Phenylsilver - an unexpected one-dimensional coordination polymer of silver(I) tetrads.

Herein we present the structures of two distinct one-dimensional coordination polymers of phenylsilver. Both polymers consist of phenylsilver tetrads inter-connected via short silver-silver contacts (either one or two). The underlying mechanism for the formation by transmetalation was validated by synthesising an analogous fluorinated derivative of phenylsilver.

6-Pyrazolylpurine and its deaza derivatives as nucleobases for silver(I)-mediated base pairing with pyrimidines.

The artificial nucleobase 6-pyrazolylpurine (6PP) and its deaza derivatives 1-deaza-6-pyrazolylpurine (1D6PP), 7-deaza-6-pyrazolylpurine (7D6PP), and 1,7-dideaza-6-pyrazolylpurine (1,7D6PP) were investigated with respect to their ability to differentiate between the canonical nucleobases cytosine and thymine by means of silver(I)-mediated base pairing. As shown by temperature-dependent UV spectroscopy and by circular dichroism spectroscopy, 6PP and (to a lesser extent) 7D6PP form stable silver(I)-mediated base pairs with cytosine, but not with thymine. 1D6PP and 1,7D6PP do not engage in the formation of stabilizing silver(I)-mediated base pairs with cytosine or thymine. The different behavior of 1D6PP, 7D6PP, and 1,7D6PP indicates that silver(I) binding occurs via the N1 position of the purine derivative, i.e. via the Watson-Crick face. The data show that 6PP is capable of differentiating between cytosine and thymine, which is potentially relevant in the context of detecting single-nucleotide polymorphisms.

Enhancing Repair of Oxidative DNA Damage with Small-Molecule Activators of MTH1.

Impaired DNA repair activity has been shown to greatly increase rates of cancer clinically. It has been hypothesized that upregulating repair activity in susceptible individuals may be a useful strategy for inhibiting tumorigenesis. Here, we report that selected tyrosine kinase (TK) inhibitors including nilotinib, employed clinically in the treatment of chronic myeloid leukemia, are activators of the repair enzyme Human MutT Homolog 1 (MTH1). MTH1 cleanses the oxidatively damaged cellular nucleotide pool by hydrolyzing the oxidized nucleotide 8-oxo-2'-deoxyguanosine (8-oxo-dG)TP, which is a highly mutagenic lesion when incorporated into DNA. Structural optimization of analogues of TK inhibitors resulted in compounds such as SU0448, which induces 1000 ± 100% activation of MTH1 at 10 µM and 410 ± 60% at 5 µM. The compounds are found to increase the activity of the endogenous enzyme, and at least one (SU0448) decreases levels of 8-oxo-dG in cellular DNA. The results suggest the possibility of using MTH1 activators to decrease the frequency of mutagenic nucleotides entering DNA, which may be a promising strategy to suppress tumorigenesis in individuals with elevated cancer risks.

Monoanionic C

A family of Pt(II) complexes bearing monoanionic C^N^N ligands as luminophoric units as well as a set of monodentate ligands derived from allenylidene and carbene species were synthesized and characterized in terms of structure and photophysical properties. In addition, we present the extraordinary molecular structure of a phosphorescent complex carrying an allenylidene ligand. Depending on the co-ligand, an effect can be observed in the photoluminescence lifetimes and quantum yields as well as in the radiative and radiation less deactivation rate constants. Their correlation with the substitution pattern was analyzed by comparing the photoluminescence in fluid solution at room temperature and in frozen glassy matrices at 77 K. Moreover, in order to gain a deeper understanding of the electronic states responsible for the optical properties, density functional theory calculations were performed. Finally, the cytotoxicity of the complexes was evaluated in vitro, showing that the cationic complexes exhibit strong effects at low micromolar concentrations. The calculated half-maximum effective concentrations (EC50 values) were 4 times lower in comparison to the established antitumor agent oxaliplatin. In contrast, the neutral species are less toxic, rendering them as potential bioimaging agents.

Silver(I)-mediated base pairing in DNA involving the artificial nucleobase 7,8-dihydro-8-oxo-1,N6-ethenoadenine.

The artificial nucleobase 7,8-dihydro-8-oxo-1,N6-ethenoadenine (X) was investigated with respect to its ability to engage in Ag(I)-mediated base pairing in DNA. Spectroscopic data indicate the formation of dinuclear X-Ag(I)2-X homo base pairs and mononuclear X-Ag(I)-C base pairs (C, cytosine). Density functional theory calculations and molecular dynamics simulations indicate that the nucleobase changes from its lactam tautomeric form prior to the formation of the Ag(I)-mediated base pair to the lactim form after the incorporation of the Ag(I) ions. Fluorescence spectroscopy indicates that the two Ag(I) ions of the homo base pair are incorporated sequentially. Isothermal titration calorimetry confirms that the affinity of one of the Ag(I) ions is about tenfold higher than that of the other Ag(I) ion. The computational analysis by means of density functional theory confirms a much larger reaction energy for the incorporation of the first Ag(I) ion. The thermal stabilization upon the formation of the dinuclear Ag(I)-mediated homo base pair exceeds the one previously observed for the closely related nucleobase 1,N6-ethenoadenine by far, despite very similar structures. This additional stabilization may stem from the presence of water molecules engaged in hydrogen bonding with the additional oxygen atom of the artificial nucleobase X. The highly stabilizing Ag(I)-mediated base pair is a valuable addition to established dinuclear metal-mediated base pairs.

