"Metal-modified base pairs" vs. "metal-mediated pairs of bases": not just a semantic issue!

A "nucleobase pair" is not identical with a "pair of basic ligands", as only in the first case, the existence of inter-base hydrogen bonds is implied. The cross-linking of two nucleobases or two basic ligands by a metal ion of suitable geometry produces either "metal-modified" or "metal-mediated" species, but in the author's opinion, this difference is not always properly made. This commentary is an attempt to provide a clearer distinction between the two scenarios.

Mixed guanine, adenine base quartets: possible roles of protons and metal ions in their stabilization.

Structural variations of the well-known guanine quartet (G4) motif in nucleic acid structures, namely substitution of two guanine bases (G) by two adenine (A) nucleobases in mutual trans positions, are discussed and studied by density functional theory (DFT) methods. This work was initiated by three findings, namely (1) that GA mismatches are compatible with complementary pairing patterns in duplex-DNA structures and can, in principle, be extended to quartet structures, (2) that GA pairs can come in several variations, including with a N1 protonated adeninium moiety (AH), and (3) that cross-linking of the major donor sites of purine nucleobases (N1 and N7) by transition metal ions of linear coordination geometries produces planar purine quartets, as demonstrated by some of us in the past. Here, possible structures of mixed AGAG quartets both in the presence of protons and alkali metal ions are discussed, and in particular, the existence of a putative four-purine, two-metal motif.

The Renaissance of Metal-Pyrimidine Nucleobase Coordination Chemistry.

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 Hg(2+) 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 Pt(II) and Pd(II). 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-a2Pt(II) (a = NH3 or amine), into perspective with those of other metal ions, notably Ag(+) and Hg(2+). Irrespective of major differences in kinetics and lability/inertness between d(8) and d(10) 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.

The exocyclic amino group of adenine in PtII and PdII complexes: a critical comparison of the X-ray crystallographic structural data and gas phase calculations.

A detailed computational (DFT level of theory) study regarding the nature of the exocyclic amino group, N6H2, of the model nucleobase 9-methyladenine (9MeA) and its protonated (9MeAH+) and deprotonated forms (9MeA-H), free and metal-complexed, has been conducted. The metals are PtII and PdII, bonded to nitrogen-containing co-ligands (NH3, dien, bpy), with N1, N6, and N7 being the metal-binding sites, individually or in different combinations. The results obtained from gas phase calculations are critically compared with X-ray crystallography data, whenever possible. In the majority of cases, there is good qualitative agreement between calculated and experimentally determined C6-N6 bond lengths, but calculated values always show a trend to larger values, by 0.02-0.08 Å. Both methods indicate, with few exceptions, a high degree of double-bond character of C6-N6, consistent with an essentially sp2-hybridized N6 atom. The shortest values for C6-N6 distances in X-ray crystal structures are around 1.30 Å. Exceptions refer to cases in which DFT calculations suggest the existence of a hydrogen bond with N6H2 acting as a H bond acceptor, hence a situation with N6 having undergone a substantial hybridization shift toward sp3. Nevertheless, even in these cases the C6-N6 bond (1.392 Å) is still halfway between a typical C-N single bond (1.48 Å) and a typical C=N double bond (1.28 Å). This scenario is, however, not borne out by X-ray crystallographic results, and is attributed to the absence of counter anions and solvent molecules in the calculated structures.

Multiple Condensation Reactions Involving Pt(II) /Pd(II) -OH2 , Pt-NH3 , and Cytosine-NH2 Groups: New Twists in Cisplatin-Nucleobase Chemistry.

