-pairing patterns exist. Association into planar or saddle-shaped cyclic quartets has been verified for all three pym bases, either by NMR spectroscopy, X-ray diffraction, or computational methods, subject to variations.10,11 U4 and T4 quartets usually have a cation in their center,12−16 a feature seen first in a model complex12 and subsequently confirmed in an RNA structure16 (Figure 2). The U quartet

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SELECTED PROPERTIES OF PYM NUCLEOBASES N1-blocked pym nucleobases occur predominantly in their dioxo (T, U) and amino,oxo (C) tautomer forms (Figure 1).

Figure 1. (top) Major tautomer and (bottom) one minor tautomer of T, U, and C. Also shown for C is a simplified mesomeric structure that is generally used in the literature although it does not reflect the actual electronic structure properly.

Rare tautomer forms have been implicated in mispairing scenarios and mutagenesis. The three common pym bases (N1blocked) are amphoteric. T and U are weak Brønsted acids (pKa values of N3H are on the order of 9−10), and C is a very weak acid (pKa of N4H2 ca. 15.5−17). At the same time, pym molecules are weak (C) or very weak (T, U) Brønsted bases. C can be protonated at N3 (pKa of N3H+ ca. 4 in isolated C yet may have higher values in specific cases, e.g., hemiprotonated CHC+ structures), but protonation of T and U occurs in superacidic media only. The three standard pym nucleobases can occur, in DNA and notably in RNA, in an ever-increasing number of modified versions brought about by post-transcriptional changes. Clearly, these modifications lead to changes in physicochemical properties, base-pairing patterns, and metal binding behavior. The nature of the exocyclic N4H2 amino group of C deserves some extra comment, in particular also with regard to its involvement in metal coordination (see below). Contrary to early views that this group has a lone electron pair available, very much as aliphatic amines or aniline, it is today clear that this is not the case. Rather, the “lone” pair is delocalized into the π-deficient aromatic ring, as evidenced by, among others, the shortness of the C4−N4 bond (ca. 1.32 Å) and the almost ideal sp2 hybridization of the N4 atom.9 Furthermore, the

Figure 2. Metal-stabilized cyclic pym aggregates.

reveals a hydrogen-bonding scheme analogous to that of the famous G quartet in its interior, but the pym quartet lacks the outer four hydrogen bonds, which makes it inferior to G4 as far as stability is concerned. An unusual triplet with unsubstituted C has been reported to form on a Au(111) surface in the presence of Ni atoms.17 This example is mentioned because the N1H position is not involved in either metal coordination or hydrogen-bond formation, suggesting that N1-substituted C may be capable of forming analogous triplets. A specialty of neutral C is its ability to accept a proton at its N3 position to form the cytosinium cation whenever this is advantageous for base pairing (Figure 3). In achieving this, either weakly acidic conditions or a favorable microenvironment is required (see above). Thus, it is well-known that in the Hoogsteen pair between G and C or in the C,G,C triple in fact one of the C bases is protonated and hence is present as CH. B


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M−OH and the weakly acidic proton, leading subsequently to a chelate intermediate, followed by migration of M to N4(C) or N3(T,U). Alternatively, initial nucleophilic attack of M−OH at C4 in T/U or C followed by metal coordination to N3 or N4, respectively, and liberation of H2O is also a possibility. The behavior of the catalytic ZnL(OH) center in carbonic anhydrase and that of related model Zn2+ complexes in binding to N3 of T and U could proceed in similar fashions.21 Enzymatic deamination of C to form U involves nucleophilic attack at C4 by a M−OH species.22 (ii) Reprotonation of metalated anionic pym ligands is possible, producing metal complexes with pym in their rare tautomeric structures. At least with kinetically robust metals such complexes have been crystallized in several cases (Figure 4).23,24 (iii) Deprotonated,

Figure 3. Protonated cytosine occurring in (a) the CHC+ pair, (b) the Hoogsteen pair GHC+, (c) a CGHC+ triplet, and (d) six CHC+ pairs in an i-motif. C and HC+ are shown in their simplified mesomeric forms.

