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The Journal of Organic Chemistry Jun 2024Conjugated ynones represent an important class of reactive species, useful synthetic intermediates, and synthons. However, the reactivity and synthetic applications of...
Conjugated ynones represent an important class of reactive species, useful synthetic intermediates, and synthons. However, the reactivity and synthetic applications of ynones are usually focused on the transformation of mono- or dual-functional groups. Herein, we developed a straightforward synthesis of pyridin-2(1)-imines from the transformation of conjugated ynones. This cascade process probably began with a Michael addition of ynones and 2-aminopyridines, further underwent an intramolecular cyclization to generate the ,-bidentate intermediates, and finally reacted with sulfonyl azides giving the pyridin-2(1)-imines with accompanying loss of diazo.
PubMed: 38861494
DOI: 10.1021/acs.joc.4c01071 -
Angewandte Chemie (International Ed. in... Jun 2024Dichloromethane, as a readily available and inexpensive C1 synthon is proposed as a powerful building block for cyclopropanation of alkenes under mild conditions....
Dichloromethane, as a readily available and inexpensive C1 synthon is proposed as a powerful building block for cyclopropanation of alkenes under mild conditions. Herein, we report a highly efficient and versatile dual photoredox system, involving a nickel aminopyridine coordination complex and a photocatalyst, for the cyclopropanation of aromatic olefins using dichloromethane, under visible-light irradiation. The cyclopropanation protocol has been successfully applied at gram scale. Mechanistic studies suggest a Ni(II) pyridyl radical complex as the key intermediate for the homolytic cleavage of the Csp3-Cl bond, generating a chloromethyl radical that is captured by the olefin coupling partner. Our findings also highlight the versatility of this methodology. By directing the radical/polar crossover process, we were able to selectively drive the reaction towards either the formation of cyclopropyl derivatives or the corresponding non-cyclic alkyl chloride products. The methodology also successfully apply to geminal dichloroalkanes, including the formation of spiro[2,2] compounds. Moreover, our methodology extends to the synthesis of deuterium-labelled cyclopropanes, demonstrating its utility in isotopic labelling and broadening its applicability in chemical synthesis and drug development.
PubMed: 38858168
DOI: 10.1002/anie.202405580 -
Molecular Cancer Jun 2024Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes...
BACKGROUND
Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality.
METHODS
To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy.
RESULTS
Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair.
CONCLUSIONS
We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.
Topics: Animals; Humans; Glioma; Proto-Oncogene Proteins c-met; Mice; Xenograft Model Antitumor Assays; Brain Neoplasms; Benzamides; Cell Line, Tumor; Oncogene Proteins, Fusion; Female; Protein Kinase Inhibitors; Pyridines; Crizotinib; Disease Models, Animal; Child; Neoplasm Grading; Anilides; Imidazoles; Triazines
PubMed: 38849845
DOI: 10.1186/s12943-024-02027-6 -
Saudi Medical Journal Jun 2024To shed some light on a potential therapeutic modality that may facilitate resolution of botulism symptoms, namely 3,4-diaminopyridine (3,4-DAP).
OBJECTIVES
To shed some light on a potential therapeutic modality that may facilitate resolution of botulism symptoms, namely 3,4-diaminopyridine (3,4-DAP).
METHODS
In Riyadh, Saudi Arabia, we recently encountered a foodborne botulism outbreak that, luckily, was discovered early. In Prince Sultan Military Medical city, we admitted, during a period of approximately 3 weeks, 15 probable cases, 2 of which were excluded due to more likely alternative diagnoses. We report in this case series 13 highly suspected cases of botulism that we encountered during the outbreak.
RESULTS
A total of 12 out of 13 patients required intensive care unit (ICU) admission, one of which required intubation. Symptoms included cranial nerve palsies, gastrointestinal symptoms, limb and respiratory muscle weakness. Patients showed clinical improvement when received botulinum antitoxin and 3,4-DAP if given early in the course of the disease.
CONCLUSION
Early admisntration of 3,4-DAP may facilitate recovery and prevent disease progression. Larger prospective trials should be carried out to confirm that.