The coordination chemistry of the antitumor agent cisplatin and related complexes with DNA and its constituents, that is, the nucleobases, appears to be dominated by 1:1 and 1:2 adducts of the types cis-[Pta2 (nucleobase)X] and cis-[Pta2 (nucleobase)2 ] (a=NH3 or amine; a2 =diamine or diimine; X=Cl, OH or OH2 ). Here, we have studied the interactions of the putative 1:1 adducts cis-[Pta2 (1-MeC-N3)(OH2 )](2+) (with a=NH3 , a2 =2,2'-bpy (2,2'-bipyridine), 1-MeC=model nucleobase 1-methylcytosine) with additional cis-[Pt(NH3 )2 (OH2 )2 ](2+) or its kinetically superior analogues [Pd(en)(OH2 )2 ](2+) (en=ethylenediamine) and [Pd(2,2'-bpy)(OH2 )2 ](2+) . Depending upon the conditions applied different compounds of different nuclearity are formed. Without exception they represent condensation products of the components, containing µ-1-MeC-H , µ-OH(-) , as well as µ-NH2 (-) bridges. In the presence of Ag(+) ions, the isolated products in several cases display additionally Pt→Ag dative bonds. On the basis of the cytosine-containing structures established by X-ray crystallography, it is proposed that any of the feasible initial 1:1 nucleobase adducts of cisplatin could form dinuclear Pt complexes upon reaction with additional hydrolyzed cisplatin, thereby generating nucleobase adducts other than the presently established ones. Two findings appear to be of particular significance: First, hydrolyzed cisplatin can have a moderately accelerating effect on the formation of a secondary nucleobase product. Second, NH3 ligands of the cisplatin moiety can be converted into bridging amido ligands following condensation with the diaqua species of cisplatin.

The challenge of deciphering linkage isomers in mixtures of oligomeric complexes derived from 9-methyladenine and trans-(NH3)2Pt(II) units.

Metal coordination to N9-substituted adenines, such as the model nucleobase 9-methyladenine (9MeA), under neutral or weakly acidic pH conditions in water preferably occurs at N1 and/or N7. This leads, not only to mononuclear linkage isomers with N1 or N7 binding, but also to species that involve both N1 and N7 metal binding in the form of dinuclear or oligomeric species. Application of a trans-(NH3)2Pt(II) unit and restriction of metal coordination to the N1 and N7 sites and the size of the oligomer to four metal entities generates over 50 possible isomers, which display different feasible connectivities. Slowly interconverting rotamers are not included in this number. Based on (1)H NMR spectroscopic analysis, a qualitative assessment of the spectroscopic features of N1,N7-bridged species was attempted. By studying the solution behavior of selected isolated and structurally characterized compounds, such as trans-[PtCl(9MeA-N7)(NH3)2]ClO4⋅2H2O or trans,trans-[{PtCl(NH3)2}2(9MeA-N1,N7)][ClO4]2⋅H2O, and also by application of a 9MeA complex with an (NH3)3Pt(II) entity at N7, [Pt(9MeA-N7)(NH3)3][NO3]2, which blocks further cross-link formation at the N7 site, basic NMR spectroscopic signatures of N1,N7-bridged Pt(II) complexes were identified. Among others, the trinuclear complex trans-[Pt(NH3)2{µ-(N1-9MeA-N7)Pt(NH3)3}2][ClO4]6⋅2H2O was crystallized and its rotational isomerism in aqueous solution was studied by NMR spectroscopy and DFT calculations. Interestingly, simultaneous Pt(II) coordination to N1 and N7 acidifies the exocyclic amino group of the two 9MeA ligands sufficiently to permit replacement of one proton each by a bridging heterometal ion, Hg(II) or Cu(II), under mild conditions in water.

Analogues of Cis- and Transplatin with a Rich Solution Chemistry: cis-[PtCl2 (NH3 )(1-MeC-N3)] and trans-[PtI2 (NH3 )(1-MeC-N3)].

Mono(nucleobase) complexes of the general composition cis-[PtCl2 (NH3 )L] with L=1-methylcytosine, 1-MeC (1 a) and L=1-ethyl-5-methylcytosine, as well as trans-[PtX2 (NH3 )(1-MeC)] with X=I (5 a) and X=Br (5 b) have been isolated and were characterized by X-ray crystallography. The Pt coordination occurs through the N3 atom of the cytosine in all cases. The diaqua complexes of compounds 1 a and 5 a, cis-[Pt(H2 O)2 (NH3 )(1-MeC)](2+) and trans-[Pt(H2 O)2 (NH3 )(1-MeC)](2+) , display a rich chemistry in aqueous solution, which is dominated by extensive condensation reactions leading to µ-OH- and µ-(1-MeC(-) -N3,N4)-bridged species and ready oxidation of Pt to mixed-valence state complexes as well as diplatinum(III) compounds, one of which was characterized by X-ray crystallography: h,t-[{Pt(NH3 )2 (OH)(1-MeC(-) -N3,N4)}2 ](NO3 )2 ⋅2 [NH4 ](NO3 )⋅2 H2 O. A combination of (1) H NMR spectroscopy and ESI mass spectrometry was applied to identify some of the various species present in solution and the gas phase, respectively. As it turned out, mass spectrometry did not permit an unambiguous assignment of the structures of +1 cations due to the possibilities of realizing multiple bridging patterns in isomeric species, the occurrence of different tautomers, and uncertainties regarding the Pt oxidation states. Additionally, compound 1 a was found to have selective and moderate antiproliferative activity for a human cervix cancer line (SISO) compared to six other human cancer cell lines.

