Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. However, further refinement is needed to this class of agents, particularly ...in terms of adverse events (potentially driven by kinase promiscuity), which preclude their evaluation in nononcology indications. Here, we report the discovery and preclinical characterization of evobrutinib, a potent, obligate covalent inhibitor with high kinase selectivity. Evobrutinib displayed sufficient preclinical pharmacokinetic and pharmacodynamic characteristics which allowed for in vivo evaluation in efficacy models. Moreover, the high selectivity of evobrutinib for BTK over epidermal growth factor receptor and other Tec family kinases suggested a low potential for off-target related adverse effects. Clinical investigation of evobrutinib is ongoing in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.
Ruthenium(II)-arene complexes have gained significant research interest due to their possible application in cancer therapy. In this contribution two new complexes are described, namely {RuCl(η
-
...-cymene)}
(μ-Cl)(μ-1-
,
-naphthyl)X (X = Cl,
; PF
,
), which were fully characterized by IR, NMR, and elemental microanalysis. Furthermore, the structure of
in the solid state was determined by a single crystal X-ray crystallographic study, confirming the composition of the crystals as
. The Hirshfeld surface analysis was employed for the investigation of interactions that govern the crystal structure of
. The structural data for
out of
was used for the theoretical analysis of the cationic part {RuCl(η
-
-cymene)}
(μ-Cl)(μ-1-
,
-naphthyl)
(
) which is common to both
and
. The density functional theory, at B3LYP/6-31+G(d,p) basis set for H, C, N, and Cl atoms and LanL2DZ for Ru ions, was used for the optimization of the
structure. The natural bond orbital and quantum theory of atoms in molecules analyses were employed to quantify the intramolecular interactions. The reproduction of experimental IR and NMR spectra proved the applicability of the chosen level of theory. The binding of
to bovine serum albumin was examined by spectrofluorimetry and molecular docking, with complementary results obtained. Compound
acted as a radical scavenger towards DPPH
and HO
radicals, along with high activity towards cancer prostate and colon cell lines.
A common technique for analysis of protein glycosylation is HPLC coupled to mass spectrometry (LC-MS). However, analysis is challenging due to a low abundance of glycopeptides in complex protein ...digests, microheterogeneity at the glycosylation site, ion suppression effects, and competition for ionization by coeluting peptides. Specific sample preparation is necessary for a comprehensive and site-specific glycosylation analysis by MS. In this study we qualitatively compared hydrophilic interaction chromatography (HILIC) and hydrazine chemistry for the enrichment of all N-linked glycopeptides and titanium dioxide for capturing sialylated glycopeptides from a complex peptide mixture. Bare silica, microcrystalline cellulose, amino-, amide- (TSKgel Amide-80), and sulfobetaine-(ZIC-HILIC) bonded phases were evaluated for HILIC enrichment. The experiments revealed that ZIC-HILIC and TSKgel Amide-80 are very specific for capturing glycopeptides under optimized conditions. Quantitative analysis of N-glycosidase F-released and 2-aminobenzamide-labeled glycans of a ZIC-HILIC-enriched monoclonal antibody demonstrated that glycopeptides could be enriched without bias for particular glycan structures and without significant losses. Sialylated glycopeptides could be efficiently enriched by titanium dioxide and in addition to HILIC both methods enable a comprehensive analysis of protein glycosylation by MS. Enrichment of N-linked glycopeptides by hydrazine chemistry resulted in lower peptide recovery using a more complex enrichment scheme.
Ruthenium complexes have gained significant attention due to the ruthenium similarity to iron, lower toxicity, and higher anticancer effectiveness than other compounds. In this contribution, five new ...isonicotinate-polyethylene glycol ester ligands were synthesised and characterised by NMR and IR spectroscopies. The corresponding Ru(II) complexes were also obtained, and their structure was investigated by traditional methods. The optimisation of structures was performed at B3LYP/6-31+G(d,p) level of theory for H, C, N and O atoms and B3LYP/LanL2DZ for Ru. The intramolecular stabilisation interactions were assessed through the natural bond orbital approach. The NMR chemical shifts were predicted by the gauge independent atomic orbital method and compared to the experimental values. High correlation coefficients and low mean absolute errors between these data sets proved that the predicted structures described well the experimental ones. The theoretical and experimental IR spectra were also compared, and differences in the most notable bands were described. One of the ligands (L5) and complexes (5) showed fluorescent properties due to methylisatoic moiety. The electronic spectra of this compound were modelled by the time dependent-density functional theory method. The difference of 11 nm between the experimental and the theoretical wavelength was explained by the interactions between the solvent and the solute. Further biological and theoretical studies are advised for this series of compounds.
Ruthenium(II/III)-based compounds have gained significant interest due to the biocompatibility of ruthenium, its similarity to iron, and the possibility for structural diversification through the ...choice of ligands. In this contribution, two novel ligands, (2-(2-methoxyethoxy)ethyl nicotinate hydrochloride) and (2-2-(2-methoxyethoxy)ethoxyethyl nicotinate hydrochloride) (pyCOO(CH2CH2O)nCH3: L2, n = 2; L3, n = 3), were synthesized and characterized via ESI-HRMS, as well as IR and NMR spectroscopies. Their structures were optimized at the B3LYP/6-311++G(d,p) level of theory, and NMR chemical shifts were predicted, along with the most important intramolecular interactions. Additionally, two neutral complexes of the general formula RuCl2(η6-p-cym) (L-κN) (L = L2: 2; L3: 3) and two cationic complexes of the general formula RuCl(η6-p-cym)(L-κN)2PF6 (L = L1: 4; L2: 5) were obtained and characterized. The optimization of the structures was performed at the B3LYP/6-31+G(d,p)(H,C,N,O,Cl)/LanL2DZ(Ru) level of theory. Structural features were described, and intramolecular stabilization interactions were outlined.
