Assay Related Target Similarity (ARTS) - chemogenomics approach for quantitative comparison of biological targets

Computer-based chemogenomics approaches compare macromolecular drug targets based on their amino acid sequences or derived properties, by similarity of their ligands, or according to ligand-target interaction models. Here we present ARTS (Assay Related Target Similarity) as a quantitative index that estimates target similarity directly from measured affinities of a set of probe compounds. This approach reduces the risk of deducing artificial target relationships from mutually inactive compounds. ARTS implements a scoring scheme that matches intertarget similarity based on dose-response measurements. While all experimentally derived target similarities have a tendency to be data set-dependent, we demonstrate that ARTS depends less on the used data set than the commonly used Pearson correlation or Tanimoto index.     

N-(4-(di-tert-butyl[F]fluorosilyl)benzyl)-2-hydroxy-N,N-dimethylethylammonium bromide ([F]SiFANBr): A novel lead compound for the development of hydrophilic SiFA-based prosthetic groups for F-labeling

¹⁸F-labeled compounds play a major role in the development of new in vivo imaging agents for Positron Emission Tomography (PET), a non invasive imaging modality depicting the biodistribution of radioactive compounds in humans. Recently we reported a new method for the introduction of fluorine-18 into a range of organic molecules exploiting the very fast ¹⁸F-¹⁹F isotope exchange of fluorosilanes (termed SiFA compounds). Here, we wish to report the labeling of the first charged SiFA molecule N-(4-(di-tert-butylfluorosilyl)benzyl)-2-hydroxy-N,N-dimethylethylammonium bromide (SiFAN⁺Br⁻) serving as a lead compound in the development of SiFA-based prosthetic groups of reduced lipophilicity for biomolecule labeling. Mild conditions for synthesis of [¹⁸F]SiFAN⁺Br⁻ and an easy purification procedure using simple C-18 solid phase cartridge have been developed yielding the [¹⁸F]SiFAN⁺Br⁻ in radiochemical yields of 34% (non-decay corrected) within 40 min. A series of kinetic experiments were performed that show high isotopic exchange rate constants. Low activation energy (15.7 kcal/mol) and a large preexponential factor (7.9 × 10¹³ M⁻¹ s⁻¹) were calculated for the isotopic exchange reaction from a corresponding Arrhenius plot. For comparison, the ¹⁸F-fluorination of ethyleneglycol-di-p-tosylate via the formation of a carbon-¹⁸F bond showed a 1.3 kcal/mol higher activation energy and a much lower preexponential factor of 2.9 × 10⁹ M⁻¹ s⁻¹. Moderate hydrophilicity (log D = 0.44), stability in aqueous media at pH up to 7.4 and a high specific activity of [¹⁸F]SiFAN⁺Br⁻ (SA = 20.4 GBq/μmol, 0.55 Ci/μmol) make this charged SiFA compound useful for the development of novel SiFA-based ¹⁸F-labeling synthons.     

Kinetic energy release and position of transition state during the intramolecular substitution of ionized 2-benzoyl pyridines

The loss of substituents X from molecular ions of ortho substituted 2-benzoyl pyridines has been investigated as a function of the dissociation energy of the C? X bond. Comparison of unimolecular and collisional induced decompositions of the resulting [M ? X]⁺ ions and reference ions arising from 3-hydroxypyrido[1,2-α]indole shows that cyclic fragment ions are formed in every case by an intramolecular substitution reaction with the exception of the parent compound (X = H), which gives rise to a mixture of [M ? H]⁺ ions with different structures. The heat of formation of the cyclic ion has been estimated experimentally and by calculation using thermochemical data, and from this value and the appearance energies, the activation energies of the reverse reactions have been evaluated for the different reaction systems. Measurement of the kinetic energy release during the substitution reactions shows that only part of the reverse activation energy is released as kinetic energy. The energy partitioning quotient varies from 0.37 to 0.08 depending on the dissociation energy of the C? X bond or the reaction enthalpy. A sudden change in the energy partitioning quotient is observed with increasing exothermicity of the reaction, paralleling the behaviour of similar reaction systems. These results are interpreted as a demonstration of the influence of the variation of transition state position on the energy partitioning quotient.     

Measuring nitrate concentration in wastewaters with high chloride content

The presence of chloride ions in wastewaters in concentrations above 50 mg/L poses interference in several methods used for the measurement of nitrate-nitrogen. The aim of this study was to characterise the reliability and costs of some commonly available methods for the analysis of nitrate concentration in landfill leachate which contains high chloride levels. To investigate the effect of chloride interference, several widely used methods [ion chromatography (IC), continuous flow analysis (CFA), the German standard method (DIN), cuvette test (CUV), standard addition method (SAM) and reflectometric test (REF)] were used to measure the nitrate concentration in synthetic solutions containing varying concentrations of chloride and nitrate-nitrogen. Nitrate recoveries of the various methods were found to decrease in the following rank order: CUV (>95%) > IC (>90%) > CFA (89%) > DIN (88%) > REF (70%) > SAM (<80%). In the second part of the study, the same methods were used to measure nitrate concentrations in samples of biologically nitrified landfill leachate with and without chloride elimination. For leachate samples without chloride elimination, CUV results were well correlated (linear regression) with IC results (slope = 1.02/R² = 0.99) but to lesser extents with results obtained by CFA (0.91/0.86), DIN (0.89/0.97) and REF (0.86/0.77), and not correlated with SAM (0.74/–1.3). The incurred measurement costs per sample (in Euros) for the methods were as follows: CFA (<0.1) < DIN (0.6) < REF (0.7) < SAM (3) < CUV (3.8) < IC (15). Cuvette tests are recommended as the method of choice due to their accuracy and lower cost than IC.     

