General-base catalysed hydrolysis and nucleophilic substitution of activated amides in aqueous solutions

The reactivity of 1-benzoyl-3-phenyl-1,2,4-triazole (1a) was studied in the presence of a range of weak bases in aqueous solution. A change in mechanism is observed from general-base catalysed hydrolysis to nucleophilic substitution and general-base catalysed nucleophilic substitution. A slight tendency is also observed for the more hydrophobic general bases to show higher reactivity towards 1a. Aspartame is an effective nucleophile, possibly because nucleophilic substitution is subject to intramolecular general-base catalysis. A general conclusion derived from the present results is that unexpected rate effects can only be rationalised provided that the detailed reaction mechanisms are well understood. Copyright (C) 2003 John Wiley Sons, Ltd.</p

A water-soluble tetraazaperopyrene dye as strong G-quadruplex DNA binder

The interactions of the water-soluble tetraazaperopyrene dye 1 with ct-DNA, duplex-[(dAdT)12⋅(dAdT)12], duplex-[(dGdC)12⋅(dGdC)12] as well as with two G-quadruplex-forming sequences, namely the human telomeric 22AG and the promotor sequence c-myc, were investigated by means of UV/visible and fluorescence spectroscopy, isothermal titration calorimetry (ITC) and molecular docking studies. Dye 1 exhibits a high affinity for G-quadruplex structures over duplex DNA structures. Furthermore, the ligand shows promising G-quadruplex discrimination, with an affinity towards c-myc of 2×107 m−1 (i.e., Kd=50 nm), which is higher than for 22AG (4×106 m−1). The ITC data reveal that compound 1 interacts with c-myc in a stoichiometric ratio of 1:1 but also indicate the presence of two identical lower affinity secondary binding sites per quadruplex. In 22AG, there are two high affinity binding sites per quadruplex, that is, one on each side, with a further four weaker binding sites. For both quadruplex structures, the high affinity interactions between compound 1 and the quadruplex-forming nucleic acid structures are weakly endothermic. Molecular docking studies suggest an end-stacking binding mode for compound 1 interacting with quadruplex structures, and a higher affinity for the parallel conformation of c-myc than for the mixed-hybrid conformation of 22AG. In addition, docking studies also suggest that the reduced affinity for duplex DNA structures is due to the non-viability of an intercalative binding mode

A focus on computer vision for non-contact monitoring of catalyst degradation and product formation kinetics

Chemists know the value of looking at a reaction for clues about reaction progress and success, but what-it-looks-like has never been quantified. Reid and co-workers (C. Yan, M. Cowie, C. Howcutt, K. M. P. Wheelhouse, N. S. Hodnett, M. Kollie, M. Gildea, M. H. Goodfellow and M. Reid, Chem. Sci., 2023, 14, 5323–5331, https://doi.org/10.1039/d2sc05702f) have developed an approach that uses camera footage of reactions to obtain quantitative descriptors of changes in reaction mixtures to support kinetic analysis

The structure of linkers affects the DNA binding properties of tethered dinuclear ruthenium (II) metallo-intercalators

With the long-term aim of enhancing the binding properties of dinuclear RuII-based DNA light-switch complexes, a series of eight structurally related mono- and dinuclear systems are reported in which the linker of the bridging ligand has been modulated. These tethered systems have been designed to explore issues of steric demand at the binding site and the thermodynamic cost of entropy loss upon binding. An analysis of detailed spectroscopic and isothermal titration calorimetry (ITC) studies on the new complexes reveal that one of the linkers produces a dinuclear systems that binds to duplex DNA with an affinity (Kb > 107 M-1) that is higher than its corresponding monometallic complex and is the highest affinity for a non-threading bis-intercalating metal complex. These studies confirm that the tether has a major effect on the binding properties of dinuclear complexes containing nintercalating units and establishes key design rules for the construction of dinuclear complexes with enhance

Investigation of the interactions between methylene blue and intramolecular G-quadruplexes: an explicit distinction in electrochemical behavior

G-quadruplex sequences exist in eukaryotic organisms and prokaryotes, and the investigation of interactions between G-quadruplexes and small molecule ligands is important for gene therapy, biosensor fabrication, fluorescence imaging and so on. Here, we investigated the behaviour of methylene blue (MB), an electroactive molecule, in the presence of different intramolecular G-quadruplexes by electrochemical method using a miniaturized electrochemical device based on its intrinsic electrochemical property. Although the effects of MB on different intramolecular G-quadruplex structures are not obvious by circular dichroism spectroscopy, distinct differences in binding affinities of MB with different intramolecular G-quadruplexes were fast and easily observed by the electrochemical technique. At the same time, for the human telomerase G-rich sequence (HT), the diffusion current of MB changed sensitively under different ion conditions due to the formation of different conformations of HT, which indicated that our electrochemical method has the potential to study the influence of metal ions on the conformations of the G-quadruplexes with simplicity, rapid response and low cost. From all these, new stacking mechanism and rule were obtained, which were also validated by docking studies and isothermal titration calorimetry (ITC)

Halide-enhanced catalytic activity of palladium nanoparticles comes at the expense of catalyst recovery

In this communication, we present studies of the oxidative homocoupling of arylboronic acids catalyzed by immobilised palladium nanoparticles in aqueous solution. This reaction is of significant interest because it shares a key transmetallation step with the well-known Suzuki-Miyaura cross-coupling reaction. Additives can have significant effects on catalysis, both in terms of reaction mechanism and recovery of catalytic species, and our aim was to study the effect of added halides on catalytic efficiency and catalyst recovery. Using kinetic studies, we have shown that added halides (added as NaCl and NaBr) can increase the catalytic activity of the palladium nanoparticles more than 10-fold, allowing reactions to be completed in less than half a day at 30 °C. However, this increased activity comes at the expense of catalyst recovery. The results are in agreement with a reaction mechanism in which, under conditions involving high concentrations of chloride or bromide, palladium leaching plays an important role. Considering the evidence for analogous reactions occurring on the surface of palladium nanoparticles under different reaction conditions, we conclude that additives can exert a significant effect on the mechanism of reactions catalyzed by nanoparticles, including switching from a surface reaction to a solution reaction. The possibility of this switch in mechanism may also be the cause for the disagreement on this topic in the literature

The problem of racemization in drug discovery and tools to predict it

Introduction: Racemization has long been an ignored risk in drug development, probably because of a lack of convenient access to good tools for its detection and an absence of methods to predict racemization risk. As a result, the potential effects of racemization have been systematically underestimated. Areas covered: Herein, the potential effects of racemization are discussed through a review of drugs for which activity and side effects for both enantiomers are known. Subsequently, drugs known to racemize are discussed and the authors review methods to predict racemization risk. Application of a method quantitatively predicting racemization risk to databases of compounds from the medicinal chemistry literature shows that success in clinical trials is negatively correlated with racemization risk. Expert opinion: It is envisioned that a quantitative method of predicting racemization risk will remove a blind spot from the drug development pipeline. Removal of the blind spot will make drug development more efficient and result in less late-stage attrition of the drug pipeline