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The Journal of Organic Chemistry Jul 2023An efficient, diversity-oriented synthesis of oxazepino[5,4-]quinazolin-9-ones, 6-chromeno[4,3-]quinolines, and dibenzo[,][1,6]naphthyridines was established involving a...
An efficient, diversity-oriented synthesis of oxazepino[5,4-]quinazolin-9-ones, 6-chromeno[4,3-]quinolines, and dibenzo[,][1,6]naphthyridines was established involving a substrate-based approach under microwave-assisted and conventional heating conditions in high yields (up to 88%). The CuBr-catalyzed, chemoselective cascade annulation of -propargylated 2-hydroxybenzaldehydes and 2-aminobenzamides delivered oxazepino[5,4-]quinazolin-9-ones involving a 6-- cyclization-air oxidation-1,3-proton shift-7- cyclization sequence. This one-pot process showed excellent atom economy (-HO) and constructed two new heterocyclic rings (six- and seven-membered) and three new C-N bonds in a single synthetic operation. On the other side of diversification, the reaction between /-propargylated 2-hydroxy/aminobenzaldehydes and 2-aminobenzyl alcohols delivered 6-chromeno[4,3-]quinolines and dibenzo[,][1,6]naphthyridines involving sequential imine formation-[4 + 2] hetero-Diels-Alder reaction-aromatization steps. The influence of microwave assistance was superior to conventional heating, where the reactions were clean, rapid, and completed in 15 min, and the conventional heating required a longer reaction time at a relatively elevated temperature.
Topics: Molecular Structure; Oxazepines; Microwaves; Nitrogen; Naphthyridines; Quinolines
PubMed: 37318181
DOI: 10.1021/acs.joc.3c00552 -
American Journal of Physiology.... Oct 2023Diabetes-induced glomerular hyperfiltration is an early alteration in kidney function in diabetes. Previous studies have shown that reduced adenosine A2 receptor...
Diabetes-induced glomerular hyperfiltration is an early alteration in kidney function in diabetes. Previous studies have shown that reduced adenosine A2 receptor signaling contributes to diabetes-induced glomerular hyperfiltration. The present study investigated the effects of enhanced interstitial adenosine concentration by inhibition of cellular adenosine reuptake, thereby promoting endogenous adenosine signaling. Insulinopenic diabetes was induced by streptozotocin in adult male Sprague-Dawley rats. Two weeks after diabetes induction, kidney function in terms of glomerular filtration rate, and total, cortical, and medullary renal blood flows were evaluated under thiobutabarbital anesthesia during baseline and after renal artery infusion of two doses of the adenosine reuptake inhibitor dilazep. Dilazep did not affect mean arterial pressure indicating that the effects of the interventions were intrarenal. Diabetics had increased glomerular filtration rate compared with controls and dilazep dose-dependently decreased glomerular filtration rate in diabetics, whereas it had no significant effect in controls. Dilazep increased cortical renal blood flows in controls, whereas medullary blood flow was not significantly changed. Dilazep did not affect total renal blood flow in any of the groups but decreased cortical blood flow in diabetics, resulting in decreased filtration fraction by dilazep in diabetics. Pretreatment with the adenosine A2a antagonist ZM241385 prevented intrarenal dilazep-mediated effects on glomerular filtration rate and filtration fraction in diabetics. In conclusion, enhancing intrarenal adenosine signaling by dilazep normalizes diabetes-induced glomerular hyperfiltration at least in part by activation of adenosine A2a receptors.
Topics: Rats; Animals; Male; Rats, Sprague-Dawley; Dilazep; Adenosine; Kidney Glomerulus; Diabetes Mellitus; Kidney; Kidney Diseases; Glomerular Filtration Rate
PubMed: 37486069
DOI: 10.1152/ajpregu.00278.2022 -
Epilepsy Research Sep 2023Epilepsy is a chronic brain disorder characterized by unprovoked and recurrent seizures, of which 60% are of unknown etiology. Recent studies implicate microglia in the...
