Should I stay or should I go: VCP/p97-mediated chromatin extraction in the DNA damage response

The ordered assembly of DNA repair factors on chromatin has been studied in great detail, whereas we are only beginning to realize that selective extraction of proteins from chromatin plays a central role in the DNA damage response. Interestingly, the protein modifier ubiquitin not only regulates the well-documented recruitment of repair proteins, but also governs the temporally and spatially controlled extraction of proteins from DNA lesions. The facilitator of protein extraction is the ubiquitin-dependent ATPase valosin-containing protein (VCP)/p97 complex, which, through its segregase activity, directly extracts ubiquitylated proteins from chromatin. In this review, we summarize recent studies that uncovered this important role of VCP/p97 in the cellular response to genomic insults and discuss how ubiquitin regulates two intuitively counteracting activities at sites of DNA damage.     

Synthesis and binding profile of haloperidol-based bivalent ligands targeting dopamine D2-like receptors

Homodimers of dopamine D₂-like receptors are suggested to be of particular importance in the pathophysiology of schizophrenia and, thus, serve as promising targets for the discovery of atypical antipsychotics. This study describes the development of a series of novel bivalent molecules with a pharmacophore derived from the dopamine receptor antagonist haloperidol. These dimers were investigated in comparison to their monomeric analogues for their D_2long, D_2short, D₃, and D₄ receptor binding and the ability to bridge two neighboring receptor protomers. Radioligand binding studies provided diagnostic insights when Hill slopes close to two for the bivalent ligand 13 incorporating 22 spacer atoms and a comparative analysis with monovalent control ligands indicated a bivalent binding mode with a simultaneous occupancy of two neighboring binding sites.     

Antimalarial chemotherapy: Artemisinin-derived dimer carbonates and thiocarbonates

Several 2-carbon-linked trioxane dimer secondary alcohol carbonates 14 and thiocarbonates 15, combined with mefloquine and administered in a low single oral dose, prolonged the survival times of malaria-infected mice much more effectively than the popular monomeric antimalarial drug artemether plus mefloquine. Three dimer carbonates 14 and one dimer thiocarbonate 15 partially cured malaria-infected mice.     

Molecular-dynamics simulations of pyronine 6G and rhodamine 6G dimers in aqueous solution

We have carried out molecular-dynamics (MD) simulations on dimers of the positively charged laser dyes pyronine 6G (P6G) and rhodamine 6G (R6G) in aqueous solution, generating trajectories of 2.5 ns for various computational protocols. We discuss how the choice of atomic partial charges and the length of the trajectories affect the predicted structures of the dimers and compare our results to those of earlier MD-simulations, which were restricted to only 0.7 ns. Our results confirm that monomers of P6G easily undergo relative rotations within the dimer, but we found new conformations of the R6G dimer at longer simulation times. In addition, we analyzed in detail the energy change during the formation of dimers. With suitable corrections, the electrostatic energy from an Ewald treatment agrees with the results from an approach relying on a residue-based cutoff. For P6G, we show that the strong solvent-mediated electrostatic attraction between the monomers is counteracted by an almost equally large solvent-induced entropy contribution to yield a small driving force to dimer formation, in very good agreement with the free-energy change from a thermodynamic-integration procedure. Thus, earlier rationalizations of the dimer formation, based only on energy arguments, yield a qualitatively wrong picture.Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users.     

Synthesis and in vitro anticancer activity of new gemcitabine-nucleoside analogue dimers containing methyltriazole or ester-methyltriazole linker

