Pyrimidine and pyrazine as N-donor ligands in mercurous complexes: [Hg-2(Pym)]NO3)(2), [Hg-2(Pym)](ClO4)(2), and [Hg-2(Pyp)(2)](ClO4)(2)

Colourless single crystals of [Hg-2(Pym)](NO3)(2), [Hg-2(Pym)](ClO4)(2) and [Hg-2(Pyp)(2)](ClO4)(2) were obtained from aqueous solutions of the respective components Hg-2(NO3)(2).2H(2)O, Hg-2(ClO4)(2).6H(2)O, pyrimidine (Pym) and pyrazine (Pyp). The crystal structures were determined from single-crystal X-ray diffractometer data. [Hg-2(Pym)](NO3)(2): monoclinic, C2/c, Z = 8, a = 1607.4(2), b = 652.79(7), c = 2000.5(2) pm, beta = 103.42(2)degrees, R-all = 0.0530; [Hg-2(Pym)](ClO4)(2): orthorhombic, Pnma, Z = 4, a = 1182.7(2), b = 1662.5(2), c = 607.9(1) pm, R-all = 0.0438; [Hg-2(Pyp)(2)](ClO4)(2): orthorhombic, Aba2, Z = 4, a = 1529.39(9), b = 1047.10(14), c = 1133.49(15) pm, R-all = 0.0381. The crystal structures of [Hg-2(Pym)](NO3)(2) and [Hg-2(Pym)](ClO4)(2) contain polymeric cationic chains [Hg-2(Pym)](+) that are arranged to corrugated layers between which the anions are situated. [Hg-2(Pyp)(2)](ClO4)(2) consists of polymeric cationic layers that are built from (Hg-2)(2)(Hg-2)(2/2)(Pyp)(4) rings connected to each other; the perchlorate tetrahedra are located between these layers.

Chemoenzymatic synthesis of chiral 2,2 '-bipyridine ligands and their N-oxide derivatives: applications in the asymmetric aminolysis of epoxides and asymmetric allylation of aldehydes

A series of enantiopure 2,2'-bipyridines have been synthesised from the corresponding cis-dihydrodiol metabolites of 2-chloroquinolines. Several of the resulting hydroxylated 2,2'-bipyridines were found to be useful chiral ligands for the asymmetric aminolysis of meso-epoxides leading to the formation of enantioenriched amino alcohols (-> 84%ee). N-oxide and N,N'-dioxide derivatives of these 2,2'-bipyridines, including separable atropisomers, have been synthesised and used as enantioselective organocatalysts in the asymmetric allylation of aldehydes to give allylic alcohols (-> 86%ee).

Ligand and structure-based methodologies for the prediction of the activity of G protein-coupled receptor ligands

Accurate in silico models for the quantitative prediction of the activity of G protein-coupled receptor (GPCR) ligands would greatly facilitate the process of drug discovery and development. Several methodologies have been developed based on the properties of the ligands, the direct study of the receptor-ligand interactions, or a combination of both approaches. Ligand-based three-dimensional quantitative structure-activity relationships (3D-QSAR) techniques, not requiring knowledge of the receptor structure, have been historically the first to be applied to the prediction of the activity of GPCR ligands. They are generally endowed with robustness and good ranking ability; however they are highly dependent on training sets. Structure-based techniques generally do not provide the level of accuracy necessary to yield meaningful rankings when applied to GPCR homology models. However, they are essentially independent from training sets and have a sufficient level of accuracy to allow an effective discrimination between binders and nonbinders, thus qualifying as viable lead discovery tools. The combination of ligand and structure-based methodologies in the form of receptor-based 3D-QSAR and ligand and structure-based consensus models results in robust and accurate quantitative predictions. The contribution of the structure-based component to these combined approaches is expected to become more substantial and effective in the future, as more sophisticated scoring functions are developed and more detailed structural information on GPCRs is gathered.

New pinene-derived pyridines as bidentate chiral ligands

A synthesis of new bidentate pyridines has been developed, starting from ?-pinene. A copper complex of the pyridine-oxazoline ligands catalyzes asym. allylic oxidn. of cyclic olefins with good conversion rates and acceptable enantioselectivity (?67% ee). The imidazolium salt I has been identified as a precursor of the N,N'-unsym. N-heterocyclic carbene ligand, which upon complexation with palladium, catalyzed the intramol. amide enolate ?-arylation leading to oxindole in excellent yield but with low enantioselectivity.

