Christine J. Cardin

Crystal structures of Λ-[Ru(phen)2dppz]2+ with oligonucleotides containing TA/TA and AT/AT steps show two intercalation modes

The ruthenium complex [Ru(phen)2(dppz)]2+ (where phen is phenanthroline and dppz dipyridophenazine is known as a ‘light switch’ complex because its luminescence in solution is significantly enhanced in the presence of DNA. This property is poised to serve in diagnostic and therapeutic applications, but its binding mode with DNA needs to be elucidated further. Here, we describe the crystal structures of the Λ enantiomer bound to two oligonucleotide duplexes. The dppz ligand intercalates symmetrically and perpendicularly from the minor groove of the d(CCGGTACCGG)2 duplex at the central TA/TA step, but not at the central AT/AT step of d(CCGGATCCGG)2. In both structures, however, a second ruthenium complex links the duplexes through the combination of a shallower angled intercalation into the C1C2/G9G10 step at the end of the duplex, and semi-intercalation into the G3G4 step of an adjacent duplex. The TA/TA specificity of the perpendicular intercalation arises from the packing of phenanthroline ligands against the adenosine residue. Elucidating how small molecules bind to DNA is crucial to bio-sensing and therapy applications. Two crystal structures now show the binding modes of a ‘light switch’ ruthenium complex — whose luminescence in solution increases in the presence of DNA — with oligonucleotide duplexes containing either TA/TA or AT/AT central steps, revealing a specific intercalation mode with the TA/TA species.

Possible pre-dissociation of diorganotin dihalide complexes: relationship between antitumour activity and structure.

An examination of crystallographic data has indicated that the structure/activity relationship for diorganotin dihalide complexes is different from that of other metal dihalides, in that the Sn-N bond lengths appear to determine the antitumour activity.

Structure determination of an intercalating ruthenium dipyridophenazine complex which kinks DNA by semiintercalation of a tetraazaphenanthrene ligand

We describe a crystal structure, at atomic resolution (1.1 Å, 100 K), of a ruthenium polypyridyl complex bound to duplex DNA, in which one ligand acts as a wedge in the minor groove, resulting in the 51° kinking of the double helix. The complex cation Λ-[Ru(1,4,5,8-tetraazaphenanthrene)2(dipyridophenazine)]2+ crystallizes in a 1∶1 ratio with the oligonucleotide d(TCGGCGCCGA) in the presence of barium ions. Each complex binds to one duplex by intercalation of the dipyridophenazine ligand and also by semiintercalation of one of the orthogonal tetraazaphenanthrene ligands into a second symmetrically equivalent duplex. The result is noncovalent cross-linking and marked kinking of DNA.

Sequence-selective assembly of tweezer molecules on linear templates enables frameshift-reading of sequence information

Information storage and processing is carried out at the level of individual macromolecules in biological systems, but there is no reason, in principle, why synthetic copolymers should not be used for the same purpose. Previous work has suggested that monomer sequence information in chain-folding synthetic copolyimides can be recognized by tweezer-type molecules binding to adjacent triplet sequences, and we show here that different tweezer molecules can show different sequence selectivities. This work, based on 1H NMR spectroscopy in solution and on single-crystal X-ray analysis of tweezer–oligomer complexes in the solid state, provides the first clear-cut demonstration of polyimide chain-folding and adjacent-tweezer binding. It also reveals a new and entirely unexpected mechanism for sequence recognition, which, by analogy with a related process in biomolecular information processing, may be termed ‘frameshift-reading’. The ability of one particular tweezer molecule to detect, with exceptionally high sensitivity, long-range sequence information in chain-folding aromatic copolyimides is readily explained by this novel process. Monomer-sequence information in synthetic copolyimides can be recognized by tweezer-type molecules binding to adjacent triplet-sequences through complementary aromatic π–π-stacking, with different tweezer molecules showing different sequence-selectivities. Single-crystal X-ray analysis of tweezer–oligomer complexes confirms the tweezer-binding selectivity, and NMR spectroscopy reveals a new mechanism (‘frameshift-reading’) for tweezer-based sequence recognition in chain-folding copolyimides.

X‑ray crystal structure of rac-[Ru(phen)2dppz]2+ with d(ATGCAT)2 shows enantiomer orientations and water ordering

We report an atomic resolution X-ray crystal structure containing both enantiomers of rac-[Ru(phen)2dppz](2+) with the d(ATGCAT)2 DNA duplex (phen = phenanthroline; dppz = dipyridophenazine). The first example of any enantiomeric pair crystallized with a DNA duplex shows different orientations of the Λ and Δ binding sites, separated by a clearly defined structured water monolayer. Job plots show that the same species is present in solution. Each enantiomer is bound at a TG/CA step and shows intercalation from the minor groove. One water molecule is directly located on one phenazine N atom in the Δ-enantiomer only.

pH tunable hydrogelators for water purification: structural optimisation and evaluation.