Epilepsy is a chronic brain disorder characterized by unprovoked and recurrent seizures, of which 60% are of unknown etiology. Recent studies implicate microglia in the pathophysiology of epilepsy. However, their role in this process, in particular following early-life seizures, remains poorly understood due in part to the lack of suitable experimental models allowing the in vivo imaging of microglial activity. Given the advantage of zebrafish larvae for minimally-invasive imaging approaches, we sought for the first time to describe the microglial responses after acute seizures in two different zebrafish larval models: a chemically-induced epileptic model by the systemic injection of kainate at 3 days post-fertilization, and the didy genetic epilepsy model, which carries a mutation in scn1lab that leads to spontaneous epileptiform discharges. Kainate-treated larvae exhibited transient brain damage as shown by increased numbers of apoptotic nuclei as early as one day post-injection, which was followed by an increase in the number of microglia in the brain. A similar microglial phenotype was also observed in didy mutants, suggesting that microglia numbers change in response to seizure-like activity in the brain. Interestingly, kainate-treated larvae also displayed a decreased seizure threshold towards subsequent pentylenetetrazole-induced seizures, as shown by higher locomotor and encephalographic activity in comparison with vehicle-injected larvae. These results are comparable to kainate-induced rodent seizure models and suggest the suitability of these zebrafish seizure models for future studies, in particular to elucidate the links between epileptogenesis and microglial dynamic changes after seizure induction in the developing brain, and to understand how these modulate seizure susceptibility.
Topics: Animals; Zebrafish; Microglia; Kainic Acid; Seizures; Brain; Epilepsy; Pentylenetetrazole; Disease Models, Animal
PubMed: 37572541
DOI: 10.1016/j.eplepsyres.2023.107203 -
PLoS Biology May 2024Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In...
Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In order to expand the application of alkenyl oxindoles for targeted protein degradation, we designed and synthesized a series of heterobifunctional compounds by conjugating different alkenyl oxindoles with bromodomain-containing protein 4 (BRD4) inhibitor JQ1. Through structure-activity relationship study, we successfully developed JQ1-alkenyl oxindole conjugates that potently degrade BRD4. Unexpectedly, we found that these molecules degrade BRD4 through the ubiquitin-proteasome system, rather than the autophagy-lysosomal pathway. Using pooled CRISPR interference (CRISPRi) screening, we revealed that JQ1-alkenyl oxindole conjugates recruit the E3 ubiquitin ligase complex CRL4DCAF11 for substrate degradation. Furthermore, we validated the most potent heterobifunctional molecule HL435 as a promising drug-like lead compound to exert antitumor activity both in vitro and in a mouse xenograft tumor model. Our research provides new employable proteolysis targeting chimera (PROTAC) moieties for targeted protein degradation, providing new possibilities for drug discovery.
Topics: Humans; Animals; Proteolysis; Mice; Ubiquitin-Protein Ligases; Oxindoles; Cell Cycle Proteins; Transcription Factors; Cell Line, Tumor; Xenograft Model Antitumor Assays; Mice, Nude; HEK293 Cells; Structure-Activity Relationship; Proteasome Endopeptidase Complex; Azepines; Antineoplastic Agents; Female; Bromodomain Containing Proteins; Receptors, Interleukin-17
PubMed: 38768083
DOI: 10.1371/journal.pbio.3002550 -
Angewandte Chemie (International Ed. in... Mar 2024Near-infrared (NIR) emitters are of great interest for applications in bioimaging and modern technology. Yet the design of such materials with decent characteristics is... (Review)
Review
Near-infrared (NIR) emitters are of great interest for applications in bioimaging and modern technology. Yet the design of such materials with decent characteristics is challenging due to intrinsic limitations. In a recent article, Murai and Yamaguchi report the synthesis of NIR emitters with appreciable fluorescence quantum yields reaching 0.02 at 878 nm in CH Cl solution. The low band gaps were achieved by a new design strategy exploiting antiaromaticity relief. This concept was realized for compounds consisting of an antiaromatic azepine central ring fused to thiophene moieties. In these systems, thiophene unfolds its dual nature. On the one hand, it contributes to the high antiaromaticity of azepine; on the other hand, it exerts a stabilizing effect on azepine through the formation of a quinoid structure, which reduces its antiaromaticity and shifts the absorption and emission maxima into the NIR region.
PubMed: 38127576
DOI: 10.1002/anie.202317060 -
Organic & Biomolecular Chemistry Jul 2023Total synthesis of the marine natural product bengamide E and 5--bengamide E has been accomplished using two routes: (i) a polyhydroxy acid precursor involving a total...
