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Anti-cancer Drugs Aug 2023The triple-negative breast cancer (TNBC) subtype is the most aggressive type of breast cancer with a low survival prognosis and high recurrence rate. There is currently...
The triple-negative breast cancer (TNBC) subtype is the most aggressive type of breast cancer with a low survival prognosis and high recurrence rate. There is currently no effective treatment to improve it. In this work, we explored the effect of a synthetic compound named WXJ-103 on several aspects of TNBC biology. The human breast cancer cell lines MDA-MB-231 and MCF-7 were used in the experiments, and the cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, and the cell migration and invasion abilities were detected by wound healing assay and Transwell invasion assay. Cell cycle and apoptosis experiments were analyzed by flow cytometry, and protein levels related to cyclin-dependent kinase (CDK) 4/6-cyclin D-Rb-E2F pathway were analyzed by western blotting. Then, in-vivo experiments were performed to determine the clinical significance and functional role of WXJ-103. The results show that WXJ-103 can inhibit the adhesion, proliferation, migration, and invasion of TNBC cells, and can arrest the cell cycle in G1 phase. The levels of CDK4/6-cyclin D-Rb-E2F pathway-related proteins such as CDK6 and pRb decreased in a dose-dependent manner. Therefore, the antitumor activity of WXJ-103 may depend on the inhibition of CDK4/6-cyclin D1-Rb-E2F pathway. This research shows that WXJ-103 may be a new promising antitumor drug, which can play an antitumor effect on TNBC and provide new ideas for the treatment of TNBC.
Topics: Humans; Triple Negative Breast Neoplasms; Cell Proliferation; Aminopyridines; Cyclin-Dependent Kinase 4; Purines; Cell Line, Tumor
PubMed: 36729405
DOI: 10.1097/CAD.0000000000001475 -
International Journal of Molecular... Dec 2021The big problem of antimicrobial resistance is that it requires great efforts in the design of improved drugs which can quickly reach their target of action. Studies of...
The big problem of antimicrobial resistance is that it requires great efforts in the design of improved drugs which can quickly reach their target of action. Studies of antibiotic uptake and interaction with their target it is a key factor in this important challenge. We investigated the accumulation of ozenoxacin (OZN), moxifloxacin (MOX), levofloxacin (LVX), and ciprofloxacin (CIP) into the bacterial cells of 5 species, including (SA4-149), (SEP7602), (SPY165), (SAG146), and (EF897) previously characterized.The concentration of quinolone uptake was estimated by agar disc-diffusion bioassay. Furthermore, we determined the inhibitory concentrations 50 (IC) of OZN, MOX, LVX, and CIP against type II topoisomerases from .The accumulation of OZN inside the bacterial cell was superior in comparison to MOX, LVX, and CIP in all tested species. The accumulation of OZN inside the bacterial cell was superior in comparison to MOX, LVX, and CIP in all tested species. The rapid penetration of OZN into the cell was reflected during the first minute of exposure with antibiotic values between 190 and 447 ng/mg (dry weight) of bacteria in all strains. Moreover, OZN showed the greatest inhibitory activity among the quinolones tested for both DNA gyrase and topoisomerase IV isolated from with IC50 values of 10 and 0.5 mg/L, respectively. OZN intracellular concentration was significantly higher than that of MOX, LVX and CIP. All of these features may explain the higher in vitro activity of OZN compared to the other tested quinolones.
Topics: Aminopyridines; Bacterial Proteins; Gram-Positive Bacteria; Quinolones; Topoisomerase I Inhibitors
PubMed: 34948159
DOI: 10.3390/ijms222413363 -
Drug Design, Development and Therapy Jul 2010In April 2010, the European Medicines Agency Committee for Medicinal Products for Human Use recommended approval of roflumilast, a selective phosphodiesterase 4... (Review)
Review
In April 2010, the European Medicines Agency Committee for Medicinal Products for Human Use recommended approval of roflumilast, a selective phosphodiesterase 4 inhibitor, for the "maintenance treatment of severe chronic obstructive pulmonary disease (COPD, FEV(1) postbronchodilator less than 50% predicted) associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add-on to bronchodilator treatment". This decision was based, in part, on the results of several large, international, multicenter, randomized, placebo-controlled trials of either six or 12 months' duration that had been undertaken in COPD patients. Roflumilast 500 mug daily improved lung function and reduced exacerbations in patients with more severe COPD, especially those with chronic bronchitis, frequent exacerbations, or who required frequent rescue inhaler therapy in the placebo-controlled trials. It also improved lung function and reduced exacerbations in patients with moderately severe COPD treated with salmeterol or tiotropium. Advantages of roflumilast over inhaler therapy are that it is an oral tablet and only needs to be taken once daily. While taking roflumilast, the most common adverse effects patients experienced were gastrointestinal upset and headache. Weight loss, averaging 2.2 kg, occurred in patients treated with roflumilast. Patients taking roflumilast were more likely to drop out of the trials than patients in the control groups. Patients who discontinued therapy usually did so during the first few weeks and were more likely to have experienced gastrointestinal side effects. Roflumilast is the first selective phosphodiesterase 4 inhibitor and will offer physicians another treatment option for patients with more severe COPD.