Probably the best known example of this property of C is the occurrence of “hemiprotonated cytosine”. Here the two bases adopt a mutual trans orientation. In oligonucleotides the interacting strands need to be arranged in parallel fashion (“imotif”).18 This i-motif, in equilibrium with a hairpin structure, is believed to be realized in regions of double-stranded DNA opposite to G-quadruplex sequences, but it is unclear whether the two secondary DNA structures can coexist or are mutually exclusive.19

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Figure 4. X-ray crystal structures of PtII complexes containing simultaneously (a) major and minor C tautomers23 and (b) anionic U and the rare neutral U tautomer.24

METAL BINDING TO PYM NUCLEOBASES Patterns of metal binding to nucleobases in general and to pym nucleobases (N1 sites in all cases substituted by R′ groups) in particular have numerously been described. It therefore suffices to only summarize them quickly here. For cytosine, metal binding can occur at O2, N3, N4, and C5 as well as combinations thereof. For thymine, established metal binding sites are O2, N3, O4, and combinations thereof, and for uracil C5 is also a possibility. Generally speaking, metal ion binding to exocyclic O donors of pym nucleobases produces compounds of relatively low thermodynamic stability, unlike when deprotonated bases are involved. In special cases π complex formation via the C5−C6 double bond in pym bases has also been reported.20 There are some special features resulting from the above fundamental metal (M) binding patterns: (i) Binding of M to N4 or C5 of cytosine as well as to N3 of T/U or C5 of U requires proton loss from these sites. Provided that the M− aqua entity is moderately to strongly acidic, hence forming M− OH under physiological pH conditions, no high pH is required to achieve substitution of the proton by a metal ion. Relatively little is presently known regarding detailed mechanisms of such reactions involving nucleobase deprotonation and metal coordination. Feasible scenarios include direct electrophilic attack of the metal at NH or initial metal binding to an adjacent site, e.g., at N3 of C or O4 of T, allowing condensation between

metalated pym nucleobases have a tendency to add additional metal ions (identical or different) to other donor sites and hence to form multinuclear constructs. This is a consequence of the lower polarizing power of a metal compared with a proton, thereby increasing the overall basicity of the anionic pym ligand.25 Deprotonation of the pym base may be directly associated with binding of the first metal ion (U, T) or the consequence of a strong acidification of N4H2 of C following coordination of the first metal ion to N3 (Figure 5).

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METAL-MODIFIED BASE PAIRS AND LARGER AGGREGATES Nucleobase association patterns occurring through hydrogenbond formation between their constituents can be modified by replacing weakly acidic nucleobase protons by metal ions of suitable coordination geometries, preferably linear, trans square-planar, or trans octahedral ones, or by generating cross-links between unprotonated N or O sites. It is obvious that in double-stranded DNA, cross-links involving two opposite bases cause the least disturbance of the regular structure if the metal ion has a linear coordination geometry and hence carries no additional ligands. The term “metalmodified” base pair, used by us since the early 1990s, has largely C


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Hg2+-29 and Ag+-mediated30 pairs, respectively, provide structural details of these cross-links. The DNA molecule with the two T−Hg−T adducts (Figure 7a) adopts a largely

Figure 5. Principles of multinuclear complex formation of (top) U, T and (bottom) C.

been replaced today by the term “metal-mediated” base pair, but the latter is used generally if no additional hydrogen bonding between the two bases takes place (Figure 6). Typical

Figure 7. Schematic representations of Hg2+ base pairs: (a) T-N3,TN3, (b) G-N1,G-N1, (c) A-N6,T-O4, (d) A-N6,T-N3, (e) A-N6,U-C5, and (f) T-N3,C-C5.

unperturbed B-DNA structure, while the RNA with its two C− Ag−C adducts has an A-RNA structure. In both cases the metalated pym bases within the cross-links are in a head-tohead arrangement. Only for the T−Hg−T cross-link is a model compound available, in which the two parallel T’s (0.6 Å apart) display a head-to-tail orientation with two short Hg−N bonds and additional long contacts to six exocyclic O atoms, intramolecularly and intermolecularly involving O2 and O4 atoms.7 Similar features of an extended coordination geometry are seen with many “linear-coordinated” Hg(N-donor)2 compounds, possibly as a consequence of hybridization patterns involving 5d orbitals of Hg2+ that allow for an extension of the coordination geometry. In view of the fact that in T two exocyclic oxygen atoms are adjacent to the N3 sites, the difference between the relative base orientations in the model and real DNA is not crucial. It must be noted, however, that with natural DNA, T−Hg−T cross-linking causes a severe deviation from the regular B-DNA structure, consistent with Katz’ “strand slippage” model.2 The insertion of Hg2+ occurs with displacement of two protons from the T N3H sites, which is feasible as a consequence of the high acidity of the two aqua ligands of [Hg(OH2)2]2+, for which pKa1 = 3.7 and pKa2 = 2.6 (with pKa2 unexpectedly decreasing!). With the low basicity of the resulting OH groups in [Hg(OH)2], a simple acid−base mechanism leading to nucleobase deprotonation seems to be less likely than other routes (see above). On the other hand, a favorable preorganization of a thymine−(HO)Hg+ arrangement or favorable microenvironmental conditions within the DNA might facilitate a direct condensation again. Recently, a mechanism involving participation of a rare T tautomer in binding the second T has been proposed on the basis of density functional theory calculations.31

