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Organic Letters Aug 2023A Ag-catalyzed three-component annulation protocol, which uses alkynylaryl aldehydes, amines, and trifluorodiazoethane or diazoacetonitrile, to forge a new class of...
A Ag-catalyzed three-component annulation protocol, which uses alkynylaryl aldehydes, amines, and trifluorodiazoethane or diazoacetonitrile, to forge a new class of trifluoromethyl- and cyano-functionalized benzo[]azepine is presented in this Letter. The key transformations involved in this reaction are the transient formation of the isoquinolinium intermediate and the subsequent ring-expansive addition of in situ-formed silver trifluorodiazoethylide to this intermediate. The practicality of this protocol is illustrated by realizing access to a wide range of densely functionalized benzo[]azepines.
PubMed: 37530707
DOI: 10.1021/acs.orglett.3c02053 -
European Journal of Medicinal Chemistry Jun 2024Azepanes or azepines are structural motifs of many drugs, drug candidates and evaluated lead compounds. Even though compounds having N-heterocyclic 7-membered rings are... (Review)
Review
Azepanes or azepines are structural motifs of many drugs, drug candidates and evaluated lead compounds. Even though compounds having N-heterocyclic 7-membered rings are often found in nature (e.g. alkaloids), the natural compounds of this group are rather rare as approved therapeutics. Thus, recently studied and approved azepane or azepine-congeners predominantly consist of semi-synthetically or synthetically-obtained scaffolds. In this review a comparison of approved drugs and recently investigated leads was proposed taking into regard their structural aspects (stereochemistry), biological activities, pharmacokinetic properties and confirmed molecular targets. The 7-membered N-heterocycles reveal a wide range of biological activities, not only against CNS diseases, but also as e.g. antibacterial, anticancer, antiviral, antiparasitic and against allergy agents. As most of the approved or investigated potential drugs or lead structures, belonging to 7-membered N-heterocycles, are synthetic scaffolds, this report also reveals different and efficient metal-free cascade approaches useful to synthesize both simple azepane or azepine-containing congeners and those of oligocyclic structures. Stereochemistry of azepane/azepine fused systems, in view of biological data and binding with the targets, is discussed. Apart from the approved drugs, we compare advances in SAR studies of 7-membered N-heterocycles (mainly from 2018 to 2023), whereas the related synthetic part concerning various domino strategies is focused on the last ten years.
PubMed: 38879971
DOI: 10.1016/j.ejmech.2024.116556 -
Journal of Chemical Neuroanatomy Oct 2023Somatostatin interneurons exhibited anti-epileptic activity. As a result, somatostatin agonists appear to be a promising target for antiepileptic drug development...
Somatostatin interneurons exhibited anti-epileptic activity. As a result, somatostatin agonists appear to be a promising target for antiepileptic drug development (AEDs). In this regard, we investigated the effects of octreotide, a somatostatin analog, on pentylenetetrazol (PTZ)-induced seizures in male Wistar rats. Animals were given octreotide at doses of 50 or 100 µg/kg for seven days. The anxiolytic effects of octreotide were then evaluated using open field and elevated plus-maze tests. Following that, mice were intraperitoneally given a single convulsive dosage of PTZ (60 mg/kg) and then monitored for 30 min for symptoms of seizures. Finally, the antioxidant capacity of brain tissue and histopathological changes in the hippocampus were investigated. Octreotide therapy for seven days at 50 or 100 µg/kg was more effective than diazepam in preventing acute PTZ-induced seizures (P < 0.05). Furthermore, both octreotide dosages revealed substantial anxiolytic effects in open-field and elevated plus-maze tests compared to untreated rats. Nonetheless, octreotide's anxiolytic impact was less effective than diazepam's. On the other hand, octreotide also suppressed neuronal apoptosis and attenuated oxidative stress. Our results suggest that chronic administration of octreotide has anticonvulsant, anxiolytic, and antioxidant activity in the male Wistar rat model.