Surface reduction of freely floating smectic bubbles

Elongated freely floating smectic bubbles are observed during their relaxation to equilibrium sphere shape. Unlike soap bubbles that perform weakly damped oscillations into equilibrium, this relaxation is overdamped in smectics by internal structure reorganisation processes. The bubble area reduction of centimetre-sized freely floating bubbles with few nanometres film thickness is recorded with high-speed optical imaging in microgravity and analysed quantitatively. We find a nearly linear reduction of the film area with time, driven by capillary forces and inhibited by smectic layer reorganisations. Characteristic times are in the milliseconds range, with little correlation to the film thickness and bubble size. Instead, the homogeneity of the films and the number and sizes of islands of excess layers that spontaneously form on the films appear to have crucial influence on the dynamics. The efficiency of this process sets the time scale of the film area shrinkage. We discuss the limitations of a minimalistic model that captures smectic layer reorganisation processes.     

ROS‐Responsive N‐Alkylaminoferrocenes for Cancer‐Cell‐Specific Targeting of Mitochondria

Mitochondrial membrane potential is more negative in cancer cells than in normal cells, allowing cancer targeting by delocalized lipophilic cations (DLCs). However, as the difference is rather small, these drugs affect also normal cells. Now a concept of pro‐DLCs is proposed based on an N‐alkylaminoferrocene structure. These prodrugs are activated by the reaction with reactive oxygen species (ROS) forming ferrocenium‐based DLCs. Since ROS are overproduced in cancer, the high‐efficiency cancer‐cell‐specific targeting of mitochondria could be achieved as demonstrated by fluorescence microscopy in combination with two fluorogenic pro‐DLCs in vitro and in vivo. We prepared a conjugate of another pro‐DLC with a clinically approved drug carboplatin and confirmed that its accumulation in mitochondria was higher than that of the free drug. This was reflected in the substantially higher anticancer effect of the conjugate.     

Sodium halides as the source of electrophilic halogens in green synthesis of 3-halo- and 3,n-dihalobenzo[b]thiophenes

A convenient methodology for the synthesis of mono- and di-halogenated benzo[b]thiophenes is described herein, which utilizes copper(II) sulfate pentahydrate and various sodium halides in the presence of substituted 2-alkynylthioanisoles. The proposed method is facile, uses ethanol as a green solvent, and results in uniquely substituted benzo[b]thiophene structures with isolated yields up to 96%. The most useful component of this methodology is the selective introduction of bromine atoms at every available position (2–7) around the benzo[b]thiophene ring, while keeping position 3 occupied by a specific halogen atom such as Cl, Br or I. Aromatic halogens are useful reactive handles; therefore, the selective introduction of halogens at specific positions would be valuable in the targeted synthesis of bioactive molecules and complex organic materials via metal-catalyzed cross coupling reactions. This work is a novel approach towards the synthesis of dihalo substituted benzo[b]thiophene core structures, which provides a superior alternative to the current methods discussed herein.     

Syntheses,Crystal Structures,and Properties of New Ternary Chalcogenides of Group 4 Metals: Rb4Ti3S14, Cs4Zr3S14, K4Hf3Se14, and K4ZrHf2Se14

The new ternary compounds Rb₄Ti₃S₁₄, Cs₄Zr₃S₁₄, K₄Hf₃Se₁₄, and K₄ZrHf₂Se₁₄ were prepared by reacting the respective transition metals in alkali metal polychalcogenide melts. Two crystallographically independent transition metal cations are present that are coordinated by eight chalcogen atoms (Q) in an irregular fashion or by seven chalcogen atoms yielding a distorted pentagonal bipyramid. The M(1)Q₈ and M(2)Q₇ polyhedra are connected by sharing common edges or trigonal faces leading to the formation of infinite linear one‐dimensional anionic chains running parallel to the [101] direction. The chains are separated by alkali metal cations. The optical band gaps determined are 1.59 eV for Rb₄Ti₃S₁₄, 2.35 eV for Cs₄Zr₃S₁₄, and 2.02 eV for K₄Hf₃Se₁₄. In‐situ X‐ray powder diffractometry demonstrates that Rb₄Ti₃S₁₄ decomposes at 430 °C into Rb₂S₅ and TiS. During the cooling cycle the re‐formation of the polysulfide is observed. According to this result the polysulfide could be prepared using TiS instead of metallic Ti as well.