Topics: Humans; Botulism; Disease Outbreaks; Male; Saudi Arabia; Adult; Female; Middle Aged; Amifampridine; Botulinum Antitoxin; Young Adult
PubMed: 38830658
DOI: 10.15537/smj.2024.45.6.20240419 -
Human Cell Jul 2024Approximately 3-5% of non-small cell lung cancers (NSCLC) harbor ALK fusion genes and may be responsive to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors....
Approximately 3-5% of non-small cell lung cancers (NSCLC) harbor ALK fusion genes and may be responsive to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors. There are only a few reports on cell lines with EML4-ALK variant 3 (v3) and tumoroids that can be subject to long-term culture (> 3 months). In this study, we established tumoroids (PDT-LUAD#119) from a patient with lung cancer harboring EML4-ALK that could be cultured for 12 months. Whole-exome sequencing and RNA sequencing analyses revealed TP53 mutations and an EML4-ALK v3 mutation. PDT-LUAD#119 lung tumoroids were sensitive to the ALK tyrosine kinase inhibitors (ALK TKIs) crizotinib, alectinib, entrectinib, and lorlatinib, similar to NCI-H3122 cells harboring EML4-ALK variant 1 (v1). Unexpectedly, clear squamous cell carcinoma and solid adenocarcinoma were observed in xenografts from PDT-LUAD#119 lung tumoroids, indicating adenosquamous carcinoma. Immunostaining revealed that the squamous cell carcinoma was ALK positive, suggesting a squamous transformation of the adenocarcinoma. Besides providing a novel cancer model to support basic research on ALK-positive lung cancer, PDT-LUAD#119 lung tumoroids will help elucidate the pathogenesis of adenosquamous carcinoma.
Topics: Humans; Lung Neoplasms; Anaplastic Lymphoma Kinase; Carcinoma, Squamous Cell; Oncogene Proteins, Fusion; Mutation; Protein Kinase Inhibitors; Animals; Cell Transformation, Neoplastic; Adenocarcinoma; Tumor Suppressor Protein p53; Adenocarcinoma of Lung; Crizotinib; Cell Line, Tumor; Carcinoma, Non-Small-Cell Lung
PubMed: 38829559
DOI: 10.1007/s13577-024-01085-8 -
Frontiers in Pharmacology 2024Repeated and uncontrolled seizures in epilepsy result in brain cell loss and neural inflammation. Current anticonvulsants primarily target ion channels and receptors...
Repeated and uncontrolled seizures in epilepsy result in brain cell loss and neural inflammation. Current anticonvulsants primarily target ion channels and receptors implicated in seizure activity. Identification of neurotherapeutics that can inhibit epileptiform activity and reduce inflammation in the brain may offer significant benefits in the long-term management of epilepsy. Fenamates are unique because they are both non-steroidal anti-inflammatory drugs (NSAIDs) and highly subunit selective modulators of GABA receptors. In the current study we have investigated the hypothesis that fenamates have antiseizure properties using mature human stem cell-derived neuro-glia cell cultures, maintained in long-term culture, and previously shown to be sensitive to first, second and third generation antiepileptics. Mefenamic acid, flufenamic acid, meclofenamic acid, niflumic acid, and tolfenamic acid (each tested at 10-100 μM) attenuated 4-aminopyridine (4-AP, 100 μM) evoked epileptiform activity in a dose-dependent fashion. These actions were as effective diazepam (3-30 μM) and up to 200 times more potent than phenobarbital (300-1,000 μM). The low (micromolar) concentrations of fenamates that inhibited 4-AP evoked epileptiform activity correspond to those reported to potentiate GABA receptor function. In contrast, the fenamates had no effect on neural spike amplitudes, indicating that their antiseizure actions did not result from inhibition of sodium-channels. The antiseizure actions of fenamates were also not replicated by either of the two non-fenamate NSAIDs, ibuprofen (10-100 μM) or indomethacin (10-100 μM), indicating that inhibition of cyclooxygenases is not the mechanism through which fenamates have anticonvulsant properties. This study therefore shows for the first time, using functionally mature human stem cell-derived neuroglial circuits, that fenamate NSAIDs have powerful antiseizure actions independent of, and in addition to their well-established anti-inflammatory properties, suggesting these drugs may provide a novel insight and new approach to the treatment of epilepsy in the future.