Rationalizing the structural variability of the exocyclic amino groups in nucleobases and their metal complexes: cytosine and adenine.

The exocyclic amino groups of cytosine and adenine nucleobases are normally almost flat, with the N atoms essentially sp(2) hybridized and the lone pair largely delocalized into the heterocyclic rings. However, a change to marked pyramidality of the amino group (N then sp(3) hybridized, lone pair essentially localized at N) occurs during i) involvement of an amino proton in strong hydrogen bonding donor conditions or ii) with monofunctional metal coordination following removal of one of the two protons.

Mixed adenine/guanine quartets with three trans-a2 Pt(II) (a=NH(3) or MeNH(2)) cross-links: linkage and rotational isomerism, base pairing, and loss of NH(3).

Of the numerous ways in which two adenine and two guanines (N9 positions blocked in each) can be cross-linked by three linear metal moieties such as trans-a2 Pt(II) (with a=NH3 or MeNH2 ) to produce open metalated purine quartets with exclusive metal coordination through N1 and N7 sites, one linkage isomer was studied in detail. The isomer trans,trans,trans-[{Pt(NH3 )2 (N7-9-EtA-N1)2 }{Pt(MeNH2 )2 (N7-9-MeGH)}2 ][(ClO4 )6 ]⋅3H2 O (1) (with 9-EtA=9-ethyladenine and 9-MeGH=9-methylguanine) was crystallized from water and found to adopt a flat Z-shape in the solid state as far as the trinuclear cation is concerned. In the presence of excess 9-MeGH, a meander-like construct, trans,trans,trans-[{Pt(NH3 )2 (N7-9-EtA-N1)2 }{Pt(MeNH2 )2 (N7-9-MeGH)2 }][(ClO4 )6 ]⋅[(9-MeGH)2 ]⋅7 H2 O (2) is formed, in which the two extra 9-MeGH nucleobases are hydrogen bonded to the two terminal platinated guanine ligands of 1. Compound 1, and likewise the analogous complex 1 a (with NH3 ligands only), undergo loss of an ammonia ligand and formation of NH4 (+) when dissolved in [D6 ]DMSO. From the analogy between the behavior of 1 and 1 a it is concluded that a NH3 ligand from the central Pt atom is lost. Addition of 1-methylcytosine (1-MeC) to such a DMSO solution reveals coordination of 1-MeC to the central Pt. In an analogous manner, 9-MeGH can coordinate to the central Pt in [D6 ]DMSO. It is proposed that the proton responsible for formation of NH4 (+) is from one of the exocyclic amino groups of the two adenine bases, and furthermore, that this process is accompanied by a conformational change of the cation from Z-form to U-form. DFT calculations confirm the proposed mechanism and shed light on possible pathways of this process. Calculations show that rotational isomerism is not kinetically hindered and that it would preferably occur previous to the displacement of NH3 by DMSO. This displacement is the most energetically costly step, but it is compensated by the proton transfer to NH3 and formation of U(-H(+) ) species, which exhibits an intramolecular hydrogen bond between the deprotonated N6H(-) of one adenine and the N6H2 group of the other adenine. Finally the question is examined, how metal cross-linking patterns in closed metallacyclic quartets containing two adenine and two guanine nucleobases influence the overall shape (square, rectangle, trapezoid) and the planarity of a metalated purine quartet.

A conformationally flexible dinuclear Pt(II) complex with differential behavior of its two states toward quadruplex DNA.

