Nickel‐Catalyzed C–H Trifluoromethylation of Electron‐Rich Heteroarenes

The first example of a nickel‐catalyzed C–H trifluoromethylation of electron‐rich heteroarenes, including imidazopyridines, indoles and thiophenes, has been developed with the commercially available and relatively inexpensive industrial raw material iodotrifluoromethane (CF₃I) as the trifluoromethylating reagent. The synthetic potential of this method is demonstrated by its successful application to the direct trifluoromethylation of the biologically active molecules melatonin and zolmitriptan.

     

New Platinum(II) Triazole Thiosemicarbazone Complexes: Analysis of Their Reactivity and Potential Antitumoral Action

The synthesis and characterization of three new platinum complexes, with 3,5-diacetyl-1,2,4-triazole bis(4-N-isopropylthiosemicarbazone) as a ligand, are reported. The specific conditions under which solvent coordination takes place are reported and the X-ray structure of the complex with one solvent molecule of dimethyl sulfoxide is resolved. Analysis of the reactivity of these platinum compounds aids in finding the best solution profile for biological investigations. Then, the interactions of the complexes with biological models, such as calf-thymus DNA, are studied by using UV spectroscopy and tracking the changes in electrophoretic mobility produced in the supercoiled plasmid DNA model. Initial screening of these potential antitumoral compounds indicates possible selective antitumoral action.     

Catalytic Carbon‐Fluorine Bond Activation with Monocoordinated Nickel‐Carbene Complexes: Reduction of Fluoroarenes

Monocoordinate nickel/N‐heterocyclic carbene complexes reveal unexpected reactivity towards aryl fluorides. Defluorination reactions were efficiently performed with a β‐hydrogen‐containing alkoxide (3 equiv.) in the presence of 3 mol % of [1:1] Ni(0)/IMes⋅HCl catalyst (IMes=1,3‐dimesitylimidazol‐2‐ylidene).     

Rational Design of Ruthenium Complexes Containing 2,6‐Bis(benzimidazolyl)pyridine Derivatives with Radiosensitization Activity by Enhancing p53 Activation

The rational design of metal‐based complexes is an effective strategy for the discovery of potent sensitizers for use in cancer radiotherapy. In this study, we synthesized three ruthenium complexes containing bis‐benzimidazole derivatives: Ru(bbp)Cl₃ ( 1 ), [Ru(bbp)₂]Cl₂ ( 2 a ) (in which bbp=2,6‐bis(benzimidazol‐1‐yl)pyridine), and [Ru(bnbp)₂]Cl₂ ( 2 b ) (where bnbp=2,6‐bis‐(6‐nitrobenzimidazol‐2‐yl)pyridine). We evaluated their radiosensitization capacities in vitro and mechanisms of action. Complex 2 b was found to be particularly effective in sensitizing human melanoma A375 cells toward radiation, with a sensitivity enhancement ratio of 2.4. Along with this potency, complex 2 b exhibited a high degree of selectivity between human cancer and normal cells. Mechanistic studies revealed that 2 b promotes radiation‐induced accumulation of intracellular reactive oxygen species (ROS) by reacting with cellular glutathione (GSH) and then causing DNA stand breaks. The subsequent DNA damage induces phosphorylation of p53 (p‐p53) and upregulates the expression levels of p21, which inhibits the expression of cyclin‐B, leading to G2M arrest. Moreover, p‐p53 activates caspases‐3 and ‐8, triggers cleavage of poly(ADP‐ribose) polymerase (PARP), finally resulting in apoptosis. Taken together, the results of this study provide a strategy for the design of ruthenium‐based radiosensitizers for use in cancer therapy.     

Unprecedented Control of Selectivity in Nickel‐Catalyzed Hydrophosphorylation of Alkynes: Efficient Route to Mono‐ and Bisphosphonates

A unique nickel‐based catalytic system was developed where the direction of the hydrophosphorylation reaction can be controlled by varying the catalyst loading. A flexible one‐pot access to vinylmonophosphonates and alkylbisphosphonates was demonstrated using simple starting materials in an atom‐economic reaction without any specific solvents or ligands. Monitoring of the reaction mechanism with joint NMR and MS studies revealed key information about the reaction intermediates. The synthetic scope of the developed catalytic system was explored and the utility of the synthesized products for the fire protection of cotton materials was demonstrated.

     

Combining Inorganic Chemistry and Biology: The Underestimated Potential of Metal Complexes in Medicine

The vast majority of investigated compounds in modern medicine are based on organic molecules. Within the last decades, the field of medicinial chemistry is shifting towards the application of metal complexes. These compounds offer different mechanisms of action in comparison to organic molecules due to their unique properties, making them novel drug candidates. Herein, the successful combination of metal containing compounds and medicine is highlighted by their application for photodynamic therapy.     