Total synthesis of the marine natural product bengamide E and 5--bengamide E has been accomplished using two routes: (i) a polyhydroxy acid precursor involving a total of 16 steps with an overall yield of 17.0% and (ii) a cyclic lactone precursor with a total of 12 steps and overall 23.0% yield. The key steps involve (1) regioselective -methoxybenzylidine ring opening, (2) a stereoselective Grignard reaction and (3) olefin cross-metathesis. The total synthesis could provide significant quantities of bengamide E and 5--bengamide E as all the reaction processes were very efficient and the raw materials were inexpensive and highly abundant. The protocol has an advantage over previously reported methods as it provides ready access to the C-5 hydroxy group for further modification and its future structure-activity relationship studies for anti-tumor activity.
Topics: Biological Products; Azepines; Structure-Activity Relationship; Alkenes; Stereoisomerism
PubMed: 37403479
DOI: 10.1039/d3ob00922j -
Biomedicine & Pharmacotherapy =... Jan 2024Chemical kindling is broadly used experimental model to investigate novel treatments on the process of epileptogenesis and coexisting behavioral comorbidities. The...
Chemical kindling is broadly used experimental model to investigate novel treatments on the process of epileptogenesis and coexisting behavioral comorbidities. The current study aimed to investigate the low dose perampanel (PER) (0.125 and 0.5 mg/kg) and pregabalin (PG) (15 mg/kg) as standalone treatments and in combination on kindling-induced seizure progression with concurrent electroencephalographic alterations. Mice were subjected to pentylenetetrazole (PTZ)-induced kindling followed by neurobehavioral assessment for anxiety-like activity and cognitive deficit through behavioral experiments. The monotherapy with PER at 0.5 mg/kg and PG at 15 mg/kg delayed the kindling process but PRP+PG yielded pronounced benefits and hindered the development of seizures of higher severity. PER+PG combination relieved the animals from anxiety-like behavior in various employed anxiogenic tests. Furthermore, the kindling-associated cognitive deficit was protected by PER+PG combination as increased alteration behavior, discrimination index and latencies to enter the dark zone were noted in y-maze, object recognition and passive avoidance tests, respectively while shorter escape latencies were noted in water maze. The brain samples of kindled mice had elevated malondialdehyde and reduced catalase, superoxide dismutase and glutathione peroxidase enzymes while treatment with PER and PG combination shielded the mice from heightened kindling-associated oxidative stress. Overall, the findings of the present study illustrate that concurrent administration of PER and PG effectively hindered the process of epileptogenesis by protecting neuronal excitability and brain oxidative stress. The results predict the dominance of PER and PG combination over monotherapy which might serve as an effective novel combination to combat drug resistance and behavioral disorders in epileptic patients.
Topics: Humans; Mice; Animals; Pentylenetetrazole; Pregabalin; Seizures; Epilepsy; Kindling, Neurologic; Oxidative Stress; Anticonvulsants
PubMed: 38101280
DOI: 10.1016/j.biopha.2023.115935 -
Applied Biochemistry and Biotechnology Apr 2024Anxiety and depression are major side effects induced by currently available antiepileptic drugs; apart from this, they also diminish intelligence and language skills...
Anxiety and depression are major side effects induced by currently available antiepileptic drugs; apart from this, they also diminish intelligence and language skills which cause hepatic failure, anemia, etc. Hence, in this study, we assessed antiepileptic effect of a phytochemical mangiferin. Epilepsy, a prevalent non communicable neurological disorder, affects infants and older population throughout the world. Epilepsy-induced comorbidities are more severe and if not treated cautiously lead to disability and even worse cases, mortality. The onset and duration of convulsion were observed. Seizure severity score was assessed by provoking kindling with 35 mg/kg PTZ. Prooxidants and antioxidants were measured to assess the antioxidant effect of mangiferin. Inflammatory markers were measured to determine the anti-inflammatory effect of mangiferin. The levels of neurotransmitters and ATPases were quantified to evaluate the neuroprotective effect of mangiferin. Mangiferin significantly decreased the onset and duration convulsion. It also decreased the seizure severity score, locomotor activity, and immobilization effectively. The excitatory neurotransmitter was reduced, and inhibitory neurotransmitter was increased in mice treated with mangiferin. Overall, our results confirm that mangiferin efficiently protects mice from PTZ-induced seizures. It can be subjected to further research to be prescribed as a potent antiepileptic drug.