Topics: Animals; Male; Mice; Rats; Anti-Anxiety Agents; Anticonvulsants; Diazepam; Neuroprotective Agents; Octreotide; Pentylenetetrazole; Rats, Wistar; Seizures; Somatostatin
PubMed: 37499770
DOI: 10.1016/j.jchemneu.2023.102320 -
Pesticide Biochemistry and Physiology Nov 2023In this study, seven novel anthraquinones (1-7) and four described anthraquinones (8-11) were purified from Nicotiana tabacum-derived Aspergillus oryzae YNCA1220. It is...
In this study, seven novel anthraquinones (1-7) and four described anthraquinones (8-11) were purified from Nicotiana tabacum-derived Aspergillus oryzae YNCA1220. It is worth noting that only analogs of 4 and 5 have been reported as natural products to date, while the nuclei of compounds 1-3, 6 and 7 were isolated for the first time in nature. Among them, compounds 1-3 bear an unusual anthra[2,3-b]furan-9,10-dione nucleus, 4 and 5 possess a rare 3-methyl-1H-pyrrol-2-yl substituent, and 6 and 7 are new framework anthraquinones bearing a 6-methyl-1,7-dihydro-2H-azepin-2-one ring. Interestingly, the in vivo assays indicated that 1, 4 and 5 had inactivation effects against tobacco mosaic virus (TMV) with inhibition rates of 41.6%, 55.4% and 38.6%, respectively, at a concentration of 50 μg/mL, which were better than that of the positive control agent, ningnanmycin (33.8%). Compounds 1, 4 and 5 also had protective effects with inhibition rates of 48.7%, 60.2% and 43.5% at the same concentration, while 4 had a better curative effect than ningnanmycin at a concentration of 100 μg/mL. In addition, mechanistic studies also revealed that a potent direct effect on TMV, the induction of SAR in tobacco plants, and the effective regulation of defense enzymes, defense genes, and defense hormones may be the reasons for the significant effects of 4 against TMV. At the same time, downregulation of the expression of total NtHsp70 protein by inhibiting the related Hsp70 genes may also be involved in tobacco resistance to TMV. To evaluate whether compounds have broader antiviral activities, the antirotavirus activities of new isolates were also evaluated and found to be highly effective with a therapeutic index (TI) value ranging from 11.6 to 17.7. This study suggests that the above anthraquinone compounds, particularly 4, have broad spectrum antiviral activities. The successful isolation and structure identification of the above anthraquinones provide new materials for the screening of anti-TMV agents and contribute to the improved utilization of N. tabacum-derived fungi.
Topics: Aspergillus oryzae; Nicotiana; Anthraquinones; Biological Assay; Antiviral Agents; Tobacco Mosaic Virus
PubMed: 37945230
DOI: 10.1016/j.pestbp.2023.105613 -
Science (New York, N.Y.) Sep 2023Nitrogen scanning in aryl fragments is a valuable aspect of the drug discovery process, but current strategies require time-intensive, parallel, bottom-up synthesis of...
Nitrogen scanning in aryl fragments is a valuable aspect of the drug discovery process, but current strategies require time-intensive, parallel, bottom-up synthesis of each pyridyl isomer because of a lack of direct carbon-to-nitrogen (C-to-N) replacement reactions. We report a site-directable aryl C-to-N replacement reaction allowing unified access to various pyridine isomers through a nitrene-internalization process. In a two-step, one-pot procedure, aryl azides are first photochemically converted to 3-azepines, which then undergo an oxidatively triggered C2-selective cheletropic carbon extrusion through a spirocyclic azanorcaradiene intermediate to afford the pyridine products. Because the carbon of the aryl nitrene is excised from the molecule, the reaction proceeds regioselectively without perturbation of the remainder of the substrate. Applications are demonstrated in the abbreviated synthesis of a pyridyl derivative of estrone, as well as in a prototypical nitrogen scan.