Biochemical Characterization of a Uranyl Ion‐Specific DNAzyme

Uranyl ion‐specific DNAzyme : A DNAzyme (lower strand) cleaves the substrate (upper strand) in the presence of the uranyl ion. The enzyme folds into a bulged three‐way‐junction structure with catalytically important nucleotides residing in the bulge. A highly conserved G?A mismatch is also crucial for the enzyme's activity.

     

Copper(II)‐bis‐Histidine Coordination Structure in a Fibrillar Amyloid β‐Peptide Fragment and Model Complexes Revealed by Electron Spin Echo Envelope Modulation Spectroscopy

Truncated and mutated amyloid‐β (Aβ) peptides are models for systematic study—in homogeneous preparations—of the molecular origins of metal ion effects on Aβ aggregation rates, types of aggregate structures formed, and cytotoxicity. The 3D geometry of bis‐histidine imidazole coordination of Cu^II in fibrils of the nonapetide acetyl‐Aβ(13–21)H14A has been determined by powder ¹⁴N electron spin echo envelope modulation (ESEEM) spectroscopy. The method of simulation of the anisotropic combination modulation is described and benchmarked for a Cu^II‐bis‐cis‐imidazole complex of known structure. The revealed bis‐cis coordination mode, and the mutual orientation of the imidazole rings, for Cu^II in Ac‐Aβ(13–21)H14A fibrils are consistent with the proposed β‐sheet structural model and pairwise peptide interaction with Cu^II, with an alternating [‐metal‐vacancy‐]_n pattern, along the N‐terminal edge. Metal coordination does not significantly distort the intra‐β‐strand peptide interactions, which provides a possible explanation for the acceleration of Ac‐Aβ(13–21)H14A fibrillization by Cu^II, through stabilization of the associated state and low‐reorganization integration of β‐strand peptide pair precursors.     

Studies on the Synthesis and Activity of Three Tripalladium Complexes Containing Planaramine Ligands

The present study deals with the synthesis, characterization and activity against human cancer cell lines: A2780, A2780^cisR and A2780^ZD0473R of three tripalladium complexes, MH3, MH4 and MH5, that each have two planaramine ligands bound to the central metal ion. Cellular uptake levels, extent of DNA binding, and nature of interaction with salmon sperm and pBR322 plasmid DNA were determined for each complex. Palladium compounds are much more reactive than their corresponding platinum derivatives, which makes them therapeutically inactive but toxic. However, the results of the present study suggest that significant antitumour activity can be introduced in palladium complexes by lessening their reactivity by the introduction of sterically hindered ligands such as 2‐hydroxypyridine, 3‐hydroxypyridine and 4‐hydroxypyridine. When bound to the central palladium ion, 4‐hydroxypyridine appears to be more activating than 2‐hydroxypyridine and 3‐hydroxypyridine, suggesting that noncovalent interactions, such as hydrogen bonding, may also be key determinants of antitumour activity in addition to the steric effect. While cisplatin binds with DNA to form intrastrand GG adducts that causes local bending of a DNA strand, these planaramine‐derived palladium complexes are expected to bind with DNA and form a number of long‐range interstrand GG adducts that would cause a global change in DNA conformation, provided the tripalladium cations in MH3, MH4 and MH5 persist under physiological conditions.     

Improved Bioactivity of Antimicrobial Peptides by Addition of Amino‐Terminal Copper and Nickel (ATCUN) Binding Motifs

Antimicrobial peptides (AMPs) are promising candidates to help circumvent antibiotic resistance, which is an increasing clinical problem. Amino‐terminal copper and nickel (ATCUN) binding motifs are known to actively form reactive oxygen species (ROS) upon metal binding. The combination of these two peptidic constructs could lead to a novel class of dual‐acting antimicrobial agents. To test this hypothesis, a set of ATCUN binding motifs were screened for their ability to induce ROS formation, and the most potent were then used to modify AMPs with different modes of action. ATCUN binding motif‐containing derivatives of anoplin (GLLKRIKTLL‐NH₂), pro‐apoptotic peptide (PAP; KLAKLAKKLAKLAK‐NH₂), and sh‐buforin (RAGLQFPVGRVHRLLRK‐NH₂) were synthesized and found to be more active than the parent AMPs against a panel of clinically relevant bacteria. The lower minimum inhibitory concentration (MIC) values for the ATCUN–anoplin peptides are attributed to the higher pore‐forming activity along with their ability to cause ROS‐induced membrane damage. The addition of the ATCUN motifs to PAP also increases its ability to disrupt membranes. DNA damage is the major contributor to the activity of the ATCUN–sh‐buforin peptides. Our findings indicate that the addition of ATCUN motifs to AMPs is a simple strategy that leads to AMPs with higher antibacterial activity and possibly to more potent, usable antibacterial agents.     

Chromate Binding and Removal by the Molybdate‐Binding Protein ModA

Effective and cheap methods and techniques for the safe removal of hexavalent chromate from the environment are in increasingly high demand. High concentrations of hexavalent chromate have been shown to have numerous harmful effects on human biology. We show that the E. coli molybdate‐binding protein ModA is a genetically encoded tool capable of removing chromate from aqueous solutions. Although previously reported to not bind chromate, we show that ModA binds chromate tightly and is capable of removing chromate to levels well below current US federal standards.     

