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Molecules (Basel, Switzerland) May 2024Chronic inflammation contributes to a number of diseases. Therefore, control of the inflammatory response is an important therapeutic goal. To identify novel...
Chronic inflammation contributes to a number of diseases. Therefore, control of the inflammatory response is an important therapeutic goal. To identify novel anti-inflammatory compounds, we synthesized and screened a library of 80 pyrazolo[1,5-]quinazoline compounds and related derivatives. Screening of these compounds for their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor κB (NF-κB) transcriptional activity in human THP-1Blue monocytic cells identified 13 compounds with anti-inflammatory activity (IC < 50 µM) in a cell-based test system, with two of the most potent being compounds (5-[(4-sulfamoylbenzyl)oxy]pyrazolo[1,5-]quinazoline-3-carboxamide) and (5-[(4-(methylsulfinyl)benzyloxy]pyrazolo[1,5-]quinazoline-3-carboxamide). Pharmacophore mapping of potential targets predicted that and may be ligands for three mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 2 (ERK2), p38α, and -Jun -terminal kinase 3 (JNK3). Indeed, molecular modeling supported that these compounds could effectively bind to ERK2, p38α, and JNK3, with the highest complementarity to JNK3. The key residues of JNK3 important for this binding were identified. Moreover, compounds and exhibited micromolar binding affinities for JNK1, JNK2, and JNK3. Thus, our results demonstrate the potential for developing lead anti-inflammatory drugs based on the pyrazolo[1,5-]quinazoline and related scaffolds that are targeted toward MAPKs.
Topics: Humans; Quinazolines; Anti-Inflammatory Agents; NF-kappa B; Lipopolysaccharides; Molecular Docking Simulation; Pyrazoles; Structure-Activity Relationship; THP-1 Cells
PubMed: 38893295
DOI: 10.3390/molecules29112421 -
International Journal of Molecular... Jun 2024Cardiac arrhythmias remain a significant concern with Ibrutinib (IBR), a first-generation Bruton's tyrosine kinase inhibitor (BTKi). Acalabrutinib (ABR), a...
Cardiac arrhythmias remain a significant concern with Ibrutinib (IBR), a first-generation Bruton's tyrosine kinase inhibitor (BTKi). Acalabrutinib (ABR), a next-generation BTKi, is associated with reduced atrial arrhythmia events. However, the role of ABR in ventricular arrhythmia (VA) has not been adequately evaluated. Our study aimed to investigate VA vulnerability and ventricular electrophysiology following chronic ABR therapy in male Sprague-Dawley rats utilizing epicardial optical mapping for ventricular voltage and Ca dynamics and VA induction by electrical stimulation in ex-vivo perfused hearts. Ventricular tissues were snap-frozen for protein analysis for sarcoplasmic Ca and metabolic regulatory proteins. The results show that both ABR and IBR treatments increased VA vulnerability, with ABR showing higher VA regularity index (RI). IBR, but not ABR, is associated with the abbreviation of action potential duration (APD) and APD alternans. Both IBR and ABR increased diastolic Ca leak and Ca alternans, reduced conduction velocity (CV), and increased CV dispersion. Decreased SERCA2a expression and AMPK phosphorylation were observed with both treatments. Our results suggest that ABR treatment also increases the risk of VA by inducing proarrhythmic changes in Ca signaling and membrane electrophysiology, as seen with IBR. However, the different impacts of these two BTKi on ventricular electrophysiology may contribute to differences in VA vulnerability and distinct VA characteristics.
Topics: Animals; Benzamides; Male; Rats; Rats, Sprague-Dawley; Agammaglobulinaemia Tyrosine Kinase; Arrhythmias, Cardiac; Piperidines; Action Potentials; Ventricular Remodeling; Protein Kinase Inhibitors; Pyrazines; Calcium; Adenine; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Heart Ventricles; Pyrimidines; Calcium Signaling; Pyrazoles; Tyrosine Kinase Inhibitors
PubMed: 38892396
DOI: 10.3390/ijms25116207 -
International Journal of Molecular... Jun 2024In order to overcome the resistance to radiotherapy in human chondrosarcoma cells, the prevention from efficient DNA repair with a combined treatment with the...
