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Organic Letters May 2024We present a novel approach for the skeletal rearrangement of an oxazole into an azepine and pyrrole through a dynamic electrocyclization process, showing an innovative,...
We present a novel approach for the skeletal rearrangement of an oxazole into an azepine and pyrrole through a dynamic electrocyclization process, showing an innovative, unconventional reaction sequence. This method enables precise control of regioselectivity in competitive 6π and 8π electrocyclization reactions, rendering the final products rich in functional groups that can be further developed for the synthesis of nitrogen-containing scaffolds. This is an unprecedented example of the selective synthesis of seven- and five-member heterocycles via dynamic electrocyclization ring opening or closure.
PubMed: 38742794
DOI: 10.1021/acs.orglett.4c00826 -
Biomedicine & Pharmacotherapy =... Jun 2024Brain apoptosis is one of the main causes of epileptogenesis. The antiapoptotic effect and potential mechanism of Q808, an innovative anticonvulsant chemical, have never...
Brain apoptosis is one of the main causes of epileptogenesis. The antiapoptotic effect and potential mechanism of Q808, an innovative anticonvulsant chemical, have never been reported. In this study, the seizure stage and latency to reach stage 2 of pentylenetetrazol (PTZ) seizure rat model treated with Q808 were investigated. The morphological change and neuronal apoptosis in the hippocampus were detected by hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, respectively. The hippocampal transcriptomic changes were observed using RNA sequencing (RNA-seq). The expression levels of hub genes were verified by quantitative reverse-transcription PCR (qRT-PCR). Results revealed that Q808 could allay the seizure score and prolong the stage 2 latency in seizure rats. The morphological changes of neurons and the number of apoptotic cells in the DG area were diminished by Q808 treatment. RNA-seq analysis revealed eight hub genes, including Map2k3, Nfs1, Chchd4, Hdac6, Siglec5, Slc35d3, Entpd1, and LOC103690108, and nine hub pathways among the control, PTZ, and Q808 groups. Hub gene Nfs1 was involved in the hub pathway sulfur relay system, and Map2k3 was involved in the eight remaining hub pathways, including Amyotrophic lateral sclerosis, Cellular senescence, Fc epsilon RI signaling pathway, GnRH signaling pathway, Influenza A, Rap1 signaling pathway, TNF signaling pathway, and Toll-like receptor signaling pathway. qRT-PCR confirmed that the mRNA levels of these hub genes were consistent with the RNA-seq results. Our findings might contribute to further studies exploring the new apoptosis mechanism and actions of Q808.
Topics: Animals; Pentylenetetrazole; Hippocampus; Apoptosis; Anticonvulsants; Male; Transcriptome; Epilepsy; Gene Expression Profiling; Rats; Rats, Sprague-Dawley; Disease Models, Animal; Neurons; Seizures
PubMed: 38739991
DOI: 10.1016/j.biopha.2024.116746 -
Molecules (Basel, Switzerland) Apr 2024Two series, "" and "", each consisting of nine chemical compounds, with 2,3-disubstituted quinazolin-4(3H)-one scaffold, were synthesized and evaluated for their...
Two series, "" and "", each consisting of nine chemical compounds, with 2,3-disubstituted quinazolin-4(3H)-one scaffold, were synthesized and evaluated for their anticonvulsant activity. They were investigated as dual potential positive allosteric modulators of the GABA receptor at the benzodiazepine binding site and inhibitors of carbonic anhydrase II. Quinazolin-4(3H)-one derivatives were evaluated in vivo (D = 50, 100, 150 mg/kg, administered intraperitoneally) using the pentylenetetrazole (PTZ)-induced seizure model in mice, with phenobarbital and diazepam, as reference anticonvulsant agents. The in silico studies suggested the compounds act as anticonvulsants by binding on the allosteric site of GABA receptor and not by inhibiting the carbonic anhydrase II, because the ligands-carbonic anhydrase II predicted complexes were unstable in the molecular dynamics simulations. The mechanism targeting GABA receptor was confirmed through the in vivo flumazenil antagonism assay. The pentylenetetrazole experimental anticonvulsant model indicated that the tested compounds, - and -, present a potential anticonvulsant activity. The evaluation, considering the percentage of protection against PTZ, latency until the onset of the first seizure, and reduction in the number of seizures, revealed more favorable results for the "" series, particularly for compound .
Topics: Anticonvulsants; Animals; Mice; Seizures; Receptors, GABA-A; Pentylenetetrazole; Quinazolinones; Molecular Docking Simulation; Male; Structure-Activity Relationship; Molecular Dynamics Simulation; Computer Simulation; Disease Models, Animal; Molecular Structure; Allosteric Site
PubMed: 38731442
DOI: 10.3390/molecules29091951 -
Brain Research Sep 2024PTZ kindling induces oxidative stress, neuronal cell degeneration, and neurobehavioral alterations in rodents that mimic neuropsychiatric comorbidities of epilepsy,...