A focused library of potential hydrogelators each containing two substituted aromatic residues separated by a urea or thiourea linkage have been synthesised and characterized. Six of these novel compounds are highly efficient hydrogelators, forming gels in aqueous solution at low concentrations (0.03-0.60 wt%). Gels were formed through a pH switching methodology, by acidification of a basic solution (pH 14 to ≈ 4) either by addition of HCl or via the slow hydrolysis of glucono-δ-lactone. Frequently, gelation was accompanied by a dramatic switch in the absorption spectra of the gelators, resulting in a significant change in colour, typically from a vibrant orange to pale yellow. Each of the gels was capable of sequestering significant quantities of the aromatic cationic dye, methylene blue, from aqueous solution (up to 1.02 g of dye per gram of dry gelator). Cryo-transmission electron microscopy of two of the gels revealed an extensive network of high aspect ratio fibers. The structure of the fibers altered dramatically upon addition of 20 wt% of the dye, resulting in aggregation and significant shortening of the fibrils. This study demonstrates the feasibility for these novel gels finding application as inexpensive and effective water purification platforms.

Anticancer activity of organotin compounds. 2. Interaction of diorganotin dihalides with nucleic acid bases and nucleosides; the synthesis of adenine, adenosine and 9-methyladenine adducts

The syntheses of the complexes formulated as SnMe2Cl2(Ad)2 (I), SnMe2Cl2(Ado)2 (II), SnMe2Cl2- (9-MeAd)2 (III) [Ad = adenine, Ado = adenosine, 9-MeAd = 9-methyladenine] as well as the more unexpected SnPhCl2(OH)(Ad)2·3H2O (IV) and SnPhCl3(Ado)2 (V) by reaction of SnMe2Cl2 or SnPh2Cl2 with the appropriate bases in methanol is described. 1H NMR studies suggest that coordination is through the N-7 position of the adenine base.

Conformational and Hydration Effects of Site-selective Sodium, Calcium and Strontium Ion Binding to the DNA Holliday Junction Structure d(TCGGTACCGA)4

The role of metal ions in determining the solution conformation of the Holliday junction is well established, but to date the picture of metal ion binding from structural studies of the four-way DNA junction is very incomplete. Here we present two refined structures of the Holliday junction formed by the sequence d(TCGGTACCGA) in the presence of Na(+) and Ca(2+), and separately with Sr(2+) to resolutions of 1.85A and 1.65A, respectively. This sequence includes the ACC core found to promote spontaneous junction formation, but its structure has not previously been reported. Almost complete hydration spheres can be defined for each metal cation. The Na(+) sites, the most convincing observation of such sites in junctions to date, are one on either face of the junction crossover region, and stabilise the ordered hydration inside the junction arms. The four Ca(2+) sites in the same structure are at the CG/CG steps in the minor groove. The Sr(2+) ions occupy the TC/AG, GG/CC, and TA/TA sites in the minor groove, giving ten positions forming two spines of ions, spiralling through the minor grooves within each arm of the stacked-X structure. The two structures were solved in the two different C2 lattices previously observed, with the Sr(2+) derivative crystallising in the more highly symmetrical form with two-fold symmetry at its centre. Both structures show an opening of the minor groove face of the junction of 8.4 degrees in the Ca(2+) and Na(+) containing structure, and 13.4 degrees in the Sr(2+) containing structure. The crossover angles at the junction are 39.3 degrees and 43.3 degrees, respectively. In addition to this, a relative shift in the base pair stack alignment of the arms of 2.3A is observed for the Sr(2+) containing structure only. Overall these results provide an insight into the so-far elusive stabilising ion structure for the DNA Holliday junction.

Molybdate and tungstate transfer by rat ileum competitive inhibition by sulphate

For both MoO42- and WO42- the maximum rate of uptake by the small intestine of the rat (studied in vitro using the everted sac technique) occurs in the lower ileum. Kinetic constants, derived by a least squares procedure, are compared with those previously obtained for SO42- transport. For both V and Ka, SO42- greater than MoO42- greater than WO42-, with only small differences between sacs IV and V. Mutual inhibition of MoO42- and WO42- transport and inhibition of both by SO42- are competitive processes. This is shown by the generally good agreement between Ka values and derived Ki values and by V values in the presence and absence of the inhibiting species. The three ions SO42-, MoO42- and WO42- are probably transferred across the intestine by a common carrier system. Implications for the sulphate-molybdenum interaction in molybdosis are discussed.

Sulphate transport by rat ileum. Effect of molybdate and other anions

Kinetic constants for SO4-2- transport by upper and lower rat ileum in vitro have been determined by computer fitting of rate vs concentration data obtained using the everted sac technique. MoO-4-2- inhibition of this transport is competitive, and kinetic constants for the inhibition were similarly determined. Transport is also inhibited by the anions WO4-2-, S2O3-2- and SeO4-2-, in the order S2O3-2- greater than SeO4-2- greater than or equal to MoO4-2- greater than WO4-2-. These anions have no effect on the transport of L-valine. Low SO4-2- transport rates were observed in sacs from animals fed a high-molybdenum diet. The significance of the results with respect to the problem of molybdate toxicity in animals is discussed, and related to the known protective effect of SO4-2-.