Two series of novel gemcitabine-nucleoside analogue dimers were synthesized using the ‘click’ chemistry approach. In the first series of dimers (21–30), the nucleoside units were connected with a stable methyltriazole 4N-3′(or 5′)C linker whereas in the second series (31–40) with a cleavable ester-methyltriazole 4N-3′(or 5′)C linker. Dimers 21–40 were evaluated for their cytotoxic activity in five human cancer cell lines such as cervical (HeLa), nasopharyngeal (KB), lung (A549), brain (U87), liver (HepG2) and normal dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Compound 29 comprising two gemcitabine (dFdC) units exhibited the highest activity among dimers 21–30. The activity of compound 29 was higher than that of dFdC in all the studied cancer cell lines. A similar order of activity was observed for compounds 25, 28, and 30. The best activity among all the dimers synthesized was displayed by compound 39, comprising two gemcitabine units with a cleavable linker. The activity of compound 39 was 5 to 9 times higher than that of dFdC, depending on the cell line. In addition, marked cytotoxic activity was shown by compounds 31, 36, 38, and 40.     

Chlorinated Fullerene Dimers for Interfacial Engineering Toward Stable Planar Perovskite Solar Cells with 22.3% Efficiency

A major limit for planar perovskite solar cells is the trap‐mediated hysteresis and instability, due to the defective metal oxide interface with the perovskite layer. Passivation engineering with fullerenes has been identified as an effective approach to modify this interface. The rational design of fullerene molecules with exceptional electrical properties and versatile chemical moieties for targeted defect passivation is therefore highly demanded. In this work, novel fulleropyrrolidine (NMBF‐X, X?H or Cl) monomers and dimers are synthesized and incorporated between metal oxides (i.e. TiO₂, SnO₂) and perovskites (i.e. MAPbI₃ and (FAPbI₃)_x(MAPbBr₃)_1‐x). The fullerene dimers provide superior stability and efficiency improvements compared to the corresponding monomers, with chlorinated fullerene dimers being most effective at coordinating with both metal oxides and perovskite via the chlorine terminals. The non‐encapsulated planar device delivers a maximum power conversion efficiency of 22.3% without any hysteresis, while maintaining over 98% of initial efficiency after ambient storage for 1000 h, and exhibiting an order of magnitude improvement of the T₈₀ lifetime.     

A Nucleotide Dimer Synthesis Without Protecting Groups Using Montmorillonite as Catalyst

A synthesis has been developed providing nucleotide dimers comprising natural or unnatural nucleoside residues. A ribonucleoside 5′-phosphorimidazolide is added to a nucleoside adsorbed on montmorillonite at neutral pH with the absence of protecting groups. Approximately 30% of the imidazolide is converted into each 2′-5′ dimer and 3′-5′ dimer with the rest hydrolyzed to the 5′-monophosphate. Experiments with many combinations have suggested the limits to which this method may be applied, including heterochiral and chimeric syntheses. This greener chemistry has enabled the synthesis of dimers from activated nucleotides themselves, activated nucleotides with nucleosides, and activated nucleotides with nucleotide 5′-monophosphates.

[Supplemental materials are available for this article. Go to the publisher's online edition of Nucleosides, Nucleotides & Nucleic Acids to view the free supplemental files.]     

Dimeric oligonucleotide probes enhance diagnostic macroarray performance

Disease management can be improved with rapid and accurate pathogen detection and identification techniques. Here we describe the development of a macroarray diagnostic technique with enhanced detection sensitivity and only small reduction in specificity. With probes designed based on the internal transcribed spacer sequences of the rRNA genes of fungal and oomycete strains, we produced a macroarray, which included five types of oligonucleotide probes: monomers (20-24 nt), dimers (40-48 nt), dimers with a poly-A spacer of 10 bases between the two repeats (50-58 nt), monomers with a poly-A tail of 10 (30-34 nt) and 20 (40-44 nt) bases. The use of repeat sequence probes (dimers) greatly improved the sensitivity of the macroarray. The dimeric probes could reliably detect 0.01 fg target genomic DNA, which is lower than the detection limits of most currently available molecular diagnostic methods, such as the conventional PCR and real-time PCR. Dimer probes also had lower signal variability, thereby increasing the macroarray signal uniformity. However, in a few cases, specificity was reduced in the dimer probes. Cross-hybridization occurred in highly similar sequences where the mismatched base was located near the end or in a chain of the same base, but this should be prevented in future array probe design.