PTZ kindling induces oxidative stress, neuronal cell degeneration, and neurobehavioral alterations in rodents that mimic neuropsychiatric comorbidities of epilepsy, which could be initiated or aggravated by some antiepileptic drugs. Here, we investigated the effects of the methanol extract of Ficus platyphylla (FP) on severity scores for seizures, neuronal cell degeneration, and neurobehavioral alterations in rats kindled with pentylenetetrazole (PTZ) and probed the involvement of oxidative stress in these ameliorative effects of FP. FP (50 and 100 mg/kg, p.o.) ameliorated seizure severity, neuronal cell degeneration, depressive behaviors, cognitive dysfunctions, and oxidative stress in rats kindled with PTZ (42.5 mg/kg, i.p.). The findings from this study give additional insights into the potential values of FP in the treatment of persistent epilepsy and major neuropsychiatric comorbidities via modulation of oxidative stress.
Topics: Animals; Ficus; Oxidative Stress; Pentylenetetrazole; Plant Extracts; Kindling, Neurologic; Male; Seizures; Rats; Anticonvulsants; Rats, Wistar; Disease Models, Animal; Behavior, Animal; Epilepsy
PubMed: 38729331
DOI: 10.1016/j.brainres.2024.148994 -
Cellular Signalling Aug 2024Control of angiogenesis is widely considered a therapeutic strategy, but reliable control methods are still under development. Phosphorylation of myosin light chain 2...
BACKGROUND
Control of angiogenesis is widely considered a therapeutic strategy, but reliable control methods are still under development. Phosphorylation of myosin light chain 2 (MLC2), which regulates actin-myosin interaction, is critical to the behavior of vascular endothelial cells (ECs) during angiogenesis. MLC2 is phosphorylated by MLC kinase (MLCK) and dephosphorylated by MLC phosphatase (MLCP) containing a catalytic subunit PP1. We investigated the potential role of MLC2 in the pharmacological control of angiogenesis.
METHODS AND RESULTS
We exposed transgenic zebrafish Tg(fli1a:Myr-mCherry) embryos to chemical inhibitors and observed vascular development. PP1 inhibition by tautomycetin increased length of intersegmental vessels (ISVs), whereas MLCK inhibition by ML7 decreased it; these effects were not accompanied by structural dysplasia. ROCK inhibition by Y-27632 also decreased vessel length. An in vitro angiogenesis model of human umbilical vein endothelial cells (HUVECs) showed that tautomycetin increased vascular cord formation, whereas ML7 and Y-27632 decreased it. These effects appear to be influenced by regulation of cell morphology rather than cell viability or motility. Actin co-localized with phosphorylated MLC2 (pMLC2) was abundant in vascular-like elongated-shaped ECs, but poor in non-elongated ECs. pMLC2 was associated with tightly arranged actin, but not with loosely arranged actin. Moreover, knockdown of MYL9 gene encoding MLC2 reduced total MLC2 and pMLC2 protein and inhibited angiogenesis in HUVECs.
CONCLUSION
The present study found that MLC2 is a pivotal regulator of angiogenesis. MLC2 phosphorylation may be involved in the regulation of of cell morphogenesis and cell elongation. The functionally opposite inhibitors positively or negatively control angiogenesis, probably through the regulating EC morphology. These findings may provide a unique therapeutic target for angiogenesis.
Topics: Myosin Light Chains; Phosphorylation; Humans; Zebrafish; Animals; Human Umbilical Vein Endothelial Cells; Neovascularization, Physiologic; Cardiac Myosins; Pyridines; Myosin-Light-Chain Kinase; Animals, Genetically Modified; Amides; rho-Associated Kinases; Azepines; Actins; Zebrafish Proteins; Angiogenesis; Naphthalenes
PubMed: 38729320
DOI: 10.1016/j.cellsig.2024.111223 -
Cancer Letters Jun 2024Efforts to develop targetable molecular bases for drug resistance for pancreatic ductal adenocarcinoma (PDAC) have been equivocally successful. Using RNA-seq and...