PubMed: 37769067
DOI: 10.1126/science.adj5331 -
Inorganic Chemistry Dec 2023Herein, we present the synthesis and coordination chemistry of copper(II) and zinc(II) complexes of two novel heterocyclic triazacyclononane (tacn)-based chelators (H...
Herein, we present the synthesis and coordination chemistry of copper(II) and zinc(II) complexes of two novel heterocyclic triazacyclononane (tacn)-based chelators (H and ). The chelator H was further derivatized to obtain a novel PSMA-based bioconjugate () and a bifunctional photoactivatable azamacrocyclic analogue, , for the development of copper-64 radiopharmaceuticals. Cu radiolabeling experiments were performed on the different metal-binding chelates, whereby quantitative radiochemical conversion (RCC) was obtained in less than 10 min at room temperature. The stability of in human plasma was assessed by ligand-challenge and copper-exchange experiments. Next, we investigated the viability of the photoactivatable analog () for the light-induced photoradiosynthesis of radiolabeled proteins. One-pot photoconjugation reactions to human serum albumin (HSA) as a model protein and the clinically relevant monoclonal antibody formulation MetMAb were performed. [Cu]Cu--azepin-HSA and [Cu]Cu--azepin-onartuzumab were prepared in less than 15 min by irradiation at 395 nm, with radiochemical purities (RCP) of >95% and radiochemical yields (RCYs) of 42.7 ± 5.3 and 49.6%, respectively. Together, the results obtained here open the way for the development of highly stable Cu-radiopharmaceuticals by using -heterocyclic tacn-based chelators, and the method can easily be extended to the development of Cu radiopharmaceuticals for future applications in molecularly targeted radio(immuno)therapy.
Topics: Humans; Chelating Agents; Radiopharmaceuticals; Copper; Copper Radioisotopes; Aza Compounds; Positron-Emission Tomography
PubMed: 37487036
DOI: 10.1021/acs.inorgchem.3c01616 -
International Immunopharmacology Mar 2024Epilepsy is a severe neurological disorder associated with substantial morbidity and mortality. Vanillin (Van) is a natural phenolic aldehyde with beneficial...
Ameliorative effects of vanillin against pentylenetetrazole-induced epilepsy and associated memory loss in mice: The role of Nrf2/HO-1/NQO1 and HMGB1/RAGE/TLR4/NFκB pathways.
BACKGROUND
Epilepsy is a severe neurological disorder associated with substantial morbidity and mortality. Vanillin (Van) is a natural phenolic aldehyde with beneficial pharmacological properties. This study investigated the neuroprotective effects of Van in epilepsy and elucidated its mechanism of action.
METHODS
Swiss albino mice were divided into the following five groups: "normal group", 0.9 % saline; "pentylenetetrazole (PTZ) group", intraperitoneal administration of 35 mg/kg PTZ on alternate days up to 42 days; and "PTZ + Van 20", "PTZ + Van 40", and "PTZ + sodium valproate (Val)" groups received PTZ injections in conjunction withVan 20 mg, Van 40 mg/kg, and Val 300 mg/kg, respectively. Behavioural tests and hippocampal histopathological analysis were performed in all groups. The Nrf2/HO-1/NQO1 and HMGB1/RAGE/TLR4/NFκB pathways, oxidative stress, neuro-inflammation, and apoptotic markers were analysed. Furthermore, brain acetylcholinesterase (AChE) activity and levels of dopamine (DA), gamma-aminobutyric acid GABA, and serotonin 5-HT were assessed.
RESULTS
Van prolonged seizure manifestations and improved electroencephalogram (EEG)criteriain conjunction with 100 mg/kg PTZ once daily. Van administration increased Nrf2/HO-1/NQO1 levels, with subsequent attenuation of malondialdehyde (MDA) and nitric oxide (NO) levels with elevated glutathione (GSH) levels and intensified superoxide dismutase (SOD) and catalase activities. Van reduced the gene and protein expression of HMGB1/RAGE/TLR4/NFκB and decreased the levels of inflammatory and apoptotic markers. In addition, Van reduced AChE activity, and elevated glial fibrillary acidic proteins (GFAP) increased neurotransmitter and brain-derived neurotrophic factors (BDNF).