The reaction of tetrakis(pyridine-2-yl)pyrazine (tppz) with 2 equiv of (2,2'-bpy)Pt(II) in water yields two isomeric dinuclear cations, [{Pt(2,2'-bpy)}2 (tppz)](4+) , in which Pt coordination exclusively takes place through the two pairs of pyridine-2-yl nitrogen atoms. The two conformational isomers differ in their overall shape, with the formation of "Z" and "U" shapes, which are formed at 40 °C (Z isomer, 1) and under reflux conditions (U isomer, 2), respectively. X-ray crystal-structure analyses of the Z isomer, [{Pt(2,2'-bpy)}2 (tppz)](PF6 )4 ⋅3 CHCl3 ⋅4 H2 O (1 a), and of the U isomer, [{Pt(2,2'-bpy)}2 ](PF6 )4 ⋅2 CH3 CN⋅1.5 H2 O (2 a), were carried out. Co-crystallization of compound 2 with PtCl2 (2,2'-bpy) yielded [{Pt(2,2'-bpy)}2 (tppz)](BF4 )4 ⋅[PtCl2 (2,2'-bpy)]⋅4.5 H2 O (3), in which the PtCl2 (2,2'-bpy) entity was sandwiched between the two 2,2'-bpy faces of the U-shaped cation (2). Quantum chemical calculations revealed that the U isomer was more stable than the Z isomer, both in the gas phase and in an aqueous environment. These two isomers display different affinities toward duplex DNA and human telomeric quadruplex DNA (Htelo), as concluded from CD spectroscopy and FID assays. Thus, the U isomer binds significantly more strongly to quadruplex DNA (DC50 =0.38 µM) than the Z isomer (DC50 =8.50 µM).

Stepwise coordination of Pt(II)-180° and Pd(II)-90° metal fragments to the purine nucleobase 9-methylhypoxanthine affords a closed octadecanuclear Pt6Pd12 cluster.

Crossing the line: A pH-induced "crossover" in 3D shapes of supramolecular constructs derived from trans(NH3)2Pt(II), [Pd(II)(en)], and the purine model nucleobase 9-methylhypoxanthine (see figure) is reported in which [Pd(en)(H2O)](2+) and [Pd(en)(OH)](+) are the decisive players (en = ethylenediamine).

Different rotamer states of cytosine nucleobases in heteronuclear PtPd-, PtPd2, and Pt2Pd2Ag complexes derived from [Pt(2,2'-bpy)(1-MeC-N3)2]2+ (1-MeC = 1-methylcytosine): first examples of species with head-head oriented 1-MeC(-) ligands.

[Pt(2,2'-bpy)(1-MeC-N3)(2)](NO(3))(2) (1) (2,2'-bpy = 2,2'-bipyridine; 1-MeC = 1-methylcytosine) exists in water in an equilibrium of head-tail and head-head rotamers, with the former exceeding the latter by a factor of ca. 20 at room temperature. Nevertheless, 1 reacts with (en)Pd(II) (en = ethylenediamine) to give preferentially the dinuclear complex [Pt(2,2'-bpy)(1-MeC(-)-N3,N4)(2)Pd(en)](NO(3))(2)·5H(2)O (2) with head-head arranged 1-methylctosinato (1-MeC(-)) ligands and Pd being coordinated to two exocyclic N4H(-) positions. Addition of AgNO(3) to a solution of 2 leads to formation of a pentanuclear chain compound [{Pt(2,2'-bpy)(1-MeC(-))(2)Pd(en)}(2)Ag](NO(3))(5)·14H(2)O (5) in which Ag(+) cross-links two cations of 2 via the four available O2 sites of the 1-MeC(-) ligands. 2 and 5 appear to be the first X-ray structurally characterized examples of di- and multinuclear complexes derived from a Pt(II) species with two cis-positioned cytosinato ligands adopting a head-head arrangement. (tmeda)Pd(II) (tmeda = N,N,N',N'-tetramethylethylenediamine) and (2,2'-bpy)Pd(II) behave differently toward 1 in that in their derivatives the head-tail orientation of the 1-MeC(-) nucleobases is retained. In [Pt(2,2'-bpy)(1-MeC(-))(2){Pd(2,2'-bpy)}(2)](NO(3))(4)·10H(2)O (4), both (2,2'-bpy)Pd(II) entities are pairwise bonded to N4H(-) and O2 sites of the two 1-MeC(-) rings, whereas in [Pt(2,2'-bpy)(1-MeC(-))(2){Pd(tmeda)}(2)(NO(3))](NO(3))(3)·5H(2)O (3) only one of the two (tmeda)Pd(II) units is chelated to N4H(-) and O2. The second (tmeda)Pd(II) is monofunctionally attached to a single N4H(-) site. On the basis of these established binding patterns, ways to the formation of mixed Pt/Pd complexes and possible intermediates are proposed. The methylene protons of the en ligand in 2 are special in that they display two multiplets separated by 0.64 ppm in the (1)H NMR spectrum.