Figure 6. Differentiation between metal-mediated and metal-modified base pairs/base triplets.

examples are T−Hg−T and C−Ag−C as well as the numerous examples of “metal-mediated” pairs generated with artificial nucleobase surrogates in so-called M-DNA.26,27 The principle of “metal modification” has been extended by us also to larger nucleobase aggregates such as triplets and quartets.28

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THE SPECIAL CASES OF T−Hg−T AND C−Ag−C As mentioned in the Introduction, these two metal pym base pairs have markedly contributed to the present hype regarding metallo-base pairs and their applications. Two recently published X-ray crystal structures of DNA and RNA dodecamers with two T,T and two C,C mismatches and D


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Accounts of Chemical Research Since the pKa of guanine N1H is rather close to that of thymine, the question may be asked why T−Hg−T is so much favored over G−Hg−G? A possible answer could be the difference in the number of long intramolecular Hg−O contacts in the two cross-links: four in the case of T−Hg−T as opposed to two in G−Hg−G, accompanied by two unfavorable Hg··· NH2 contacts. The greater thermodynamic stability of T−Hg− T over G−Hg−G is also reflected by the redistribution of the mixed nucleobase complex T−Hg−G into the symmetrical T− Hg−T and G−Hg−G species (Figure 7b).32 The possibilities for Hg2+ coordination in more complex nucleic acid structures may not fully reflect the situation seen with isolated nucleobases, however, as the metal ion may have to compromise between large distortions caused by strandslippage reactions and weaker cross-linking products leading to less severe distortions. In fact, if for steric reasons T−Hg−T cannot form, HgII binds to GC sequences.33 Moreover, alternative T,A5,34,35 (Figures 7c-7e) and G,C cross-links in most cases would require only minor lateral shifts of the two nucleobases to accomplish metal binding. It should also be pointed out that the low acidity of the exocyclic amino group of A (pKa ca. 17) is no real obstacle to prevent condensation with a Hg−OH moiety even at neutral pH, as is evident from numerous model compounds. It is important to differentiate between Hg2+ salts that are fully dissociated in water (e.g., nitrate, perchlorate) and HgCl2, which is poorly dissociated. Indeed, binding of HgCl2 to nucleobases is different than that of [Hg(OH2)2]2+ in that it prefers to coordinate to neutral nucleobases, e.g., O4 of U6 or N3/O2 of C, while keeping the Cl ligands.36 (CH3)Hg+ behaves similar to [Hg(OH2)2]2+, albeit monofunctionally, and hence prefers to substitute weakly acidic protons.32 Finally, [Hg(OAc)2] has a pronounced affinity for the 5-positions of C and U, which is useful to probe unpaired C and U residues in DNA and RNA37 and has even been applied in synthesizing 5substituted pym nucleosides. These “mercuration” reactions follow an electrophilic aromatic substitution pathway. Most interesting in the present context is a recent observation according to which a Hg2+ ion positioned at the 5-position of a cytosine efficiently cross-links to T or G (with deprotonation), requiring a simple syn−anti switch of the glycosidic bond of C only (Figure 7f).38 Similar cross-links have been studied with 5mercurated U models.39 Unlike [Hg(OH2)2]2+, aqua cations of Ag+ are only very weakly acidic, with pKa1 values on the order of 11.9. Therefore, at acidic pH, Ag+ ions do not readily deprotonate nucleobases and consequently are expected to preferentially bind, with loss of aqua ligands, to unprotonated donor sites. C−Ag−C formation30 reflects this feature, as do the Hoogsteen C− Ag−G pairs in the C−Ag−G,C triplex40 or the C−Ag−A mispair.41 Coordination with concomitant nucleobase deprotonation is nevertheless possible, either at alkaline pH (or by applying Ag2O), with an excess of Ag+, and/or in combination with other transition metals already coordinated. For example, poly(rU) starts to become deprotonated by Ag+ above pH 6,42 and T’s in (TA′)9 (A′ = 7-deazaadenine) bind Ag+ through N3 at neutral pH.43 Once formed, U−Ag and T−Ag moieties are candidates for additional Ag+ coordination via exocyclic O sites (see above).25,44 This principle has been confirmed for DNA 15-mers containing mispairs of substituted pym′ bases in which the N3H has a lowered pKa.45 It is also true for Hoogsteen base pairs between T and 1,3-dideazaadenine in duplex DNA (Figure 8).46 Surprisingly a simple C−Ag−C model complex