PubMed: 38828453
DOI: 10.3389/fphar.2024.1385523 -
PeerJ 2024To investigate the interaction between tramadol and representative tyrosine kinase inhibitors, and to study the inhibition mode of drug-interaction.
OBJECTIVES
To investigate the interaction between tramadol and representative tyrosine kinase inhibitors, and to study the inhibition mode of drug-interaction.
METHODS
Liver microsomal catalyzing assay was developed. Sprague-Dawley rats were administrated tramadol with or without selected tyrosine kinase inhibitors. Samples were prepared and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used for analysis. Besides, liver, kidney, and small intestine were collected and morphology was examined by hematoxyline-eosin (H&E) staining. Meanwhile, liver microsomes were prepared and carbon monoxide differential ultraviolet radiation (UV) spectrophotometric quantification was performed.
RESULTS
Among the screened inhibitors, crizotinib takes the highest potency in suppressing the metabolism of tramadol in rat/human liver microsome, following non-competitive inhibitory mechanism. , when crizotinib was co-administered, the AUC value of tramadol increased compared with the control group. Besides, no obvious pathological changes were observed, including cell morphology, size, arrangement, nuclear morphology with the levels of alanine transaminase (ALT) and aspartate transaminase (AST) increased after multiple administration of crizotinib. Meanwhile, the activities of CYP2D1 and CYP3A2 as well as the total cytochrome P450 abundance were found to be decreased in rat liver of combinational group.
CONCLUSIONS
Crizotinib can inhibit the metabolism of tramadol. Therefore, this recipe should be vigilant to prevent adverse reactions.
Topics: Animals; Tramadol; Rats, Sprague-Dawley; Crizotinib; Rats; Microsomes, Liver; Cytochrome P-450 CYP3A; Male; Drug Interactions; Humans; Tandem Mass Spectrometry; Cytochrome P450 Family 2; Protein Kinase Inhibitors; Analgesics, Opioid
PubMed: 38827306
DOI: 10.7717/peerj.17446 -
The International Journal of... Jul 2024Abemaciclib (ABM), a cyclin-dependent kinase 4/6 inhibitor, shows pharmacological effects in cell cycle arrest. Epithelial-mesenchymal transition is an important...
Abemaciclib (ABM), a cyclin-dependent kinase 4/6 inhibitor, shows pharmacological effects in cell cycle arrest. Epithelial-mesenchymal transition is an important cellular event associated with pathophysiological states such as organ fibrosis and cancer progression. In the present study, we evaluated the contribution of factors associated with cell cycle arrest to ABM-induced epithelial-mesenchymal transition. Treatment with 0.6 µM ABM induced both cell cycle arrest and epithelial-mesenchymal transition-related phenotypic changes. Interestingly, the knockdown of cyclin-dependent kinase 4/6, pharmacological targets of ABM or cyclin D1, which forms complexes with cyclin-dependent kinase 4/6, resulted in cell cycle arrest at the G1-phase and induction of epithelial-mesenchymal transition, indicating that downregulation of cyclin-dependent kinase 4/6-cyclin D1 complexes would mimic ABM. In contrast, knockdown of the Rb protein, which is phosphorylated by cyclin-dependent kinase 4/6, had no effect on the expression level of α-smooth muscle actin, an epithelial-mesenchymal transition marker. Furthermore, ABM-induced epithelial-mesenchymal transition was not affected by Rb knockdown, suggesting that Rb is not involved in the transition process. Our study is the first to suggest that cyclin-dependent kinase 4/6-cyclin D1 complexes, as pharmacological targets of ABM, may contribute to ABM-induced epithelial-mesenchymal transition, followed by clinical disorders such as organ fibrosis and cancer progression. This study suggests that blocking epithelial-mesenchymal transition might be a promising way to prevent negative side effects caused by a medication (ABM) without affecting its ability to treat the disease.
Topics: Epithelial-Mesenchymal Transition; Benzimidazoles; Humans; Cyclin-Dependent Kinase 4; Aminopyridines; Cyclin-Dependent Kinase 6; Cell Cycle Checkpoints; Cyclin D1
PubMed: 38821314
DOI: 10.1016/j.biocel.2024.106601 -
The Biological Bulletin Aug 2023AbstractExtracellular calcium has been known to be required for nematocyst discharge for more than 60 years, yet calcium's role in nematocyst discharge is poorly...