Multiple metal binding to the 9-methyladenine model nucleobase involving N1, N6, and N7: discrete di- and trinuclear species with different combinations of monofunctional Pd(II) and Pt(II) entities.

Several di- and trinuclear metal complexes consisting of the model nucleobase 9-methyladenine (9-MeA) or its mono-deprotonated form (9-MeA(-)) and monofunctional (dien)Pd(II), (dien)Pt(II), (NH(3))(3)Pt(II), or (trpy)Pd(II) in different combinations have been prepared and/or studied in solution by NMR spectroscopy: [{Pd(dien)}(3)(9-MeA(-)-N1,N6,N7)]Cl(3.5)(PF(6))(1.5)·3H(2)O (1), [(dien)Pd(N1-9-MeA-N7)Pt(NH(3))(3)](ClO(4))(4)·9.33H(2)O (2), [(dien)Pt(N1-9-MeA-N7)Pt(NH(3))(3)](ClO(4))(4)·H(2)O (3), and [{(trpy)Pd}(2)(N1,N6-9-MeA(-)-N7)Pt(NH(3))(3)](ClO(4))(5)·3H(2)O (4). A migration product of 3, [(dien)Pt(N6-9-MeA(-)-N7)Pt(NH(3))(3)](3+) (3a), has been identified in solution. Unlike Pt-adenine bonds, Pd-adenine bonds are substantially labile, and consequently all Pd-containing complexes discussed here (1, 2, 4) exist in aqueous solution in equilibria of slowly interconverting species, which give rise to individual resonances in the (1)H NMR spectra. For example, 1 exists in an equilibrium of five adenine-containing species when dissolved in D(2)O, 2 undergoes dissociation to [Pt(NH(3))(3)(9-MeA-N7)](2+) or forms the migration product [(dien)Pd(N6-9-MeA(-)-N7)Pt(NH(3))(3)](3+) (2a), depending on pD, and 4 loses both (trpy)Pd(II) entities as the pD is increased. In no case is Pd binding to N3 of the adenine ring observed. A comparison of the solid-state structures of the two trinuclear complexes 1 and 4 reveals distinct differences between the Pd atoms bonded to N1 and N6 in that these are substantially out of the nucleobase plane in 1, by ca. 0.6 Å and -1.0 Å, respectively, whereas they are coplanar with the 9-MeA(-) plane in 4. These out-of-plane movements of the two (dien)Pd(II) units in 1 are not accompanied by changes in hybridization states of the N1 and N6 atoms.

Metallatriangles and metallasquares: the diversity behind structurally characterized examples and the crucial role of ligand symmetry.

Reports on spontaneous self-assembly processes between metal fragments and organic ligands frequently tend to ignore the fact that the product isolated and structurally characterized in most cases is only one out of a more or less large series of feasible ones. This is true even for rings containing as few as three or four metal ions. Here we shall review metallatriangles and metallasquares containing predominantly cis-square-planar metal entities and a range of bidentate bridging ligands. The most significant features contributing to the number of possible stereoisomers appear to be ligand symmetry and flexibility, viz. rotation of two halves of a ligand about a single bond, or rotation of the whole ligand about the metal-donor atom bonds. With low-symmetry bidentate ligands the number of isomers increases dramatically with ring size as a consequence of an increase in possible connectivity patterns, hence linkage isomers, and an increase in possible rotamer states of the bridging ligands. In this tutorial review it is demonstrated how complexity increases as the symmetry of the bridging ligands is lowered from D(∞h) and D(2h) to C(∞v), C(2v), C(2h) and C(s). Special attention will be paid to cyclic tri- and tetranuclear complexes of substituted pyrimidine ligands (C(2v) and C(s) symmetries) as well as the flexible 2,2'-bipyrazine, which can adopt states of either C(2v) or C(2h) symmetry. Uses of these complexes and ways to reduce the number of isomers will be pointed out.

"Directed" assembly of metallacalix[n]arenes with pyrimidine nucleobase ligands of low symmetry: metallacalix[n]arene derivatives of cis-[a2M(cytosine-N3)2]2+ (M=Pt(II), Pd(II); n=4 and 6).