Efforts to develop targetable molecular bases for drug resistance for pancreatic ductal adenocarcinoma (PDAC) have been equivocally successful. Using RNA-seq and ingenuity pathway analysis we identified that the superpathway of cholesterol biosynthesis is upregulated in gemcitabine resistant (gemR) tumors using a unique PDAC PDX model with resistance to gemcitabine acquired in vivo. Analysis of additional in vitro and in vivo gemR PDAC models showed that HMG-CoA synthase 2 (HMGCS2), an enzyme involved in cholesterol biosynthesis and rate limiting in ketogenesis, is overexpressed in these models. Mechanistic data demonstrate the novel findings that HMGCS2 contributes to gemR and confers metastatic properties in PDAC models, and that HMGCS2 is BRD4 dependent. Further, BET inhibitor JQ1 decreases levels of HMGCS2, sensitizes PDAC cells to gemcitabine, and a combination of gemcitabine and JQ1 induced regressions of gemR tumors in vivo. Our data suggest that decreasing HMGCS2 may reverse gemR, and that HMGCS2 represents a useful therapeutic target for treating gemcitabine resistant PDAC.
Topics: Animals; Humans; Mice; Antimetabolites, Antineoplastic; Azepines; Bromodomain Containing Proteins; Carcinoma, Pancreatic Ductal; Cell Cycle Proteins; Cell Line, Tumor; Deoxycytidine; Drug Resistance, Neoplasm; Gemcitabine; Gene Expression Regulation, Neoplastic; Hydroxymethylglutaryl-CoA Synthase; Pancreatic Neoplasms; Transcription Factors; Triazoles; Xenograft Model Antitumor Assays; Female; Mice, SCID
PubMed: 38704133
DOI: 10.1016/j.canlet.2024.216919 -
Nigerian Journal of Physiological... Dec 2023Epilepsy is a chronic disease of the brain characterized by seizures. The currently available anticonvulsants only treat symptoms with serious adverse drug reactions....
Epilepsy is a chronic disease of the brain characterized by seizures. The currently available anticonvulsants only treat symptoms with serious adverse drug reactions. Therefore, there is need for new therapeutic intervention that will prevent epileptogenesis with greater therapeutic success. Quercetin (QT) is a flavonoid with known neuroprotective and anti-inflammatory properties. The study aimed to investigate its effects against pentylenetetrazole (PTZ)-induced seizures. Animals were divided into four groups (n = 10). Group 1(control) only received vehicle (10 mL/kg), group 2 received vehicle, groups 3 and 4 received QT 12.5 mg/kg and 25 mg/kg respectively. Sixty minutes after treatments, animals in groups 2 to 4 were injected with sub-convulsive dose of pentylenetetrazole (35 mg/kg, i.p.) on every alternate day (48±2h) for 21 days. The mice were observed for 30 minutes after each PTZ injection for seizure activity. Brain samples were collected for biochemical assays. Administration of PTZ caused significant increase in the intensity of seizures, neuronal degeneration and level of proinflammatory cytokines in animals compared to control. These behavioural alterations were attenuated significantly by QT (12.5 and 25 mg/kg). The PTZ-induced increase in IL-12, TNF-α and IFN-ɣ were significantly reduced by pre-treatment with the QT (12.5 and 25 mg/kg, p.o). Quercetin also reduced neuronal loss compared to control. Quercetin attenuates seizures in kindled mice and reduces neuroinflammation and neurodegeneration. This neuroprotective effect may be attributed to its ability to inhibit inflammatory mediators in the brain.
Topics: Animals; Quercetin; Pentylenetetrazole; Seizures; Mice; Anticonvulsants; Male; Neuroinflammatory Diseases; Cytokines; Disease Models, Animal; Brain; Neuroprotective Agents; Anti-Inflammatory Agents
PubMed: 38696687
DOI: 10.54548/njps.v38i2.7 -
Advanced Materials (Deerfield Beach,... May 2024Ultrapure deep-blue emitters are in high demand for organic light-emitting diodes (OLEDs). Although color coordinates serve as straightforward parameters for assessing...
Ultrapure deep-blue emitters are in high demand for organic light-emitting diodes (OLEDs). Although color coordinates serve as straightforward parameters for assessing color purity, precise control over the maximum wavelength and full-width at half-maximum is necessary to optimize OLED performance, including luminance efficiency and luminous efficacy. Multiple-resonance (MR) emitters are promising candidates for achieving ideal luminescence properties; consequently, a wide variety of MR frameworks have been developed. However, most of these emitters experience a wavelength displacement from the ideal color, which limits their practical applicability. Therefore, a molecular design that is compatible with MR emitters for modulating their energy levels and color output is particularly valuable. Here, it is demonstrated that the azepine donor unit induces an appropriate blue-shift in the emission maximum while maintaining efficient MR characteristics, including high photoluminescence quantum yield, narrow emission, and a fast reverse intersystem crossing rate. OLEDs using newly developed MR emitters based on the ν-DABNA framework simultaneously exhibit a high quantum efficiency of ≈30%, luminous efficacy of ≈20 lm W, exceptional color purity with Commission Internationale de l'Éclairage coordinates as low as (0.14, 0.06), and notably high operational stability. These results demonstrate unprecedentedly high levels compared with those observed in previously reported deep-blue emitters.
