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Objective: Benzoylaminoalkanohydroxamic acids, including 5-(4-dimethylaminobenzoyl)aminovaleric acid hydroxamide (4-Me2N-BAVAH), are structural analogues of Trichostatin A, a naturally occurring histone deacetylase inhibitor (HDACi). 4-Me2N-BAVAH has been shown to induce histone hyperacetylation and to inhibit proliferation in Friend erythroleukaemia cells in vitro. However, the molecular mechanisms have remained unidentified. Materials and Methods: In this study, we evaluated the effects of 4-Me2N-BAVAH on proliferation in non-malignant cells, namely epidermal growth factor-stimulated primary rat hepatocytes. Results and Conclusion: We have found that 4-Me2N-BAVAH inhibits HDAC activity at non-cytotoxic concentrations and prevents cells from responding to the mitogenic stimuli of epidermal growth factor. This results in an early G1 cell cycle arrest that is independent of p21 activity, but instead can be attributed to inhibition of cyclin D1 transcription through a mechanism involving inhibition of nuclear factor-kappaB activation. In addition, 4-Me2N-BAVAH delays the onset of spontaneous apoptosis in primary rat hepatocyte cultures as evidenced by down-regulation of the pro-apoptotic proteins Bid and Bax, and inhibition of caspase-3 activation. [ABSTRACT FROM AUTHOR]

Brain metastases (BMs) are associated with poor prognosis in epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). Osimertinib is a third-generation, irreversible, EGFR-tyrosine kinase inhibitor that potently and selectively inhibits EGFR-sensitizing and T790M resistance mutations with efficacy in EGFRm NSCLC including central nervous system (CNS) metastases. The open-label phase I positron emission tomography (PET) and magnetic resonance imaging (MRI) study (ODIN-BM) assessed [ 11 C]osimertinib brain exposure and distribution in patients with EGFRm NSCLC and BMs. Three dynamic 90-min [ 11 C]osimertinib PET examinations were acquired together with metabolite-corrected arterial plasma input functions at: baseline, after first oral osimertinib 80 mg dose, and after greater than or equal to 21 days of osimertinib 80 mg q.d. treatment. Contrast-enhanced MRI was performed at screening and after 25-35 days of osimertinib 80 mg q.d.; treatment effect was assessed per CNS Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and per volumetric changes in total BM using a novel analysis approach. Four patients (aged 51-77 years) completed the study. At baseline, ~1.5% injected radioactivity reached the brain (ID max[brain] ) 22 min (median, T max[brain] ) after injection. Total volume of distribution (V T ) in whole brain was numerically higher compared with the BM regions. After a single oral osimertinib 80 mg dose, there was no consistent decrease in V T in whole brain or BMs. After greater than or equal to 21 days' daily treatment, V T in whole brain and BMs were numerically higher versus baseline. MRI revealed 56%-95% reduction in total BMs volume after 25-35 days of osimertinib 80 mg q.d. treatment. The [ 11 C]osimertinib crossed the blood-brain and brain-tumor barriers and had a high, homogeneous brain distribution in patients with EGFRm NSCLC and BMs., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. This analysis evaluates acquired resistance mechanisms to second-line osimertinib (n = 78) in patients with EGFR T790M advanced non-small cell lung cancer (NSCLC) from AURA3 (NCT02151981), a randomized phase 3 study comparing osimertinib with chemotherapy. Plasma samples collected at baseline and disease progression/treatment discontinuation are analyzed using next-generation sequencing. Half (50%) of patients have undetectable plasma EGFR T790M at disease progression and/or treatment discontinuation. Fifteen patients (19%) have >1 resistance-related genomic alteration; MET amplification (14/78, 18%) and EGFR C797X mutation (14/78, 18%)., (© 2023. The Author(s).)

Two salts were prepared by methyl-ation of the respective imidazoline-2-thione at the sulfur atom, using Meerwein's salt (tri-methyl-oxonium tetra-fluorido-borate) in CH 2 Cl 2 . 1,3-Dimeth-oxy-2-(methyl-sulfan-yl)imidazolium tetra-fluorido-borate ( 1 ), C 6 H 11 N 2 O 2 S + ·BF 4 - , displays a syn conformation of its two meth-oxy groups relative to each other whereas the two benz-yloxy groups present in 1,3-dibenz-yloxy-2-(methyl-sulfan-yl)imidazolium tetra-fluorido-borate ( 2 ), C 18 H 19 N 2 O 2 S + ·BF 4 - , adopt an anti conformation. In the mol-ecules of 1 and 2 , the methyl-sulfanyl group is rotated out of the plane of the respective heterocyclic ring. In both crystal structures, inter-molecular inter-actions are dominated by C-H⋯F-B contacts, leading to three-dimensional networks. The tetra-fluorido-borate counter-ion of 2 is disordered over three orientations (occupancy ratio 0.42:0.34:0.24), which are related by rotation about one of the B-F bonds., (© Gelbrich et al. 2020.)