In order to overcome the resistance to radiotherapy in human chondrosarcoma cells, the prevention from efficient DNA repair with a combined treatment with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) inhibitor AZD7648 was explored for carbon ion (C-ion) as well as reference photon (X-ray) irradiation (IR) using gene expression analysis, flow cytometry, protein phosphorylation, and telomere length shortening. Proliferation markers and cell cycle distribution changed significantly after combined treatment, revealing a prominent G/M arrest. The expression of the G/M checkpoint genes cyclin B, CDK1, and WEE1 was significantly reduced by IR alone and the combined treatment. While IR alone showed no effects, additional AZD7648 treatment resulted in a dose-dependent reduction in AKT phosphorylation and an increase in Chk2 phosphorylation. Twenty-four hours after IR, the key genes of DNA repair mechanisms were reduced by the combined treatment, which led to impaired DNA repair and increased radiosensitivity. A time-dependent shortening of telomere length was observed in both cell lines after combined treatment with AZD7648 and 8 Gy X-ray/C-ion IR. Our data suggest that the inhibition of DNA-PKcs may increase sensitivity to X-rays and C-ion IR by impairing its functional role in DNA repair mechanisms and telomere end protection.
Topics: Humans; DNA-Activated Protein Kinase; Cell Line, Tumor; Chondrosarcoma; Heavy Ion Radiotherapy; Telomere; Cell Cycle Checkpoints; DNA Repair; Radiation Tolerance; Pyrazoles; Cell Proliferation; Bone Neoplasms; G2 Phase Cell Cycle Checkpoints
PubMed: 38892366
DOI: 10.3390/ijms25116179 -
International Journal of Molecular... May 2024(1) Head and neck squamous cell carcinoma (HNSCC) is common, while treatment is difficult, and mortality is high. Kinase inhibitors are promising to enhance the effects...
(1) Head and neck squamous cell carcinoma (HNSCC) is common, while treatment is difficult, and mortality is high. Kinase inhibitors are promising to enhance the effects of radiotherapy. We compared the effects of the PARP inhibitors talazoparib and niraparib and that of the DNA-PKcs inhibitor AZD7648, combined with ionizing radiation. (2) Seven HNSCC cell lines, including Cal33, CLS-354, Detroit 562, HSC4, RPMI2650 (HPV-negative), UD-SCC-2 and UM-SCC-47 (HPV-positive), and two healthy fibroblast cell lines, SBLF8 and SBLF9, were studied. Flow cytometry was used to analyze apoptosis and necrosis induction (AnnexinV/7AAD) and cell cycle distribution (Hoechst). Cell inactivation was studied by the colony-forming assay. (3) AZD7648 had the strongest effects, radiosensitizing all HNSCC cell lines, almost always in a supra-additive manner. Talazoparib and niraparib were effective in both HPV-positive cell lines but only consistently in one and two HPV-negative cell lines, respectively. Healthy fibroblasts were not affected by any combined treatment in apoptosis and necrosis induction or G2/M-phase arrest. AZD7648 alone was not toxic to healthy fibroblasts, while the combination with ionizing radiation reduced clonogenicity. (4) In conclusion, talazoparib, niraparib and, most potently, AZD7648 could improve radiation therapy in HNSCC. Healthy fibroblasts tolerated AZD7648 alone extremely well, but irradiation-induced effects might occur. Our results justify in vivo studies.
Topics: Humans; Phthalazines; Indazoles; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Cell Line, Tumor; Radiation-Sensitizing Agents; Squamous Cell Carcinoma of Head and Neck; Apoptosis; Head and Neck Neoplasms; DNA-Activated Protein Kinase
PubMed: 38891817
DOI: 10.3390/ijms25115629 -
Influenza and Other Respiratory Viruses Jun 2024This phase 2b/3, randomized, placebo-controlled trial explored the efficacy and evaluated the safety of ensitrelvir. This trial involved individuals with asymptomatic... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
This phase 2b/3, randomized, placebo-controlled trial explored the efficacy and evaluated the safety of ensitrelvir. This trial involved individuals with asymptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patients with mild symptoms of coronavirus disease 2019 (COVID-19).
METHODS
The trial was conducted at 57 medical institutions in Japan, South Korea, and Vietnam (study period: January 6-August 14, 2022). Eligible participants were randomized (1:1:1) to the ensitrelvir 125-mg, ensitrelvir 250-mg, or placebo group, received the allocated intervention orally, and were followed up until Day 28. Participants self-rated the severity of 14 typical COVID-19 symptoms and recorded the data in an electronic diary.
