Bernhard Lippert

Multiplicity of metal ion binding patterns to nucleobases

Abstract The systematic study of interactions between metal ions and nucleobases, the constituents of nucleic acids, as well as nucleic acids in general started some 50 years ago, around 1950. This review is an attempt to recall the developments in this field, to list metal binding patterns as established today, and to examine prospects for the future. The focus of this survey will be on the coordination chemistry of metal species with the heterocyclic parts of nucleobases.

Simple 1:1 and 1:2 complexes of metal ions with heterocycles as building blocks for discrete molecular as well as polymeric assemblies

Abstract The use of transition metals with low coordination numbers or blocked bonding positions in combination with nitrogen heterocyclic ligands of different geometries (e.g. pyrazole, imidazole, bipyrazine, pyrimidine or purine) leads to formation of both discrete supramolecular assemblies and 1D polymers. When highly coordinating ‘naked’ metal ions are applied instead, 2D and 3D frameworks are generated. Some of the assemblies, both molecular and polymeric, possess cavities or channels that can reversibly include guest molecules, including anions. The chemistry reported provides a vast playground for potential applications and future synthetic work.

Impact of Cisplatin on the recent development of Pt coordination chemistry: a case study

Abstract An overview is presented on recent developments in selected areas of Pt coordination chemistry which were a direct consequence of the discovery of the antitumor activity of cis-Pt(NH3)2Cl2 (Cisplatin). These include complexes of PtII with oxygen donor atoms, mixed-valence state Pt compounds as well as diplatinum(III) complexes, and compounds containing nucleobases as well as a limited number of other heterocyclic ligands. Both the potential biological relevance of these compounds and the role cis- and trans-(am)2MII (am=NH3 or amine; M=Pt, Pd) entities are playing in the construction of regularly shaped molecules (‘molecular architecture’) are briefly outlined.

Molecular architecture with metal ions, nucleobases and other heterocycles

Abstract The combination of transition metal fragments with 90 or 180° angles, viz. cis -a 2 M II (a=amine or a 2 =diamine; M=Pt or Pd) and trans -a 2 Pt II or Hg II , respectively, with (heterocyclic ligands providing 90, 120, or 180° angles leads, either in a self-assembly process or in a stepwise fashion, to cations of versatile shapes and charges. Examples include open boxes, molecular squares, hexagons, triangles and cups. Intermolecular H bonding can assist association of smaller entities. Synthetic and structural aspects as well as physico–chemical properties of selected examples with be discussed.

MOLECULAR TRIANGLE FROM ENPTII AND 2,2'-BIPYRAZINE

Twisting of the two pyrazine halves of the 2,2′-bipyrazine ligands appears to be responsible for the facile formation of a enPtII triangle (shown schematically on the right; en=ethylenediamine, omitted from the sketch for clarity).

Effects of (N7)-Coordinated Nickel(II), Copper(II), or Platinum(II) on the Acid–Base Properties of Guanine Derivatives and Other Related Purines[≠]

Guanine is an important nucleobase residue in nucleic acids; for example, the anticancer drug cisplatin, cis-[(NH3)2PtCl2], preferably binds to N7 of this site. In this study the effect of (N7)-coordinated Ni2+ (which is expected to correspond to that of Zn2+), Cu2+, and cis-a2Pt2+ or trans-a2Pt2+ (where a = NH3 or CH3NH2) on the acid–base properties of guanine derivatives (see diagram) is quantified. Several related purines are included for comparison. Micro-acidity-constant evaluations are presented and more than 60 acidity constants are listed.

Adduct formation of cis-(NH3)2PtX2 (X = Cl−, I−) with formamides and the crystal structures of cis-(NH3)2PtCl2·(CH3)2NCHO. Application for the purification of the antitumor agent cisplatin