A fluorescent hydrazone exchange probe of pyridoxal phosphate for the assessment of vitamin B6 status.

Abnormal vitamin B6 status, marked by deficient intracellular concentrations of pyridoxal phosphate (PLP), is classified as a direct biomarker based on its biomedical significance. However, there exist no direct methods for measuring vitamin B6 status in intact cells. Here we describe the development of a fluorogenic probe, RAB6, which shows remarkable selectivity for PLP among the B6 vitamers and other cellular aldehydes.

Dual Inhibitors of 8-Oxoguanine Surveillance by OGG1 and NUDT1.

Oxidative damage in DNA is one of the primary sources of mutations in the cell. The activities of repair enzymes 8-oxoguanine DNA glycosylase (OGG1) and human MutT Homologue 1 (NUDT1 or MTH1), which work together to ameliorate this damage, are closely linked to mutagenesis, genotoxicity, cancer, and inflammation. Here we have undertaken the development of small-molecule dual inhibitors of the two enzymes as tools to test the relationships between these pathways and disease. The compounds preserve key structural elements of known inhibitors of the two enzymes, and they were synthesized and assayed with recently developed luminescence assays of the enzymes. Further structural refinement of initial lead molecules yielded compound 5 (SU0383) with IC50(NUDT1) = 0.034 µM and IC50(OGG1) = 0.49 µM. The compound SU0383 displayed low toxicity in two human cell lines at 10 µM. Experiments confirm the ability of SU0383 to increase sensitivity of tumor cells to oxidative stress. Dual inhibitors of these two enzymes are expected to be useful in testing multiple hypotheses regarding the roles of 8-oxo-dG in multiple disease states.

AgI -Induced Switching of DNA Binding Modes via Formation of a Supramolecular Metallacycle.

The histidine derivative L1 of the DNA intercalator naphthalenediimide (NDI) forms a triangular AgI complex (C2). The interactions of L1 and of C2 with DNA were studied by circular dichroism (CD) and UV/Vis spectroscopy and by viscosity studies. Different binding modes were observed for L1 and for C2, as the AgI complex C2 is too large in size to act as an intercalator. If AgI is added to the NDI molecule that is already intercalated into a duplex, higher order complexes are formed within the DNA duplex and cause disruptions in the helical duplex structure, which leads to a significant decrease in the characteristic CD features of B-DNA. Thus, via addition of a metal we show how a classic and well-known organic intercalator unit can be turned into a partial metallo insertor. We also show how electrochemical impedance spectroscopy (EIS) can be used to probe DNA binding modes on DNA films that are immobilized on gold surfaces.

Phosphorescent Pt(ii) complexes bearing a monoanionic C

A versatile design strategy is presented towards new monoanionic pincer luminophores, showing that cyclometallating C^N^N ligands can yield phosphorescent Pt(ii) complexes even if a neutral 1,2,3-triazole ring is inserted by click chemistry. The overall charge, intermolecular interactions and excited state properties can be manipulated and controlled by varying the nature of the ancillary ligand, and its effect on the structural and the triplet state characteristics can be thoroughly investigated and correlated by means of theory and spectroscopy.

Relative Strand Orientation in a DNA Duplex Controls the Nuclearity of a Metal-Mediated Base Pair.

1,N6 -Ethenoadenine (ϵA) and cytosine (C) are able to form two different metal-mediated base pairs. When the glycosidic bonds are arranged in a cisoid manner (i.e., in antiparallel-stranded DNA), the ϵA:C mispair binds one AgI ion, leading to a mononuclear ϵA-AgI -C base pair that contains a synergistic hydrogen bond. In contrast, a transoid orientation of the glycosidic bonds (as found in parallel-stranded DNA) results in the formation of a dinuclear metal-mediated base pair ϵA-AgI2 -C.

A Dinuclear Mercury(II)-Mediated Base Pair in DNA.

The first dinuclear metal-mediated base pair containing divalent metal ions has been prepared. A combination of the neutral bis(monodentate) purine derivative 1,N6 -ethenoadenine (ϵA), which preferentially binds two metal ions with a parallel alignment of the N-M bonds, and the canonical nucleobase thymine (T), which readily deprotonates in the presence of HgII and thereby partially compensates the charge accumulation due to the two closely spaced divalent metal ions, yields the dinuclear T-HgII2 -ϵA base pair. This metal-mediated base pair stabilizes the DNA oligonucleotide duplex as shown by an increase of 8 °C in its melting temperature. Formation of the base pair was demonstrated by temperature-dependent UV spectroscopy as well as by titration experiments monitored by UV and CD spectroscopy.