Introduction: Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor (TKI). Durvalumab is an anti-programmed death ligand 1 monoclonal antibody. The phase III open-label CAURAL trial (NCT02454933) investigated osimertinib plus durvalumab versus osimertinib monotherapy in patients with EGFR-TKI sensitizing and EGFR T790M mutation-positive advanced NSCLC and disease progression after EGFR-TKI therapy., Methods: Patients were randomly assigned 1:1 to receive orally administered osimertinib (80 mg once daily) with or without durvalumab (10 mg/kg administered intravenously every 2 weeks) until progression. Treatment could continue beyond progression, providing clinical benefit continued (judged by the investigator). The amended primary objective was to assess the safety and tolerability of osimertinib plus durvalumab; efficacy was an exploratory objective., Results: CAURAL recruitment was terminated early because of increased incidence of interstitial lung disease-like events in the osimertinib plus durvalumab arm from the separate phase Ib TATTON trial (NCT02143466). At termination of CAURAL recruitment, 15 patients had been randomly assigned to treatment with osimertinib and 14 to treatment with osimertinib plus durvalumab. The most common AEs were diarrhea (53% [grade ≥3 in 6% of patients]) in the osimertinib arm and rash (67% [grade ≥3 in 0 patients]) in the combination arm. One patient who had been randomized to the combination arm reported grade 2 interstitial lung disease while receiving osimertinib monotherapy (after discontinuing durvalumab therapy after one dose). The objective response rates were 80% in the osimertinib arm and 64% in the combination arm., Conclusion: Limited patient numbers preclude formal safety and efficacy comparisons between the two treatment arms. The combination of programmed cell death 1/programmed death ligand 1 inhibitors and EGFR-TKIs as therapy for NSCLC is not well understood, but it requires a careful approach if considered in the future., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Attempts at direct bromination of 1,3-di-methyl-imidazolium salts were futile. The title compounds, 2-bromo-1,3-di-methyl-imidazolium iodide chloro-form 0.33-solvate, C 5 H 8 BrN 2 + ·I - ·0.33CHCl 3 , 2-bromo-1,3-di-methyl-imidazolium iodide di-chloro-methane hemisolvate, C 5 H 8 BrN 2 + ·I - ·0.5CH 2 Cl 2 , and 2-bromo-1,3-di-methyl-imidazolium iodide hemi(diiodide), C 5 H 8 BrN 2 + ·I - ·0.5I 2 , were obtained by methyl-ation of 2-bromo-1-methyl-imidazole. They crystallized as CHCl 3 , CH 2 Cl 2 or I 2 solvates/adducts. The Br atom acts as a σ-hole to accept short C-Br⋯I inter-actions. C-H⋯I hydrogen bonds are observed in each structure.

The title compound, C 21 H 12 Br 2 F 13 NO·2CH 3 OH, was obtained by condensation of 4-methyl-1-(1 H ,1 H ,2 H ,2 H -perfluoro-oct-yl)pyridinium iodide and 3,5-di-bromo-4-hy-droxy-benzaldehyde, followed by deprotonation. It crystallizes as a methanol disolvate and exhibits short O-H⋯O hydrogen bonds and a disordered perfluoro-alkyl chain [occupancy ratio 0.538 (7):0.462 (7)]. Significant π-π stacking inter-actions are observed between the benzene and pyridine rings of neighbouring mol-ecules along the b- axis direction.

The title salt, [Ag(C5H8N2O2)2]PF6, was obtained by deprotonation and metalation of 1,3-di-meth-oxy-imidazolium hexa-fluorido-phosphate using silver(I) oxide in methanol. The C-Ag-C angle in the cation is 178.1 (2)°, and the N-C-N angles are 101.1 (4) and 100.5 (4)°. The meth-oxy groups adopt an anti conformation. In the crystal, anions (A) are sandwiched between cations (C) in a layered arrangement {C…A…C} n stacked along [001]. Within a C…A…C layer, the hexafluoridophosphate anions accept several C-H⋯F hydrogen bonds from the cationic complex.