Topics: Adult; Aminopyridines; Animals; Benzamides; Cyclopropanes; Humans; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Respiratory Function Tests; Severity of Illness Index
PubMed: 20689641
DOI: 10.2147/dddt.s7667 -
Acta Neurobiologiae Experimentalis 2023Aminopyridines constitute a drug family with the ability to enhance synaptic transmission. In particular, 4‑aminopyridine (4‑AP) has been used as a model of... (Review)
Review
Aminopyridines constitute a drug family with the ability to enhance synaptic transmission. In particular, 4‑aminopyridine (4‑AP) has been used as a model of generalized seizures. 4‑AP is a K+ channel blocker, but its mechanism of action has not yet been fully described; some evidence has shown that it acts on the K+ channel types Kv1.1, Kv1.2, Kv1.4 and Kv4, which are localized in the axonic terminals of pyramidal neurons and interneurons. When 4‑AP blocks the K+ channels it triggers depolarization and prolongs the action potential in the neuron, which causes nonspecific neurotransmitter release. Among these neurotransmitters, glutamate is the principal excitatory neurotransmitter released in the hippocampus. Once glutamate is released, it reaches its ionotropic and metabotropic receptors continuing the neuronal depolarization chain and propagation of hyperexcitability. This brief review is focused on the use of 4‑AP as an effective seizure model for testing antiseizure drugs in relevant in vitro and in vivo studies.
Topics: Humans; Potassium Channels; Seizures; Neurons; Glutamic Acid; Hippocampus; Aminopyridines; Neurotransmitter Agents
PubMed: 37078815
DOI: 10.55782/ane-2023-007 -
Thorax Jul 2014
Topics: Aminopyridines; Benzamides; Cyclopropanes; Female; Humans; Male; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive
PubMed: 24550059
DOI: 10.1136/thoraxjnl-2014-205175 -
Scientific Reports Jul 2018Characterization of the genomic landscapes of intracranial tumours has revealed a clear role for the PI3K-AKT-mTOR pathway in tumorigenesis and tumour maintenance of...
Characterization of the genomic landscapes of intracranial tumours has revealed a clear role for the PI3K-AKT-mTOR pathway in tumorigenesis and tumour maintenance of these malignancies, making phosphatidylinositol 3-kinase (PI3K) inhibition a promising therapeutic strategy for these tumours. Buparlisib is a novel pan-PI3K inhibitor that is currently in clinical development for various cancers, including primary and secondary brain tumours. Importantly however, earlier studies have revealed that sufficient brain penetration is a prerequisite for antitumor efficacy against intracranial tumours. We therefore investigated the brain penetration of buparlisib using a comprehensive set of in vitro and in vivo mouse models. We demonstrate that buparlisib has an excellent brain penetration that is unaffected by efflux transporters at the blood-brain barrier, complete oral bioavailability and efficient intracranial target inhibition at clinically achievable plasma concentrations. Together, these characteristics make buparlisib the ideal candidate for intracranially-targeted therapeutic strategies that involve PI3K inhibition.
Topics: Administration, Oral; Aminopyridines; Animals; Blood-Brain Barrier; Brain; Female; Male; Mice; Morpholines; Phosphoinositide-3 Kinase Inhibitors
PubMed: 30018387
DOI: 10.1038/s41598-018-29062-w -
Esophagus : Official Journal of the... Oct 2022PI3K/AKT/mTOR pathway is frequently overactive in esophageal squamous cell carcinoma (ESCC), making it an attractive treatment target. BKM120 is an oral pan-class I PI3K...
BACKGROUND
PI3K/AKT/mTOR pathway is frequently overactive in esophageal squamous cell carcinoma (ESCC), making it an attractive treatment target. BKM120 is an oral pan-class I PI3K inhibitor with promising activity in several cancers. We prospectively investigated efficacy, safety, and biomarkers of BKM120 in advanced ESCC. We conducted a multicenter phase II study of BKM120 monotherapy in patients with pretreated advanced ESCC.
METHODS
BKM120 (100 mg/day) was administered orally in a 28-day cycle. The primary end point was disease control rate (DCR). Tumor samples for all patients were collected for gene alteration analysis in a comprehensive genomic profiling assay.
RESULTS
Of 42 patients enrolled, 20 had stable disease and two had confirmed partial response. One ineligible patient was excluded from the primary analysis, which met the primary end point (DCR 51.2%; 95% confidence interval [CI], 35.1-67.1). In the 42 patients, median progression-free survival and overall survival were 2.3 (95% CI 1.8-3.2) and 9.0 (95% CI 6.5-11.4) months, respectively. Common grade 3 or 4 adverse events were rash, anorexia, hyponatremia, and abnormal hepatic function; profiles of these events in this study were similar to those in previous studies of BKM120 monotherapy. No treatment-related deaths occurred. PI3K pathway activation was observed in patients with good clinical response.
CONCLUSIONS
BKM120 monotherapy showed promising efficacy and a manageable toxicity profile even in patients with pretreated advanced ESCC. This study showed the potential target PI3K for ESCC, and further confirmatory trial will be necessary to confirm it. Unique ID issued by UMIN: UMIN 000011217.