Pyrimidine (pym) ligands with their two endocyclic N-donor atoms provide 120° angles for molecular constructs, which, with the 90° angle metal fragments cis-a(2)M(II) (M=Pt, Pd; a=NH(3) or a(2)=diamine), form cyclic complexes known as metallacalix[n]arenes (with n=3, 4, 6, 8, …). The number of possible isomers of these species depends on the symmetry of the pym ligand. Although highly symmetrical (C(2v)) pym ligands form a single linkage isomer for any n and can adopt different conformations (e.g., cone, partial cone, 1,3-alternate, and 1,2-alternate in the case of n=4), low-symmetry pym ligands (C(s)) can produce a higher number of linkage isomers (e.g., four in the case of n=4) and a large number of different conformers. In the absence of any self-sorting bias, the number of possible species derived from a self-assembly process between cis-a(2)M(II) and a C(s)-symmetrical pym ligand can thus be very high. By using the C(s)-symmetric pym nucleobase cytosine, we have demonstrated that the number of feasible isomers for n=4 can be reduced to one by applying preformed building blocks such as cis-[a(2)M(cytosine-N3)(2)](n+) or cis-[a(2)M(cytosinate-N1)(2)] (for the latter, see the accompanying paper: A. Khutia, P. J. Sanz Miguel, B. Lippert, Chem. Eur. J. 2011, 17, DOI: 10.1002/chem.2010002723) and treating them with additional cis-a(2)M(II) . Moreover, intramolecular hydrogen-bonding interactions between the O2 and N4H(2) sites of the cytosine ligands reduce the number of possible rotamers to one. This approach of the "directed" assembly of a defined metallacalix[4]arene is demonstrated.

"Directed" assembly of metallacalix[n]arenes with pyrimidine nucleobase ligands of low symmetry: interchanging metals in mixed-metal metallacalix[4]arenes and incorporating additional metals at the exocyclic groups.

The pyrimidine (pym) nucleobase cytosine (H(2)C) forms cyclic ring structures ("metallacalix[n]arenes") when treated with square-planar cis-a(2)M(II) entities (M=Pt, Pd; a=NH(3) or a(2)=diamine). The number of possible linkage isomers for a given n and the number of possible rotamers can be substantially reduced if a "directed" approach is pursued. Hence, two cytosine ligands are bonded in a defined way to a kinetically robust platinum corner stone. In the accompanying paper (Part I: A. Khutia, P. J. Sanz Miguel, B. Lippert, Chem. Eur. J. 2010, 17, DOI: 10.1002/chem.2010002722) we have demonstrated this principle by allowing cis-[Pta(2)(H(2)C-N3)(2)](2+) to react with (en)Pd(II) to give cycles of (N1,N3⋅N3,N1▪)(x) (with x=2 or 3; ⋅ represents Pt(II) and ▪ represents Pd(II)). In an extension of this work we have now prepared cis-[Pta(2)(HC-N1)(2)] (1; HC=monoanion of cytosine) and treated it with (bpy)Pd(II) (bpy=2,2'-bipyridine) to give the Pt(2) Pd(2) cycle cis-[{Pt(NH(3))(2)(N1-HC-N3)(2)Pd(bpy)}(2)](NO(3))(4) ⋅13H(2)O (5) with the coordination sites of the metals inverted; hence, platinum is bonded to N1 and palladium is bonded to N3 sites. Again, not only the expected single linkage isomer is formed, but at the same time the solid-state structure and (1)H NMR spectroscopy reveal the preferential occurrence of a single rotamer (1,3-alternate). The addition of (bpy)Pd(II) to 5 led to the formation of Pd(6) Pt(2) complex 6 in which the exocyclic N4H(2) groups of the cytosine ligands have undergone deprotonation and chelate four more (bpy)Pd(II) entities through the O2 and N4H sites. With a large excess of (bpy)Pd(II) over 5 (4:1), cis-(NH(3))(2) Pt(II) is eventually substituted by (bpy)Pd(II) to give the Pd(8) complex 7. In both 6 and 7 stacks of three (bpy)Pd(II) entities occur. The linkage isomer of 5,cis-[{Pt(NH(3))(2)(N3-HC-N1)(2)Pd(bpy)}(2)](NO(3))(4) ⋅9H(2)O (8), has been structurally characterized and the two complexes compared. The acid/base properties of cis-[Pt(NH(3))(2)(H(2)C-N1)(2)] (1) have been determined and compared with those of the corresponding N3 isomer. The complexation of AgCl by 1 is reported.