The title compound, C12H11N5·2H2O, which crystallizes as a dihydrate, was obtained by Cu(I)-catalysed azide-alkyne cyclo-addition from 2-azido-1-methyl-imidazole and phenyl-ethyne. The dihedral angles between the central triazole ring (r.m.s. deviation = 0.004 Å) and the pendant imidazole (r.m.s. deviation = 0.006 Å) and phenyl rings are 12.3 (2) and 2.54 (19)°, respectively. In the crystal, the water mol-ecules are connected into [010] chains by O-H⋯O hydrogen bonds, while O-H⋯N hydrogen bonds connect the water mol-ecules to the organic mol-ecules, generating corrugated (100) sheets.

Mutual carbox-yl-carboxyl O-H⋯O hydrogen bonds link the mol-ecules of the title compound, C7H5BrO3, into centrosymmetric dimers which display a central R 2 (2)(8) ring motif. In addition, there is an intra-molecular hydrox-yl-carboxyl O-H⋯O inter-action present. A comparison with the crystal structures of 59 other substituted derivatives of salicylic acid shows that both the centrosymmetric carbox-yl-carboxyl O-H⋯O dimer and the stacking mode of mol-ecules along the short a axis observed in the title structure are frequent packing motifs in this set.

The title compound, (C10H21N3)[CuCl4], is composed of one 1-[2-(di-ethyl-aza-nium-yl)eth-yl]-3-methyl-imidazolium dication and a tetra-chlorido-cuprate(II) dianion. The anion adopts a distorted tetra-hedral geometry. Bifurcated interionic N-H⋯Cl hydrogen bonds and several C-H⋯Cl contacts are observed, leading to a layer-like arrangement of the components parallel to (100).

The title compound, C5H9BrN4O, was obtained as a minor by-product in the synthesis of 4-di-methyl-amino-1-methyl-1,2,4-triazolin-5-one. Except for the methyl groups of the 4-dimethylamino moiety, all the non-H atoms lie on a crystallographic mirror plane." In the crystal, the mol-ecules are linked by C-Br⋯O=C inter-actions [Br⋯O = 2.877 (2) Å, C-Br⋯O = 174.6 (1)°] into infinite chains in the c-axis direction.

The crystal structures of three salts of anionic 5-aminotetrazole are described. The tetramethylammonium salt ( P [Formula: see text]) forms hydrogen-bonded ribbons of anions which accept weak C-H⋯N contacts from the cations. The cystamine salt ( C 2/ c ) shows wave-shaped ribbons of anions linked by hydrogen bonds to screw-shaped dications. The tetramethylguanidine salt ( P 2 1 / c ) exhibits layers of anions hydrogen-bonded to the cations.

Pseudomonas putida is a member of the fluorescent pseudomonads known to produce the yellow-green fluorescent pyoverdine siderophore. P. putida W15Oct28, isolated from a stream in Brussels, was found to produce compound(s) with antimicrobial activity against the opportunistic pathogens Staphylococcus aureus, Pseudomonas aeruginosa, and the plant pathogen Pseudomonas syringae, an unusual characteristic for P. putida. The active compound production only occurred in media with low iron content and without organic nitrogen sources. Transposon mutants which lost their antimicrobial activity had the majority of insertions in genes involved in the biosynthesis of pyoverdine, although purified pyoverdine was not responsible for the antagonism. Separation of compounds present in culture supernatants revealed the presence of two fractions containing highly hydrophobic molecules active against P. aeruginosa. Analysis of the draft genome confirmed the presence of putisolvin biosynthesis genes and the corresponding lipopeptides were found to contribute to the antimicrobial activity. One cluster of ten genes was detected, comprising a NAD-dependent epimerase, an acetylornithine aminotransferase, an acyl CoA dehydrogenase, a short chain dehydrogenase, a fatty acid desaturase and three genes for a RND efflux pump. P. putida W15Oct28 genome also contains 56 genes encoding TonB-dependent receptors, conferring a high capacity to utilize pyoverdines from other pseudomonads. One unique feature of W15Oct28 is also the presence of different secretion systems including a full set of genes for type IV secretion, and several genes for type VI secretion and their VgrG effectors.

The title compound, C9H10N4O, was obtained unintentionally by hydrolysis of 4-amino-1-benzyl-5-methyl-sulfanyl-1,2,4-triazolium tetra-fluoro-borate in the presence of sodium azide. In the crystal, alternating layers of polar amino-triazolinone and apolar benzene moieties are observed. N-H⋯O hydrogen bonds between the amino and carbonyl groups form infinite chains along [010]. These infinite chains are linked by additional C-H⋯O contacts.