Topics: Aminopyridines; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Humans; Morpholines; Phosphatidylinositol 3-Kinases
PubMed: 35904643
DOI: 10.1007/s10388-022-00928-3 -
Journal of Molecular Modeling Sep 2012Quantum-chemical calculations {DFT(B3LYP)/6-311+G(d,p)} were performed for all possible tautomers (aromatic and nonaromatic) of neutral 2- and 4-aminopyridines and their...
Quantum-chemical calculations {DFT(B3LYP)/6-311+G(d,p)} were performed for all possible tautomers (aromatic and nonaromatic) of neutral 2- and 4-aminopyridines and their oxidized and reduced forms. One-electron oxidation has no important effect on the tautomeric preference for 2-aminopyridine. The amine tautomer is favored. However, oxidation increases the stability of the imine NH tautomer, and its contribution in the tautomeric mixture cannot be neglected. In the case of 4-aminopyridine, one-electron oxidation increases the stability of both the amine and imine NH tautomers. Consequently, they possess very close energies. As major tautomers, they dictate the composition of the tautomeric mixture. The CH tautomers may be considered as very rare forms for both neutral and oxidized aminopyridines. A reverse situation takes place for the reduced forms of aminopyridines. One-electron reduction favors the C3 atom for the labile proton for both aminopyridines. This may partially explain the origin of the CH tautomers for the anionic states of nucleobases containing the exo NH(2) group.
Topics: 4-Aminopyridine; Aminopyridines; Aniline Compounds; Electrons; Entropy; Models, Molecular; Molecular Conformation; Oxidation-Reduction; Quantum Theory; Stereoisomerism
PubMed: 22585356
DOI: 10.1007/s00894-012-1446-8 -
Primary Care Respiratory Journal :... Dec 2010Therapeutic interventions in chronic obstructive pulmonary disease (COPD) shown to reduce exacerbations include smoking cessation, vaccination and appropriate... (Review)
Review
Therapeutic interventions in chronic obstructive pulmonary disease (COPD) shown to reduce exacerbations include smoking cessation, vaccination and appropriate pharmacological therapy. Long-acting bronchodilators are the cornerstone of COPD pharmacotherapy, whereas inhaled corticosteroids and mucolytics have shown benefit in subgroups of patients. Despite management with existing therapies, clinical trials confirm the persistent nature of exacerbations throughout the course of the disease. Roflumilast - a phosphodiesterase-4 (PDE4) inhibitor - received European Marketing Approval in 2010 and represents a new class of drug in the management of COPD. Through selective inhibition of the PDE4 enzyme, roflumilast prevents the breakdown of cyclic AMP, which plays an important role in regulating inflammatory cell activity. Early trials in patients with a forced expiratory volume in one second (FEV1) less than 50% predicted suggest that roflumilast offers sustained and significant improvement in lung function and a reduction in exacerbations compared with placebo, irrespective of concomitant bronchodilator therapy. Common adverse events include headache, diarrhoea and weight loss, with the majority occurring at the beginning of treatment, being transient and not leading to sequelae. Serious adverse events tended to be low across all studies. Roflumilast is currently licensed in Europe, and is indicated as maintenance treatment in severe COPD (i.e. in patients with post-bronchodilator FEV1 <50% predicted) associated with chronic bronchitis in adult patients with a history of frequent exacerbations as an add-on to bronchodilator treatment. Clear identification of patients eligible for roflumilast will require improved characterisation and phenotyping of patients in primary care, including lung function measurement, accurate health status classification, and recording of chronic cough and regular sputum production.
Topics: Adult; Aminopyridines; Benzamides; Bronchodilator Agents; Clinical Trials as Topic; Cyclopropanes; Drug Therapy, Combination; Humans; Primary Health Care; Pulmonary Disease, Chronic Obstructive
PubMed: 21085915
DOI: 10.4104/pcrj.2010.00066 -
The FEBS Journal May 2009We summarize the currently available information regarding the state of ionization and tautomerization of the 4'-aminopyrimidine ring of the thiamine diphosphate on... (Review)
Review
We summarize the currently available information regarding the state of ionization and tautomerization of the 4'-aminopyrimidine ring of the thiamine diphosphate on enzymes requiring this coenzyme. This coenzyme forms a series of covalent intermediates with its substrates as an electrophilic catalyst, and the coenzyme itself also carries out intramolecular proton transfers, which is virtually unprecedented in coenzyme chemistry. An understanding of the state of ionization and tautomerization of the 4'-aminopyrimidine ring in each of these intermediates provides important details about proton movements during catalysis. CD spectroscopy, both steady-state and time-resolved, has proved crucial for obtaining this information because no other experimental method has provided such atomic detail so far.
Topics: Aminopyridines; Catalysis; Circular Dichroism; Coenzymes; Kinetics; Models, Molecular; Structure-Activity Relationship; Substrate Specificity; Thiamine Pyrophosphate
PubMed: 19476485
DOI: 10.1111/j.1742-4658.2009.06964.x