AbstractExtracellular calcium has been known to be required for nematocyst discharge for more than 60 years, yet calcium's role in nematocyst discharge is poorly understood. Currently, we know that extracellular calcium plays at least two distinct roles in nematocyst discharge. First, calcium plays a role in the triggering of discharge by physical contact, most likely involving transient receptor potential channels. Second, activated L-type calcium channels desensitize nematocyst discharge predisposed to discharge by stimulated chemoreceptors for -acetylated sugars, such as -acetylneuraminic acid (NANA). It is not known whether the stimulated NANA signaling pathway activates L-type channels electrogenically through membrane depolarization or directly by phosphorylation of the channel. We hypothesize that the activated NANA signaling pathway initiates desensitization by depolarizing cell membrane potentials to activate voltage-gated L-type calcium channels. Consistent with our hypothesis, we show that depolarization induced by blocking voltage-gated potassium channels with 4-aminopyridine selectively activates Ca influx into tentacle ectodermal cells L-type channels and inhibits nematocyst discharge from chemosensitized anemones. Furthermore, preventing membrane depolarization with valinomycin or hyperpolarizing resting membrane potentials with low-potassium seawater suppresses NANA-induced Ca influx, prevents desensitization of nematocyst discharge, and enhances NANA sensitivity. Thus, changing resting membrane potentials modulates NANA sensitivity, and NANA-induced depolarization drives desensitization. We suggest that desensitization of the NANA signaling pathway occurs by a feedback pathway involving calcium channels that are activated by NANA-induced depolarization. Elucidating the desensitization pathway may suggest methods to protect or prevent public health cases of nematocyst stinging.
Topics: Animals; Sea Anemones; Membrane Potentials; Nematocyst; Chemoreceptor Cells; Calcium; Calcium Channels, L-Type; Signal Transduction
PubMed: 38820288
DOI: 10.1086/729603 -
Cellular and Molecular Biology... May 2024Milrinone, a phosphodiesterase III inhibitor with contractile and vasodilatory effects, is widely used in acute decompensated heart failure and medically refractory...
Milrinone, a phosphodiesterase III inhibitor with contractile and vasodilatory effects, is widely used in acute decompensated heart failure and medically refractory end-stage heart failure (HF). The adverse reactions of milrinone have been extensively explored clinically, but its possible toxicities and underlying molecular mechanisms in embryo development need further understanding as its clinical applications increase. Herein, we assessed the milrinone toxicity using the zebrafish embryotoxicity test (ZET), with a view of providing evidence and guidance for gravidas medicine. We carried out ZET by exposing embryos to a milrinone culture with a series concentration gradients since 1.5 hours post fertilization (hpf) and observed and assessed mortality and hatching rates of drug-treated zebrafishes at 24, 48, 72, and 96 hpf. No significant lethal effect was found in milrinone-treated zebrafish, but hatching rate of eggs at 48 hpf was up-regulated with the increase of milrinone concentration. The impact of milrinone on embryogenesis was assessed through body length, eye area, yolk sac area, swim bladder inflation area, pericardial area and venous congestion area at 96hpf. 150 μg/mL or higher milrinone treatment showed significant effects in the indicators. Organ disorders including enlarged pericardium, liver atrophy and decreased blood vessels were observed in dysplasia individuals versus controls. TUNEL assay suggested the ability of milrinone to induce apoptosis in malformation embryos. Quantitative real-time PCR showed aberrant expressions of transcription factors associated with heart development and genes related to liver development and apoptosis regulation. Therefore, ZET is feasible for the milrinone toxicity test, and high-dose milrinone causes harm to the embryonic development of zebrafish, especially in embryonic carcinogenesis, vasculogenesis, and hepatogenesis.
Topics: Animals; Milrinone; Zebrafish; Embryo, Nonmammalian; Embryonic Development; Apoptosis; Toxicity Tests; Gene Expression Regulation, Developmental
PubMed: 38814231
DOI: 10.14715/cmb/2024.70.5.12