Xanthohumol (XN) and isoxanthohumol (IXN), prenylated flavonoids from Humulus lupulus, have been shown to possess antitumor/cancerprotective, antioxidant, antiinflammatory, and antiangiogenic ...properties. In this study, mesoporous silica (SBA-15) was loaded with different amounts of xanthohumol and isoxanthohumol and characterized by standard analytical methods. The anticancer potential of XN and IXN loaded into SBA-15 has been evaluated against malignant mouse melanoma B16F10 cells. When these cells were treated with SBA-15 containing xanthohumol, an increase of the activity correlated with a higher immobilization rate of XN was observed. Considering the amount of XN loaded into SBA-15 (calculated from TGA), an improved antitumor potential of XN was observed (IC50 = 10.8 ± 0.4 and 11.8 ± 0.5 µM for SBA-15|XN2 and SBA-15|XN3, respectively; vs. IC50 = 18.5 ± 1.5 µM for free XN). The main mechanism against tumor cells of immobilized XN includes inhibition of proliferation and autophagic cell death. The MC50 values for SBA-15 loaded with isoxanthohumol were over 300 µg/mL in all cases investigated.
Test beam measurements at the test beam facilities of DESY have been conducted to characterise the performance of the EUDET-type beam telescopes originally developed within the EUDET project. The ...beam telescopes are equipped with six sensor planes using MIMOSA 26 monolithic active pixel devices. A programmable Trigger Logic Unit provides trigger logic and time stamp information on particle passage. Both data acquisition framework and offline reconstruction software packages are available. User devices are easily integrable into the data acquisition framework via predefined interfaces.
The biased residual distribution is studied as a function of the beam energy, plane spacing and sensor threshold. Its standard deviation at the two centre pixel planes using all six planes for tracking in a 6 GeV electron/positron-beam is measured to be (2.88 ± 0.08) µm. Iterative track fits using the formalism of General Broken Lines are performed to estimate the intrinsic resolution of the individual pixel planes. The mean intrinsic resolution over the six sensors used is found to be (3.24 ± 0.09) µm. With a 5 GeV electron/positron beam, the track resolution halfway between the two inner pixel planes using an equidistant plane spacing of 20 mm is estimated to (1.83 ± 0.03) µm assuming the measured intrinsic resolution. Towards lower beam energies the track resolution deteriorates due to increasing multiple scattering. Threshold studies show an optimal working point of the MIMOSA 26 sensors at a sensor threshold of between five and six times their RMS noise. Measurements at different plane spacings are used to calibrate the amount of multiple scattering in the material traversed and allow for corrections to the predicted angular scattering for electron beams.
Neutral Ru(η6-arene)Cl2{Ph2P(CH2)3SPh-κP} (arene = benzene, indane, 1,2,3,4-tetrahydronaphthalene: 2a, 2c and 2d) and cationic Ru(η6-arene)Cl(Ph2P(CH2)3SPh-κP,κS)X complexes (arene = mesitylene, ...1,4-dihydronaphthalene; X = Cl: 3b, 3e; arene = benzene, mesitylene, indane, 1,2,3,4-tetrahydronaphthalene, and 1,4-dihydronaphthalene; X = PF6: 4a–4e) complexes were prepared and characterized by elemental analysis, IR, 1H, 13C and 31P NMR spectroscopy and also by single-crystal X-ray diffraction analyses. The stability of the complexes has been investigated in DMSO. Complexes have been assessed for their cytotoxic activity against 518A2, 8505C, A253, MCF-7 and SW480 cell lines. Generally, complexes exhibited activity in the lower micromolar range; moreover, they are found to be more active than cisplatin. For the most active ruthenium(II) complex, 4b, bearing mesitylene as ligand, the mechanism of action against 8505C cisplatin resistant cell line was determined. Complex 4b induced apoptosis accompanied by caspase activation.
In this article, we examine changes in family climate during the first Covid‐19‐related lockdown in Germany. We compare the perspectives of mothers and adolescents to explore whether the factors of ...perceived changes in family climate are systematically and significantly different between these groups. We measure family climate as positive emotional climate, a sub‐dimension of the family environment scale, to capture a feeling of cohesion and emotional openness within the family. Based on family system theory and the family stress model, we expect an overall deterioration in family climate due to increased environmental adaptation in the pandemic. Furthermore, we expect family climate to deteriorate less when families have economic and social resources available. On the other hand, we assume that being employed and/or primarily responsible for family care relates to a stronger decline in the family climate. We employ longitudinal survey data (AID:A) from around 300 German families with children aged nine to 17 and apply individual fixed effects models to investigate changes in family climate from 2019 to 2020. Almost half of our respondents report a decrease in family climate. For mothers, the share of unpaid care work at home is the only significant predictor: Mothers doing more than 80% of the chores and childcare feel a greater decrease in family climate. For adolescents, however, being at risk of poverty and having less frequent family activities are important predictors of stronger decreases in family climate. In summary, our results illustrate the relevance of distinguishing between the perspective of children and parents in family studies.
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