Four (57)Fe-labeled tetrachloroferrates(III) of organic cations (1-butyl-3-methylimidazolium, 1-allyl-3-methylimidazolium, 1-methyl-1-propylpyrrolidinium, tetraphenylphosphonium) were examined by temperature-dependent Mössbauer spectroscopy. The hyperfine and dynamic parameters of the iron(III) site were determined. Single crystal X-ray diffraction data of [Ph(4)P][FeCl(4)] were collected at four temperatures (295, 223, 173, and 123 K), and the dynamics of the iron atom inferred from the Mössbauer data and the single crystal U(i,j) parameters have been compared.

Enzastaurin, an acyclic bisindolymaleimide, is a potent and selective competitive inhibitor of protein kinase Cbeta, which has been shown to inhibit cancer cell proliferation and angiogenesis in human cancer cell lines. Gemcitabine and pemetrexed are two cytotoxic drugs that are currently used in non-small cell lung cancer (NSCLC) therapy. In this study, we have investigated whether the addition of enzastaurin to gemcitabine or to pemetrexed is able to increase their antitumor activity to establish an effective schedule of combined treatment. The effects on cancer cell proliferation, cell cycle distribution, intracellular mitogenic and antiapoptotic signaling pathways, and induction of apoptosis were evaluated in three different combination sequences (concomitant treatment, sequential treatment with the cytotoxic drug followed by enzastaurin, or sequential treatment with enzastaurin followed by the cytotoxic drug) in a panel of human NSCLC cell lines. The combination of enzastaurin with either gemcitabine or pemetrexed caused different antiproliferative and proapoptotic effects depending on the treatment schedule. A synergistic antiproliferative and proapoptotic activity was only obtained when chemotherapy was followed by treatment with enzastaurin. These effects were accompanied by the arrest of the surviving cancer cells in the S phase, thus limiting their ability to proceed through the cell cycle, and by a maximum inhibition in the activated, phosphorylated forms of Akt and mitogen-activated protein kinase. In contrast, the concomitant treatments or the sequential treatments, in which enzastaurin was given before chemotherapy, resulted in significant antagonistic effects.

Objective: Benzoylaminoalkanohydroxamic acids, including 5-(4-dimethylaminobenzoyl)aminovaleric acid hydroxamide (4-Me(2)N-BAVAH), are structural analogues of Trichostatin A, a naturally occurring histone deacetylase inhibitor (HDACi). 4-Me(2)N-BAVAH has been shown to induce histone hyperacetylation and to inhibit proliferation in Friend erythroleukaemia cells in vitro. However, the molecular mechanisms have remained unidentified., Materials and Methods: In this study, we evaluated the effects of 4-Me(2)N-BAVAH on proliferation in non-malignant cells, namely epidermal growth factor-stimulated primary rat hepatocytes., Results and Conclusion: We have found that 4-Me(2)N-BAVAH inhibits HDAC activity at non-cytotoxic concentrations and prevents cells from responding to the mitogenic stimuli of epidermal growth factor. This results in an early G(1) cell cycle arrest that is independent of p21 activity, but instead can be attributed to inhibition of cyclin D1 transcription through a mechanism involving inhibition of nuclear factor-kappaB activation. In addition, 4-Me(2)N-BAVAH delays the onset of spontaneous apoptosis in primary rat hepatocyte cultures as evidenced by down-regulation of the pro-apoptotic proteins Bid and Bax, and inhibition of caspase-3 activation.

Tosylmethyl isocyanide was used to convert 7,8-didehydro-6-ketomorphinans to 6,7-didehydromorphinan-6-carbonitriles with retainment of the 4,5-epoxy ring. However, ring opening occurred in the presence of NaH giving 5,6,7,8-tetradehydromorphinan-6-carbonitriles. Addition of nucleophiles such as Li diisopropylamide or Grignard reagents to the acrylonitrile substructure yielded ring-opened 5,6-didehydro products. Seven products were characterized by X-ray crystal structure analysis and revealed insight into the mechanistic diversity of the van Leusen reaction.

In principle, all biochemical reactions are reversible, though some are more reversible than others. The classical ribonuclease mechanism involves a reversible transphosphorylation step, followed by quasi irreversible hydrolysis of the cyclic intermediate. We performed isotope-exchange and intermediate-trapping experiments showing that the second hydrolysis step is readily reversible in the presence of RNase A or RNase T1. As a consequence, the equilibrium between a phosphodiester and a 2',3'-cyclophosphate accounts for all catalysed reactions, even if the leaving/attacking group is a water molecule. Therefore, ribonucleases are transferases rather than hydrolases. The equilibrium constant for the catalysed interconversion is close to 1 M. From this result, we estimate the effective concentration of the 2'-hydroxyl nucleophile in the cyclization step to be 10(7) M. The high effective concentration of the vicinal hydroxyl group balances the strain-associated and solvation-associated instability of the pentacyclic phosphodiester.