RESULTS
In total, 572 participants (194, 189, and 189 in the ensitrelvir 125-mg, ensitrelvir 250-mg, and placebo groups, respectively) were included in the intention-to-treat population. Ensitrelvir 125-mg group observed a 77% reduction in the risk of developing any of the 14 COVID-19 symptoms or fever and a 29% reduction in the risk of worsening of such symptoms or fever versus placebo (statistically nonsignificant). The viral RNA, viral titer, and time to infectious viral clearance observed a statistically significant decrease versus placebo. Most treatment-related adverse events (TEAEs) were mild to moderate in severity, and the most common TEAE observed across groups was a decrease in high-density lipoprotein.
CONCLUSIONS
Our exploratory results suggest a potential reduction in the risk of development or worsening of COVID-19 symptoms with ensitrelvir. Ensitrelvir showed antiviral efficacy and was well tolerated.
TRIAL REGISTRATION
Japan Registry of Clinical Trials identifier: jRCT2031210350.
Topics: Humans; Male; Female; Adult; Middle Aged; SARS-CoV-2; COVID-19 Drug Treatment; COVID-19; Antiviral Agents; Treatment Outcome; Asymptomatic Infections; Vietnam; Japan; Aged; Republic of Korea; Young Adult; Indazoles; Triazines; Triazoles
PubMed: 38890511
DOI: 10.1111/irv.13338 -
Inorganic Chemistry Jun 2024Separation of CH/CH mixtures is of significant importance in the chemical industry but remains a challenge due to the physicochemical similarities of CH and CH. Herein,...
Separation of CH/CH mixtures is of significant importance in the chemical industry but remains a challenge due to the physicochemical similarities of CH and CH. Herein, a metal-organic framework (MOF), [Zn(μ-O)(PCTF)] (Zn-PCTF) (PCTF= 5-trifluoromethyl-1H-pyrazole-4-carboxylic), is provided for the removal of CH from CH/CH mixtures. Zn-PCTF displays a three-dimensional framework featuring one-dimensional pore channels with periodic bottleneck segments. The well-balanced CH adsorption capacity (79.0 cm g at 298 K) and CH/CH selectivity (1.8) for Zn-PCTF under ambient conditions boost Zn-PCTF with highly promising potentials for efficient purification of CH from CH/CH mixtures, which is verified by the dynamic column breakthrough experiments. The well-matched caged pores and suitable pore chemistry (particularly the presence of abundant Lewis base sites (N, O, and F) on the pore surfaces) for CH account for the high-performance CH/CH separation of Zn-PCTF unveiled by computational simulations.
PubMed: 38889441
DOI: 10.1021/acs.inorgchem.4c01733 -
Journal of Medicinal Chemistry Jun 2024Multiple studies have confirmed that acid sphingomyelinase (ASM) activity is associated with depression. The discovery of direct inhibitors against ASM is of great...
Multiple studies have confirmed that acid sphingomyelinase (ASM) activity is associated with depression. The discovery of direct inhibitors against ASM is of great significance for exploring antidepressants and their mechanisms of action. Herein, a series of novel phenylpyrazole analogues were rationally designed and synthesized. Among them, compound exhibited potent inhibitory activity (IC = 0.87 μM) and good drug-like properties. studies demonstrated that compound was involved in multiple antidepressant mechanisms of action, which were associated with a decline of ceramide, including increasing the Bcl-2/Bax ratio and BDNF expression, down-regulating caspase-3 and caspase-9, ameliorating oxidative stress, reducing the levels of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6, and elevating 5-HT levels in the brains of mice, respectively. These meaningful results reveal for the first time that direct inhibitors exhibit remarkable antidepressant effects in the CUMS-induced mouse model through multiple mechanisms of antidepressant action.
Topics: Animals; Antidepressive Agents; Pyrazoles; Mice; Sphingomyelin Phosphodiesterase; Structure-Activity Relationship; Male; Depression; Drug Discovery; Enzyme Inhibitors; Humans; Brain-Derived Neurotrophic Factor; Oxidative Stress
PubMed: 38888140
DOI: 10.1021/acs.jmedchem.4c00831 -
Chemphyschem : a European Journal of... Jun 2024Coordination complexes of rare-earth ions (REI) show optical transitions with narrow linewidths enabling the creation of coherent light-matter interfaces for quantum...