Supramolecular isomerism of 2,2'-bipyrazine complexes with cis-(NH(3))(2)Pt(II): ligand rotational state and sequential orientation determine the 3D shape of metallacycles.

2,2'-Bipyrazine (2,2'-bpz) reacts with cis-(NH(3))(2)Pt(II) in water to give a variety of products, several of which were isolated and characterized by X-ray analysis: cis-[Pt(NH(3))(2)(2,2'-bpz-N4)(2)](NO(3))(2)·3H(2)O (1), [{cis-Pt(NH(3))(2)(2,2'-bpz-N4,N4')}(3)]-(PF(6))(5)NO(3)·7H(2)O (2a), [{cis-Pt(NH(3))(2)(2,2'-bpz-N4,N4')}(3)](BF(4))(2)-(SiF(6))(2)·15H(2)O (2b), and [{cis-Pt(NH(3))(2)(2,2'-bpz-N4,N4')}(4)]-(SO(4))(4)·22H(2)O (3). In 1, 2b, and 3 the 2,2'-bpz ligands adopt approximately C(2h) symmetries, hence the two pyrazine halves are in trans orientation, whereas in 2a all three 2,2'-bpz bridges are approximately C(2v) symmetric, with the pyrazine halves cis to each other. The topologies of the two triangular complexes 2a and 2b are consequently distinctly different, but nevertheless both cations act as hosts for anions. In 2a a PF(6)(-) and a NO(3)(-) anion are associated simultaneously with the +6 cation, whereas in 2b it is a BF(4)(-) anion and a water molecule, which are trapped in its cavity. There is no anion inclusion in case of the metallasquare 3. In principle, 3 can exist in a large number of stereoisomers, depending on the rotational states of the bridging 2,2'-bpz ligands. Isolation of a single rotamer form of 3 with C(2h) symmetric 2,2'-bpz ligands and an overall meso form is proposed to be a consequence of a highly efficient self-assembly process that starts from the precursor 1 and reaction with two cis-(NH(3))(2)Pt(II) units. This process leads to the isolated rotamer of 3 regardless of whether two cations 1 in head-head form react with two cis-(NH(3))(2)Pt(II), or whether the Δ enantiomer of the chiral head-tail form of 1 combines with its Λ enantiomer through two cis-(NH(3))(2)Pt(II) entities.

Pt(II) coordination to N1 of 9-methylguanine: why it facilitates binding of additional metal ions to the purine ring.

The preparation and X-ray crystal structure analysis of {trans-[Pt(MeNH(2))(2)(9-MeG-N1)(2)]}⋅{3 K(2)[Pt(CN)(4)]}⋅6 H(2)O (3 a) (with 9-MeG being the anion of 9-methylguanine, 9-MeGH) are reported. The title compound was obtained by treating [Pt(dien)(9-MeGH-N7)](2+) (1; dien=diethylenetriamine) with trans-[Pt(MeNH(2))(2)(H(2)O)(2)](2+) at pH 9.6, 60 °C, and subsequent removal of the [(dien)Pt(II)] entities by treatment with an excess amount of KCN, which converts the latter to [Pt(CN)(4)](2-). Cocrystallization of K(2)[Pt(CN)(4)] with trans-[Pt(MeNH(2))(2)(9-MeG-N1)(2)] is a consequence of the increase in basicity of the guanine ligand following its deprotonation and Pt coordination at N1. This increase in basicity is reflected in the pK(a) values of trans-[Pt(MeNH(2))(2)(9-MeGH-N1)(2)](2+) (4.4±0.1 and 3.3±0.4). The crystal structure of 3 a reveals rare (N7,O6 chelate) and unconventional (N2,C2,N3) binding patterns of K(+) to the guaninato ligands. DFT calculations confirm that K(+) binding to the sugar edge of guanine for a N1-platinated guanine anion is a realistic option, thus ruling against a simple packing effect in the solid-state structure of 3 a. The linkage isomer of 3 a, trans-[Pt(MeNH(2))(2)(9-MeG-N7)(2)] (6 a) has likewise been isolated, and its acid-base properties determined. Compound 6 a is more basic than 3 a by more than 4 log units. Binding of metal entities to the N7 positions of 9-MeG in 3 a has been studied in detail for [(NH(3))(3)Pt(II)], trans-[(NH(3))(2)Pt(II)], and [(en)Pd(II)] (en=ethylenediamine) by using (1)H NMR spectroscopy. Without exception, binding of the second metal takes place at N7, but formation of a molecular guanine square with trans-[(Me(2)NH(2))Pt(II)] cross-linking N1 positions and trans-[(NH(3))(2)Pt(II)] cross-linking N7 positions could not be confirmed unambiguously, despite the fact that calculations are fully consistent with its existence.