PubMed: 38695744
DOI: 10.1002/adma.202402905 -
Dalton Transactions (Cambridge, England... May 2024The new hydrazine 5-dibenzo[,]azepin-5-amine (2) reacts with P- and Si-electrophiles deprotonation to afford P(III)-, P(V)-, and TMS-hydrazides 3-8 and with carbonyl...
The new hydrazine 5-dibenzo[,]azepin-5-amine (2) reacts with P- and Si-electrophiles deprotonation to afford P(III)-, P(V)-, and TMS-hydrazides 3-8 and with carbonyl electrophiles acid-free condensation to the -substituted hydrazones 9-12 that are potential -alkene ligands. While β-ketohydrazone 9 and α-dihydrazone 10 react with [Mes(Cu)], [Cu(NCCCH)]PF, and FeCl(THF) to afford complexes devoid of alkene interaction, [Cu(OTf)]·CH reacts with the α-keto hydrazone 11 or with , dimethyl-hydrazone 12 to form the neutral dimeric Cu(I) complex 18 with bridging Cu(I)-alkene interactions or the tetrahedral cationic complex 19 in which 12 binds as a bidentate hydrazone-alkene ligand, respectively. The surprising stability of the alkene coordination in complexes 18 and 19 prevents substitutions with, , PPh.
PubMed: 38695637
DOI: 10.1039/d4dt00749b -
Journal of Ethnopharmacology Sep 2024The use of medicinal plants for central nervous system (CNS)-related ailments, such as epilepsy and anxiety, is prevalent in South Africa. Plants from the Lamiaceae...
ETHNOPHARMACOLOGICAL RELEVANCE
The use of medicinal plants for central nervous system (CNS)-related ailments, such as epilepsy and anxiety, is prevalent in South Africa. Plants from the Lamiaceae family are commonly used for their therapeutic benefits. Leonotis leonurus (L.) R.Br. has been reported in ethnobotanical literature to have anticonvulsant and anxiolytic effects through the inhalation of pyrolysis products obtained by combustion of the aerial parts.
AIM AND OBJECTIVES
To explore the chemical profiles and CNS activity of the smoke extract and isolated constituents of L. leonurus in zebrafish larvae, through anticonvulsive and anxiolytic activity assays.
MATERIALS AND METHODS
The smoke extract of L. leonurus was obtained through the combustion of the aerial parts of the plant using a custom-built smoke recovery apparatus. The chemical profile of the smoke constituents was determined using Ultra-Performance Liquid Chromatography coupled with Mass Spectrometry (UPLC-MS). Targeted compounds were subjected to preparative High-Performance Liquid Chromatography for separation before structure elucidation using Nuclear Magnetic Resonance (NMR). The maximum tolerated concentrations, as well as the anxiolytic activity of the smoke extract were determined in five days post fertilisation zebrafish larvae. Reverse-thigmotaxis and locomotor activity of larvae in the light/dark transition assay were used to determine anxiolytic activity. Zebrafish larvae at six days post fertilisation (dpf) were subjected to several concentrations of the smoke constituents of L. leonurus. The baseline locomotor activity of the larvae was tracked for 30 min, prior to addition of pentylenetetrazole (PTZ) to induce seizure-like behaviour in the larvae, after which the locomotor activity of the larvae was once again tracked for an additional 30 min.
RESULTS
The UPLC-MS profiles of the smoke extract revealed the presence of two main compounds, leoleorin A and leoleorin B, which were targeted and isolated. Upon subjection to NMR spectroscopy for structure elucidation, the compounds were confirmed to be labdane diterpenoids. Both leoleorin A and leoleorin B, and the smoke extract displayed suppression of the PTZ induced seizure-like behaviour in zebrafish larvae. Under light and dark conditions, the smoke extract and compounds displayed potential anxiolytic activity at different concentrations.
CONCLUSION
Our results suggest that the smoke constituents of L. leonurus may exert anticonvulsant and anxiolytic effects which align with the traditional indications and the mode of administration.
Topics: Animals; Zebrafish; Anti-Anxiety Agents; Smoke; Plant Extracts; Anticonvulsants; Seizures; Larva; Lamiaceae; Pentylenetetrazole; Plant Components, Aerial; South Africa; Behavior, Animal
PubMed: 38688356
DOI: 10.1016/j.jep.2024.118271