Synthesis of 2,3‐Diarylbenzo[b]thiophenes via Nickel‐Catalyzed Suzuki–Miyaura Cross‐Coupling and Palladium‐Catalyzed Decarboxylative Arylation

We report a new approach to 2,3‐diarylbenzo[b]thiophenes based on the nickel‐catalyzed Suzuki–Miyaura cross‐coupling/palladium‐catalyzed decarboxylative arylation sequence of 3‐chloro‐2‐methoxycarbonylbenzo[b]thiophenes, which are readily accessible from the corresponding cinnamic acids. In addition, this methodology can be applied to the concise synthesis of π‐extended 2,3,6,7‐tetraarylbenzo[1,2‐b;4,5‐b′]dithiophenes. Their optical properties are also described.     

The Dynamic Regulation of G-Quadruplex DNA Structures by Cytosine Methylation

It is well known that certain non B-DNA structures, including G-quadruplexes, are key elements that can regulate gene expression. Here, we explore the theory that DNA modifications, such as methylation of cytosine, could act as a dynamic switch by promoting or alleviating the structural formation of G-quadruplex structures in DNA or RNA. The interaction between epigenetic DNA modifications, G4 formation, and the 3D architecture of the genome is a complex and developing area of research. Although there is growing evidence for such interactions, a great deal still remains to be discovered. In vivo, the potential effect that cytosine methylation may have on the formation of DNA structures has remained largely unresearched, despite this being a potential mechanism through which epigenetic factors could regulate gene activity. Such interactions could represent novel mechanisms for important biological functions, including altering nucleosome positioning or regulation of gene expression. Furthermore, promotion of strand-specific G-quadruplex formation in differentially methylated genes could have a dynamic role in directing X-inactivation or the control of imprinting, and would be a worthwhile focus for future research.     

Molecular Recognition of Parallel DNA Quadruplex d(TTAGGGT)4 by Mitoxantrone: Binding with 1:2 Stoichiometry Leading to Thermal Stabilization and Telomerase Inhibition

The interaction of the anthraquinone derivative mitoxantrone, a semisynthetic anti‐cancer drug with two non‐planar side chains, with heptamer G‐quadruplex d(TTAGGGT)₄, which contains the human telomere DNA sequence, was evaluated by differential scanning calorimetry, fluorescence Job plotting, absorption, and NMR and CD spectroscopy. Binding led to thermal stabilization of DNA (ΔT_m=13–20 °C). The spectra revealed that two mitoxantrone molecules bind externally at two sites of the DNA quadruplex as monomers, by partial insertion of the chromophore and side‐chain interaction at the grooves. The inhibition of telomerase (IC₅₀=2 μm), as determined by a TRAP assay, can be attributed to thermal stabilization of the DNA quadruplex because of the interactions with mitoxantrone. The studies revealed highly specific molecular recognition between a ligand and a parallel‐stranded G‐quadruplex; this might serve as a platform for the rational design of new drugs.     

Evaluation of the Toxicity of Two Electron-Deficient Half-Sandwich Complexes against Human Lymphocytes from Healthy Individuals

Electron-deficient half-sandwich complexes are a class of under-studied organometallics with demonstrated potential as metallodrug candidates. This study investigates the effect of two 16-electron organoruthenium complexes ([(p-cym)Ru(benzene-1,2-dithiolato)] ( 1 ) and [(p-cym)Ru(maleonitriledithiolate)] ( 2 )) on the cell viability of non-immortalised human lymphocytes from healthy individuals. The genotoxic effects of 1 and 2 in lymphocytes are also investigated by using the Comet and cytokinesis-block micronucleus assays. Gene expression studies were carried out on a panel of genes involved in apoptosis and the DNA damage-repair response. Results show that the two 16-electron complexes do not have significant effect on the cell viability of human lymphocytes from healthy individuals. However, an increase in DNA damage is induced by both compounds, presumably through oxidative stress production.     

Single‐Molecule Unzipping Force Analysis of HU–DNA Complexes

The genome of bacteria is organized and compacted by the action of nucleoid‐associated proteins. These proteins are often present in tens of thousands of copies and bind with low specificity along the genome. DNA‐bound proteins thus potentially act as roadblocks to the progression of machinery that moves along the DNA. In this study, we have investigated the effect of histone‐like protein from strain U93 (HU), one of the key proteins involved in shaping the bacterial nucleoid, on DNA helix stability by mechanically unzipping single dsDNA molecules. Our study demonstrates that individually bound HU proteins have no observable effect on DNA helix stability, whereas HU proteins bound side‐by‐side within filaments increase DNA helix stability. As the stabilizing effect is small compared to the power of DNA‐based motor enzymes, our results suggest that HU alone does not provide substantial hindrance to the motor's progression in vivo.