Abstract The formation of solvates of cis(NH3)2PtCl2 and cis-(NH3)2PtI2 with formamide, FA, and substituted formamides (N-methylformamide, NMF, N ,N- dimethylformamide, DMF, and N,N-diethylformamide, DEF) has been studied. Crystalline NMF and DMF adducts have been isolated with both the dichloro and the diiodo species. The infrared spectra of these solvates have been recorded, but only with cis- (NH3)2PtCl2·DMF are there major changes as compared to the two components, cis-Pt(II) and DMF. These spectral changes are discussed and attributed to hydrogen bonding interactions between the NH3 groups and the DMF molecule. The crystal structure of this compound has been determined. Cis-dichloro- diammineplatinum(II) dimethylforrnamide, cis- (NH3)2PtCl2·(CH3)2NCHO, crystallizes in the orthorhombic space group Pca21, Z = 4. The unit cell dimensions are a = 11.372(2) A, b = 7.723(2) A, c = 11.165(3) A and the volume is 980.5(4) A3. The density of the crystal was calculated to be 2.53 g cm−3. The crystal structure was determined by standard methods to R1 =0.0637 on the basis of 2542 unique reflections. The molecular structure of the platinum complex shows normal bond lengths and angles, with the platinum atom in a square planar environment. The DMF molecule is disordered as indicated by the large temperature factors on the atoms, but the disorder could not be resolved. The reported solvates of cis-(NH3)2PtCl2 are of interest with regard to methods of an efficient purification of the antitumor drug Cisplatin. Removal of DMF from the isolated DMF solvate by vacuum evaporation yields a highly pure product as judged from UV-visible spectra. Precipitation of cis(NH3)2- PtCl2 from a saturated DMF solution through addition of aqueous 0.1 N HCl solution also leads to a product meeting the well defined spectral criteria established for cis-(NH3)2PtCl2. Finally, the solution behavior of cis-(NH3),PtI2 has been studied. The compound is unstable in H2O, in aqueous KI, and in aqueous HI. Both with KI and in aqueous HI there is a release of NH3 from cis-(NH3)2PtI2 as a consequence of the trans-effect of I.

STRUCTURAL ASPECTS OF PT COMPLEXES CONTAINING MODEL NUCLEOBASES

Abstract Compounds of Pt(II) and Pt(IV)-containing nucleobases as ligands (also including a few related ligands) are summarized and described, according to the nuclearity of the complexes. The large amount of available crystallographic data allows geometrical parameters such as bond lengths and angles, angular distortions, torsional angles related to the nucleobase plane orientations etc., to be derived with relatively high accuracy. Simple relationships between some of these parameters are reported and discussed. On mononuclear Pt complexes containing one or more nucleobase ligands a simple descriptive statistical analysis has been performed. The structural properties of polynuclear, often heteronuclear species have also been reviewed where the nucleobases, particularly pyrimidines, act as polydentate-often bridging-ligands. A simple MO theoretical analysis of the metal-metal interaction in homo- and heterodinuclear species allows the degree of the intermetallic bond formation to be rationalized and the correlation of the qualitative results with the experimental metal-metal distances. Cyclic polynuclear species, which appear to be a new expanding field in the chemistry of Pt-nucleobase complexes, are also described.

Effects of N7-methylation, N7-platination, and C8-hydroxylation of guanine on H-bond formation with cytosine: platinum coordination strengthens the Watson-Crick pair

The hydrogen bonding properties of 1-methylcytosine (1-MeC) with the following guanine base derivatives have been studied in DMSO-d6, applying concentration-dependent 1H NMR spectroscopy: 9-ethylguanine, 7,9-dimethylguanine (7,9-DimeGH+), and 7,8-dihydro-8-oxo-9-methylguanine (8-O-9-MeGH), as well as three 9-ethylguanine complexes carrying different Pt(II) moieties at the N7 position. The association constants K for the Watson-Crick pairing schemes are by a factor 2–3 higher in the cases of platinated guanine complexes compared to the Watson-Crick pair between 9-ethylguanine and 1-methylcytosine (K= 6.9 ± 1.3 M−1). Similar enhanced stabilities are observed for the pairs formed between 1-MeC and 7,9-DimeGH+ or 8-O-9-MeGH. The increase in N1H acidity of the guanine derivative upon modification at the N7 or C8 positions can be correlated with the association constants K; the result is a bell-shaped curve meaning that acidification initially stabilizes hydrogen bond formation up to a certain maximum; further acidification then leads to a destabilization. For two of the examples studied in solution, hydrogen bonding according to Watson-Crick between N7-platinated 9-ethylguanine and 1-methylcytosine has also been established by X-ray crystallography.

Simultaneous binding of two different transition metals to the DNA model base 1-methylthymine: The x-ray structure of Bis[bis(μ-1-methylthyminato-N3, O4)cis-diammine platinum(II)] silver nitrate pentahydrate

Abstract Two heteronuclear complexes of 1-methylthymine with cis-Pt(NH3)2+2 and Ag+ binding N(3) and O(4), respectively, have been prepared. The structure of one of these compounds, Ag[cis-Pt(NH3)2(C6H7N2O2)2]2·5H2O, has been determined by X-ray diffraction and refined to R = 0.048 for 4971 reflections. The compound crystallizes in the triclinic space group P 1 and has cell dimensions a = 14.122(11), b = 13.422(23), c = 11.747(12) A, α = 101.60(10), β = 100.01(8), γ = 95.94(11)° with two formula units in the unit cell. The molecular cation consists of two bis(1-methylthyminato-N3)cis-diammineplatinum(II) units connected by a silver cation via the exocyclic C(4) oxygen atoms. An explanation for the unexpected ligand properties of N(3) platinated 1-methylthymine is proposed.