CONCLUSION
By increasing Nrf2/HO-1/NQO1 levels and downregulating the HMGB1/RAGE/TLR4/ NFκB pathway, Van offered protection in PTZ-kindled mice with subsequent attenuation in lipid peroxidation, upregulation in antioxidant enzyme activities, and reduction in inflammation and apoptosis.
Topics: Mice; Animals; Pentylenetetrazole; NF-E2-Related Factor 2; Toll-Like Receptor 4; HMGB1 Protein; Acetylcholinesterase; Epilepsy; Antioxidants; Oxidative Stress; Memory Disorders; Glutathione; Inflammation; Benzaldehydes
PubMed: 38335655
DOI: 10.1016/j.intimp.2024.111657 -
Movement Disorders Clinical Practice Apr 2024Chronic constipation is a common digestive complication of Parkinson's disease (PD). (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Chronic constipation is a common digestive complication of Parkinson's disease (PD).
OBJECTIVES
To verify the usefulness of elobixibat, an ileal bile acid transporter inhibitor, for chronic constipation in PD.
METHODS
This double-blind, placebo-controlled study consisted of a 2-week observation/washout period and a 4-week treatment period. All patients received a Bowel Movement Diary at Week -2 and were allocated to elobixibat (10 mg) or placebo at Week 0. Patients visited at Weeks 2 and 4 to report daily spontaneous bowel movements (SBM), stool form, drug use, quality of life (QOL), and safety. Changes in these parameters were assessed.
RESULTS
The study included 38 patients in the elobixibat group and 39 in the placebo group, and 37 each completed the study. SBM frequency/week (mean ± standard deviation) increased significantly from 4.2 ± 2.6 at baseline to 5.9 ± 3.2 at Week 4 in the elobixibat group (P = 0.0079), but not in the placebo group (4.5 ± 2.7 to 5.3 ± 3.5; P = 0.0889). On analysis of covariance, the between-group difference in frequency changes at Week 4 (primary endpoint) was not significant after adjustment by baseline and sex (point estimate = 0.8; 95% confidence interval = -0.57 to 2.09, P = 0.2601), although a significant difference (P = 0.0011) was evidenced at Week 1 by a similar analysis. Stool form and scores of satisfaction and stigma were improved by elobixibat. Adverse events were as previously reported.
CONCLUSIONS
Elobixibat improved the SBM frequency, though the defined primary endpoint was not evidenced. QOL parameters (stool consistency and treatment satisfaction) were also improved. Elobixibat may have therapeutic benefits in PD patients suffering from chronic constipation.
TRIAL REGISTRATION INFORMATION
Trial Registration Number: JPRN-jRCTs031200172 (submitted: October 26, 2020; first patient enrolment: December 23, 2020; https://jrct.niph.go.jp/en-latest-detail/jRCTs031200172).
Topics: Humans; Chronic Disease; Constipation; Dipeptides; Gastrointestinal Diseases; Parkinson Disease; Quality of Life; Thiazepines; Double-Blind Method
PubMed: 38264844
DOI: 10.1002/mdc3.13972 -
Epilepsy Research Jul 2023Epilepsy is widely investigated as a common neurological disease requiring pharmacologically effective agents. N-acetyl cysteine (NAC), has become a remarkable molecule...
INTRODUCTION/AIM
Epilepsy is widely investigated as a common neurological disease requiring pharmacologically effective agents. N-acetyl cysteine (NAC), has become a remarkable molecule with its role in both antioxidant and glutaminergic modulation. There are many points and processes waiting to be revealed regarding the role of NAC in epilepsy.