Exploring the metal coordination properties of the pyrimidine part of purine nucleobases: isomerization reactions in heteronuclear Pt(II)/Pd(II) of 9-methyladenine.

The synthesis and characterization of three heteronuclear Pt(2)Pd(2) (4, 5) and PtPd(2) (6) complexes of the model nucleobase 9-methyladenine (9-MeA) is reported. The compounds were prepared by reacting [Pt(NH(3))(3)(9-MeA-N7)](ClO(4))(2) (1) with [Pd(en)(H(2)O)(2)](ClO(4))(2) at different ratios r between Pt and Pd, with the goal to probe Pd(II) binding to any of the three available nitrogen atoms, N1, N3, N6 or combinations thereof. Pd(II) coordination occurs at N1 and at the deprotonated N6 positions, yet not at N3. 4 and 5 are isomers of [{(en)Pd}(2){N1,N6-9-MeA(-)-N7)Pt(NH(3))(3)}(2)](ClO(4))(6)·nH(2)O, with a head-head orientation of the two bridging 9-MeA(-) ligands in 4 and a head-tail orientation in 5. 6 is [{(en)Pd}(2)(OH)(N1,N6-9MeA(-)-N7)Pt(NH(3))(3)](ClO(4))(4)·4H(2)O, hence a condensation product between [Pt(NH(3))(3)(9-MeA-N7)](2+) and a µ-OH bridged dinuclear (en)Pd-OH-Pd(en) unit, which connects the N1 and N6 positions of 9-MeA(-) in an intramolecular fashion. 4 and 5, which slowly interconvert in aqueous solution, display distinct structural differences such as significantly different intramolecular Pd···Pd contacts (3.124 0(16) Å in 4; 2.986 6(14) Å in 5), among others. Binding of (en)Pd(II) to the exocyclic N6 atom in 4 and 5 is accompanied by a large movement of Pd(II) out of the 9-MeA(-) plane and a trend to a further shortening of the C6-N6 bond as compared to free 9-MeA. The packing patterns of 4 and 5 reveal substantial anion-π interactions.

On the Heterogeneous Nature of Cisplatin-1-Methyluracil Complexes: Coexistence of Different Aggregation Modes and Partial Loss of NH3 Ligands as Likely Explanation.

The conversion of the 1 : 1-complex of Cisplatin with 1-methyluracil (1MeUH), cis-[Pt(NH3 )2 (1MeU-N3)Cl] (1 a) to the aqua species cis-[Pt(NH3 )2 (1MeU-N3)(OH2 )]+ (1 b), achieved by reaction of 1 a with AgNO3 in water, affords a mixture of compounds, the composition of which strongly depends on sample history. The complexity stems from variations in condensation patterns and partial loss of NH3 ligands. In dilute aqueous solution, 1 a, and dinuclear compounds cis-[(NH3 )2 (1MeU-N3)Pt(µ-OH)Pt(1MeU-N3)(NH3 )2 ]+ (3) as well as head-tail cis-[Pt2 (NH3 )4 (µ-1MeU-N3,O4)2 ]2+ (4) represent the major components. In addition, there are numerous other species present in minor quantities, which differ in metal nuclearity, stoichiometry, stereoisomerism, and Pt oxidation state, as revealed by a combination of 1 H NMR and ESI-MS spectroscopy. Their composition appears not to be the consequence of a unique and repeating coordination pattern of the 1MeU ligand in oligomers but rather the coexistence of distinctly different condensation patterns, which include µ-OH, µ-1MeU, and µ-NH2 bridging and combinations thereof. Consequently, the products obtained should, in total, be defined as a heterogeneous mixture rather than a mixture of oligomers of different sizes. In addition, a N2 complex, [Pt(NH3 )(1MeU)(N2 )]+ appears to be formed in gas phase during the ESI-MS experiment. In the presence of Na+ ions, multimers n of 1 a with n=2, 3, 4 are formed that represent analogues of non-metalated uracil quartets found in tetrastranded RNA.