Coordination complexes of rare-earth ions (REI) show optical transitions with narrow linewidths enabling the creation of coherent light-matter interfaces for quantum information processing (QIP) applications. Among the REI-based complexes, Eu(III) complexes showing the 5D0 → 7F0 transition are of interest for QIP applications due to the narrow linewidths associated with the transition. Herein, we report on the synthesis, structure, and optical properties of a novel Eu(III) complex and its Gd(III) analogue composed of 2,9-bis(pyrazol-1-yl)-1,10-phenanthroline (dpphen) and three nitrate (NO3) ligands. The Eu(III) complex-[Eu(dpphen)(NO3)3]-showed sensitized metal-centred emission (5D0 → 7FJ; J = 0,1,2,3, 4, 5, or 6) in the visible region, upon irradiation of the ligand-centered band at 369 nm, with the 5D0 → 7F0 transition centred at 580.9 nm. Spectral hole-burning (SHB) studies of the complex with stoichiometric Eu(III) concentration revealed a narrow homogeneous linewidth (Γh) of 1.55 MHz corresponding to a 0.205 µs long optical coherence lifetime (T2opt). Remarkably, long nuclear spin lifetimes (T1spin) of up to 41 s have been observed for the complex. The narrow optical linewidths and long T1spin lifetimes obtained for the Eu(III) complex showcase the utility of Eu(III) complexes as tunable, following molecular engineering principles, coherent light-matter interfaces for QIP applications.
PubMed: 38887965
DOI: 10.1002/cphc.202400280 -
Obesity (Silver Spring, Md.) Jul 2024Targeting the cannabinoid type 1 receptor (CB1) is a clinically validated antiobesity therapeutic approach. The only such drug approved, rimonabant, was launched in 2006... (Review)
Review
Targeting the cannabinoid type 1 receptor (CB1) is a clinically validated antiobesity therapeutic approach. The only such drug approved, rimonabant, was launched in 2006 in Europe but subsequently rejected by the US Food and Drug Administration (FDA) in 2007. The FDA cited the increased risk of suicidality in its opposition to rimonabant's approval, leading to the drug's eventual worldwide withdrawal and the abandonment of this class of therapeutics. Seventeen years later, a new class of CB1-targeting drugs is emerging, but the impact of the 2007 FDA decision remains a formidable obstacle to its clinical development. We revisit the suicidality data presented by the FDA in light of the evolution of suicidality assessment and cross-reference this with the data in the subsequently published clinical trials. We conclude that the publicly available data do not support the FDA's conclusion that the use of rimonabant was associated with an increase in the risk of suicidality.
Topics: Rimonabant; Humans; United States Food and Drug Administration; United States; Anti-Obesity Agents; Suicide; Obesity; Receptor, Cannabinoid, CB1; Cannabinoid Receptor Antagonists; Drug Approval; Pyrazoles; Piperidines
PubMed: 38887179
DOI: 10.1002/oby.24019 -
Dalton Transactions (Cambridge, England... Jun 2024The current work aims to generate multifunctional MOFs by incorporating a well-known inorganic motif, a trinuclear Cu-pyrazolate [Cu(μ-OH)(μ-Pyz)] (T-CuP) unit, as a...
The current work aims to generate multifunctional MOFs by incorporating a well-known inorganic motif, a trinuclear Cu-pyrazolate [Cu(μ-OH)(μ-Pyz)] (T-CuP) unit, as a node of the network. Accordingly, we report herein the synthesis and properties of five new compounds using five V-shaped dicarboxylic acids as auxiliary ligands. The structural features are consistent with the theme of grafting T-CuP units as nodal points of architectures whose chassis are primarily made of bent acids. V-shaped acids also induce a helical nature inside resulting frameworks. Beside their structural and physical features, T-CuP unit-based MOFs also vindicate our thematic approach of the trinuclear Cu-pyrazolate unit imparting specific physicochemical properties, such as magnetic, electrical, and catalytic properties, to resultant MOFs. The MOFs show excellent catalytic properties in reducing 4-nitrophenol, which could be attributed to the porous nature of the network along with the presence of metal centres with unsaturated coordination within the T-CuP unit. Furthermore, efficient photocatalytic degradation of harmful organic dyes confirms their importance for environmental remediation. The presence of a T-CuP unit and various functional groups also make some of the MOFs suitable candidates for electrical applications, which is indeed manifested in encouraging proton conductivity. Finally, the potential of current MOFs, fitted with a magnetically important trinuclear Cu-pyrazolate motif, as magnetic materials has also been thoroughly investigated.
PubMed: 38881376
DOI: 10.1039/d4dt00986j