MATERIALS AND METHODS
Pentylenetetrazole (PTZ) was administered to induce seizures in a total number of 48 Sprague-Dawley rats. 35 mg/kg PTZ dose as a sub-convulsive dose was administered to 24 animals to monitor EEG changes, while 70 mg/kg PTZ dose which was a convulsive dose was administered to 24 animals to determine seizure-related behavioral changes with the Racine's scale. 30 min before the seizure-induced procedure, NAC was administered at doses of 300 and 600 mg/kg as pretreatment to investigate anti-seizure and anti-oxidative effects. The spike percentage, the stage of convulsion, and the onset time of the first myoclonic jerk were evaluated to determine the anti-seizure effect. Furthermore, its effect on oxidative stress was determined by measuring both malondialdehyde (MDA) level and superoxide dismutase (SOD) enzyme activity.
RESULTS
There was a dose-dependent reduction in the seizure stage and prolonged onset time of the first myoclonic jerk in rats with NAC pretreatment. EEG recordings resulted in a dose-dependent decrease in spike percentages. Moreover, the same dose-dependent changes were observed in oxidative stress biomarkers, both 300 mg/kg NAC and 600 mg/kg decreased MDA levels and ameliorated SOD activity.
CONCLUSION
We can report that 300 mg/kg and 600 mg/kg doses of NAC are promising with their reducing effect on convulsions and have a beneficial effect by preventing oxidative stress. In addition, NAC has been also determined that this effect is dose-dependent. Detailed and comparative studies are needed on the convulsion-reducing effect of NAC in epilepsy.
Topics: Rats; Animals; Pentylenetetrazole; Rats, Sprague-Dawley; Myoclonus; Acetylcysteine; Electroencephalography; Epilepsy; Seizures; Superoxide Dismutase; Anticonvulsants; Disease Models, Animal
PubMed: 37116249
DOI: 10.1016/j.eplepsyres.2023.107144 -
Biomedicine & Pharmacotherapy =... May 2024Targeting epigenetic mechanisms has emerged as a potential therapeutic approach for the treatment of kidney diseases. Specifically, inhibiting the bromodomain and...
Targeting epigenetic mechanisms has emerged as a potential therapeutic approach for the treatment of kidney diseases. Specifically, inhibiting the bromodomain and extra-terminal (BET) domain proteins using the small molecule inhibitor JQ1 has shown promise in preclinical models of acute kidney injury (AKI) and chronic kidney disease (CKD). However, its clinical translation faces challenges due to issues with poor pharmacokinetics and side effects. Here, we developed engineered liposomes loaded with JQ1 with the aim of enhancing kidney drug delivery and reducing the required minimum effective dose by leveraging cargo protection. These liposomes efficiently encapsulated JQ1 in both the membrane and core, demonstrating superior therapeutic efficacy compared to freely delivered JQ1 in a mouse model of kidney ischemia-reperfusion injury. JQ1-loaded liposomes (JQ1-NPs) effectively targeted the kidneys and only one administration, one-hour after injury, was enough to decrease the immune cell (neutrophils and monocytes) infiltration to the kidney-an early and pivotal step to prevent damage progression. By inhibiting BRD4, JQ1-NPs suppress the transcription of pro-inflammatory genes, such as cytokines (il-6) and chemokines (ccl2, ccl5). This success not only improved early the kidney function, as evidenced by decreased serum levels of BUN and creatinine in JQ1-NPs-treated mice, along with reduced tissue expression of the damage marker, NGAL, but also halted the production of extracellular matrix proteins (Fsp-1, Fn-1, α-SMA and Col1a1) and the fibrosis development. In summary, this work presents a promising nanotherapeutic strategy for AKI treatment and its progression and provides new insights into renal drug delivery.
Topics: Animals; Azepines; Reperfusion Injury; Triazoles; Renal Insufficiency, Chronic; Mice; Disease Progression; Mice, Inbred C57BL; Kidney; Male; Liposomes; Transcription Factors; Acute Kidney Injury; Disease Models, Animal; Nanoparticles; Cell Cycle Proteins; Bromodomain Containing Proteins; Nuclear Proteins
PubMed: 38537579
DOI: 10.1016/j.biopha.2024.116492