Topics: Animals; Xanthones; Mice; Pentylenetetrazole; Anticonvulsants; Seizures; Male; Antioxidants
PubMed: 37486538
DOI: 10.1007/s12010-023-04651-2 -
Bioorganic Chemistry Nov 2023Adopting the molecular overlay approach, three novel sets of thiazepinopurines with expected cytotoxicity and CDK2 inhibition potential were designed and synthesized....
Adopting the molecular overlay approach, three novel sets of thiazepinopurines with expected cytotoxicity and CDK2 inhibition potential were designed and synthesized. This was accomplished through the heteroannelation of purines, for the first time, with thiazepine. The obtained thiazepinopurines derivatives were assessed for their cytotoxicity toward tumor cells of three different types, HepG2, MCF-7, and PC-3 as well as one normal cell (WI38). Among the studied compounds, 3b and 3c exhibited significant antiproliferative activity against tumor cells presenting IC range of 5.52-17.09 µM in comparison with Roscovitine (9.32-13.82 µM). Additionally, both compounds displayed superior selectivity indices (SI = 3.00-7.15) toward tested cancer cells. The 4-chlorophenyl analog 3b has shown the best selectivity index, and hence it has been subjected to additional investigations to determine its proper mechanistic effect. Accordingly, the CDK2 inhibition potential, apoptosis induction, and cell cycle analysis of MCF-7 were evaluated. Results revealed that this analog displayed a potent CDK2 inhibition potential with an IC value of 0.219 µM. Findings also showed that 3b was thought to arrest MCF-7 cell cycle at S phase together with apoptosis induction by the increased expression of Bax, Caspase-8, and -9 markers with a concomitant decrease in Bcl-2 expression. Besides, the probable interaction of 3b with CDK2 binding pocket was investigated by molecular docking.
Topics: Humans; Molecular Docking Simulation; Cell Death; MCF-7 Cells; Thiazepines; Cyclin-Dependent Kinase 2
PubMed: 37611530
DOI: 10.1016/j.bioorg.2023.106789 -
European Journal of Pharmacology Aug 2023The sedative and anxiolytic-like activity of two coronaridine congeners, (+)-catharanthine and (-)-18-methoxycoronaridine (18-MC), was studied in male and female mice....
Coronaridine congeners induce sedative and anxiolytic-like activity in naïve and stressed/anxious mice by allosteric mechanisms involving increased GABA receptor affinity for GABA.
The sedative and anxiolytic-like activity of two coronaridine congeners, (+)-catharanthine and (-)-18-methoxycoronaridine (18-MC), was studied in male and female mice. The underlying molecular mechanism was subsequently determined by fluorescence imaging and radioligand binding experiments. The loss of righting reflex and locomotor activity results showed that both (+)-catharanthine and (-)-18-MC induce sedative effects at doses of 63 and 72 mg/kg in a sex-independent manner. At a lower dose (40 mg/kg), only (-)-18-MC induced anxiolytic-like activity in naïve mice (elevated O-maze test), whereas both congeners were effective in mice under stressful/anxiogenic conditions (light/dark transition test) and in stressed/anxious mice (novelty-suppressed feeding test), where the latter effect lasted for 24 h. Coronaridine congeners did not block pentylenetetrazole-induced anxiogenic-like activity in mice. Considering that pentylenetetrazole inhibits GABA receptors, this result supports a role for this receptor in the activity mediated by coronaridine congeners. Functional and radioligand binding results showed that coronaridine congeners interact with a site different from that for benzodiazepines, increasing GABA receptor affinity for GABA. Our study showed that coronaridine congeners induce sedative and anxiolytic-like activity in naïve and stressed/anxious mice in a sex-independent fashion, likely by a benzodiazepine-independent allosteric mechanism that increases GABA receptor affinity for GABA.
Topics: Mice; Male; Female; Animals; Anti-Anxiety Agents; Hypnotics and Sedatives; Receptors, GABA-A; Pentylenetetrazole; Benzodiazepines; gamma-Aminobutyric Acid
PubMed: 37331683
DOI: 10.1016/j.ejphar.2023.175854