Figure 8. Pym-containing Ag+ complexes in models, RNA,30 and DNA.40,43

has not been reported to date, but only a 2:2 complex with pairwise N3,O2 cross-linking and both Ag+ ions in distorted tetrahedral geometries.47 The latter is, however, an attractive model for an i-motif containing up to two Ag+ ions per step at short distances (see below). Although not unexpected for a d10 metal ion, it is striking that the coordination geometries of Ag+ in these complexes are rather variable, ranging from linear to (distorted) trigonal-planar and (distorted) tetrahedral.

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STRUCTURAL MODELS CONTAINING OTHER METAL IONS Studies carried out with linear metal entities other than Hg2+ and Ag+ have added much to our present understanding of pym coordination chemistry. With one exception (T−RhI−T48), in all cases the cross-linking metal had additional ligands, examples being trans-a2MII and trans-X2MII (a = NH3 or amine; X = halide; M = Pt or Pd), among others. Because the extra ligands (a, X) are well outside the pym planes, they do not have any marked influence on the two nucleobases. In particular, kinetically robust nucleobase complexes of transa2PtII with pym bases have been intensively studied,23,49−51 as have mixed pym,pu complexes52,53 (Figure 9). In fact, in many E


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concentrations of transition metal salts, e.g. of Ag+ via cation exchange, DNA can be loaded with the respective metal ion. Following reduction, and by repetition of this process, eventually electrically conducting “metalized” DNA nanowires can be obtained.60 Details regarding the primary metal coordination processes in both cases still await elucidation. Although model C complexes containing exclusively more than two closely spaced Ag+ are elusive at this stage, discrete heteronuclear C complexes having Pt2+ and Pd2+ in addition to Ag+ (Pt4Pd4Ag4C4,61 PtPdAg2C62) are available and reveal that as many as four metal ions can be bonded per single C nucleobase (Figure 10). Regretfully, experiments regarding the behavior of these complexes under reducing conditions are presently unavailable.

Figure 10. 1-Methylcytosine complexes revealing a multitude of metal coordination patterns possibly relevant to the formation of metal clusters at C sites: (a) discrete PtPdAg2C cation;60 (b) segment of Pt4Pd4Ag4C4.59

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Figure 9. X-ray structurally characterized model cross-links of transX2PtII (X = NH3, amine, or halide) involving pym bases.

PYM CROSS-LINKS WITH METAL COORDINATION GEOMETRIES OTHER THAN LINEAR Even tetrahedrally coordinated metal ions can form cross-links between two nucleobases while maintaining a coplanar arrangement! A unique model for such a scenario has been found in a trinuclear Zn2+ complex containing three pairs of C bases, coordinated differently through N3 and O2 each within each pair (Figure 11).63 The three Zn2+ ions are connected via μ-hydroxido bridges in such a way that the distances between the stacked C pairs are practically those between base pairs in unperturbed B-DNA. Mixed pym,pu cross-links based on the same principle are feasible. Similar models for Zn2+ binding to duplex DNA have been proposed, which at higher pH could include deprotonated sites, e.g., G-N1 and/or T-N3.64 Addition of a second tetrahedral Zn2+ across N3 and O2 in C−Zn−C removes the coplanarity of the cytosines as a result of the formation of an eight-membered metallacycle and orients the two bases in a parallel way, 1.21 Å apart.65 The question of whether cis square-planar or cis octahedral metal ions are able to cross-link two pym bases and keep these planar is to be answered in the affirmative: indeed, provided