Bridging the Gap between Ionic Liquids and Molten Salts: Group 1 Metal Salts of the Bistriflamide Anion in the Gas Phase

Fourier transform ion cyclotron resonance mass spectrometry experiments showed that liquid Group 1 metal salts of the bistriflamide anion undergoing reduced-pressure distillation exhibit a remarkable behavior that is in transition between that of the vapor-liquid equilibrium characteristics of aprotic ionic liquids and that of the Group 1 metal halides: the unperturbed vapors resemble those of aprotic ionic liquids, in the sense that they are essentially composed of discrete ion pairs. However, the formation of large aggregates through a succession of ion-molecule reactions is closer to what might be expected for Group I metal halides. Similar experiments were also carried out with bis{(trifluoromethyl)sulfonyl}amine to investigate the effect of H+, which despite being the smallest Group 1 cation, is generally regarded as a nonmetal species. In this case, instead of the complex ion-molecule reaction pattern found for the vapors of Group I metal salts, an equilibrium similar to those observed for aprotic ionic liquids was observed.

Intimate Mixing - Bridging the Gap? Catholic-Protestant Relationships in Northern Ireland

For many years Northern Ireland has been a divided society where members of the two main religious groups, Catholics and Protestants, have limited opportunities to interact due to segregation in their social lives. Attempts have been made to encourage religious mixing through integration in schools, housing and workplaces predicated on the theory that bringing people together can improve community relations and remove prejudices – known as the ‘contact hypothesis’. However, little is known about those who enter into mixed-religion partnerships often against the wishes of their families and communities. This paper examines the characteristics and attitudes of mixed-religion couples and suggests that they differ in their socio-demographic characteristics and in their attitudes from those who marry within their own religion. These findings add to the weight of evidence from other countries in conflict suggesting that intermarriage has a role to play in contributing to less sectarian views and improved community relations.

Rational Design of Acridine-Based Ligands with Selectivity for Human Telomeric Quadruplexes

Structure-based modeling methods have been used to design a series of disubstituted triazole-linked acridine compounds with selectivity for human telomeric quadruplex DNAs. A focused library of these compounds was prepared using click chemistry and the selectivity concept was validated against two promoter quadruplexes from the c-kit gene with known molecular structures, as well as with duplex DNA using a FRET-based melting method. Lead compounds were found to have reduced effects on the thermal stability of the c-kit quadruplexes and duplex DNA structures. These effects were further explored with a series of competition experiments, which confirmed that binding to duplex DNA is very low even at high duplex:telomeric quadruplex ratios. Selectivity to the c-kit quadruplexes is more complex, with some evidence of their stabilization at increasing excess over human telomeric quadruplex DNA. Selectivity is a result of the dimensions of the triazole-acridine compounds; and in particular the separation of the two alkyl-amino terminal groups. Both lead compounds also have selective inhibitory effects on the proliferation of cancer cell lines compared to a normal cell line, and one has been shown to inhibit the activity of the telomerase enzyme, which is selectively expressed in tumor cells, where it plays a role in maintaining telomere integrity and cellular immortalization.

Biaryl polyamides as a new class of DNA quadruplex-binding ligands

We report a novel class of biaryl polyamides highly selective for G-quadruplex DNA, and with significant cytotoxicity in several cancer cell lines; they form planar U-shaped structures that match the surface area dimensions of a terminal G-quartet in quadruplex structures rather than the grooves of duplex DNA.

Structure-based design of selective high-affinity telomeric quadruplex-binding ligands.

A library of triazole-based telomeric quadruplex-selective ligands has been developed that mimic an established family of tri-substituted acridine-based ligands, using crystal structure data as a starting-point for computer-based design. Binding affinities, estimated by electrospray mass spectrometry, are in accord with the design concept.

A click chemistry approach to C3 symmetric, G-quadruplex stabilising ligands.

Described is the structure-based design and synthesis of a series of tris-triazole G-quadruplex binding ligands utilising the copper catalysed azide–alkyne ‘click’ reaction. The results of G-quadruplex stabilisation by the ligands are reported and discussed.

Targeting telomerase and telomeres: a click chemistry approach towards highly selective G-quadruplex ligands.

Maintenance of telomeres—specialized complexes that protect the ends of chromosomes, is undertaken by the enzyme complex telomerase, which is a key factor that is activated in more than 80% of cancer cells, but is absent in most normal cells. Targeting telomere maintenance mechanisms could potentially halt tumour growth across a broad spectrum of cancer types, with little cytotoxic effect outside cancer cells. Here, we describe in detail a new class of G-quadruplex binding ligands synthesized using a click chemistry approach. These ligands comprise a 1,3-di(1,2,3-triazol-4-yl)benzene pharmacophore, and display high levels of selectivity for interaction with G-quadruplex DNA vs. duplex DNA. The ability of these ligands to inhibit the enzymatic activity of telomerase correlates with their ability to stabilize quadruplex DNA, and with estimates of affinity calculated by molecular modeling.