cases Ag+ and trans-a2PtII are interchangeable40,54 or form analogous mixed-metal complexes. It is worth mentioning that G−Pt−C52 represents a perfect model of the most frequent interstrand cross-link of trans-(NH3)2PtII in DNA.55 Many of these PtII complexes with pym ligands have demonstrated their propensity to add other metal ions to form multinuclear complexes, frequently with short intermetallic contacts and metal−metal bonding.56 Some of these compounds may indeed be relevant to the topics of DNAassociated luminescent metal clusters and metalized DNA, in particular those containing Ag, which have received great attention in recent years.57 As this process is preceded by coordination of Ag+ ions to DNA followed by reduction, it would appear that any spot on DNA containing several Ag+ ions at close distances might be an ideal site for initiation of cluster formation. DNA mismatches or bulges facilitate cluster formation,58 and contiguous cytosines seem to be preferred initiation points.59 Similarly, by applying relatively high F


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Figure 11. X-ray structurally characterized C,C cross-link by tetrahedral Zn2+ (top)61 and feasible mixed C,G cross-links based on analogous principles (bottom). Figure 12. Segments of (a, b) T4 with K+,15 (c) U4 with Na+,12 and hypothetical (d) TAT−M and (e, f) C−M−C structures involving 90° angles at the metal ion.

that the metal binds to two exocyclic donor atoms or a combination of endocyclic and exocyclic donors, this should be possible! U4 and T4 quartets (cf. Figure 2) contain arrangements of the first type, as would also have the two orthogonally disposed T’s in TAT triplets. Softer metals could feasibly crosslink two cytosines also via N3,O2 or even N3,N4 sites (Figure 12).

analytical sciences and DNA nanotechnology provide ample evidence that the field is alive, albeit still lacking ultimate explanations for all of the phenomena observed.

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PYM NUCLEOBASES AS BUILDING BLOCKS IN METALLACYCLIC SYSTEMS Of definitive significance are square-planar metal entities of the kind cis-a2MII (a = NH3 or amine or a2 = diamine or diimine; M = Pt or Pd) when it comes to generating cyclic constructs containing pym building blocks, with pym representing either the parent (unsubstituted) nucleobase, an N1-alkylated model base, or two pym bases covalently linked via their C5 positions directly or through a methylene bridge. It is beyond the scope of this Account to describe in detail their coordination chemistry, but it is obvious that the increase in metal coordination sites increases the number of possible variants (trimers, tetramers, hexamers, double and triple deckers, etc.). The interested reader is referred to the literature.66,67

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Bernhard Lippert is retired Professor of Bioinorganic Chemistry at Technische Universität (TU) Dortmund. After having received a Ph.D. degree at TU München in 1974, he joined the group of Barnett Rosenberg in the Biophysics Department at Michigan State University as a postdoctoral fellow and adjunct Assistant Professor for more than two years. After his return to TU München and following his habilitation, he was appointed Privatdozent at TU München in 1982 and subsequently Associate Professor at the University of Freiburg in 1985. In 1988 he was promoted to a chair at Dortmund. His primary research interests include metal−nucleic acid chemistry and supramolecular chemistry involving nucleobases.

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CONCLUSION The metal-coordinating properties of the purine nucleobases G and A have in a way dominated the past three decades, primarily and rightly, because of their significance regarding the preferred reactions of antitumor Pt drugs with these targets. This Account is intended to remind the interested audience that there are also the pyrimidine nucleobases, which have given a lot of excitement to the field of metal−nucleic acid interactions and still do so! The numerous novel applications in

Pablo J. Sanz Miguel is Associate Professor (PCDI) at the University of Zaragoza. He completed his Ph.D. degree in 2005 at the University of Dortmund. Following postdoctoral work in Dortmund, he joined the Nanostructures group of Félix Zamora (University Autónoma de Madrid) within the “Juan de la Cierva” Program before returning again G


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Accounts of Chemical Research to Dortmund. In 2010 he was awarded a “Ramón y Cajal” Fellowship and moved to Zaragoza. He is interested in sophisticated metal−ligand constructs with potential biological relevance or the ability to capture small molecules or interact with DNA and in metallophilic bonding approaches.

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ACKNOWLEDGMENTS The authors thank the Deutsche Forschungsgemeinschaft (DFG) and the University of Zaragoza for financial support and Prof. Jens Müller, Münster, for helpful discussions.

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REFERENCES

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