Synthesis of 2,3-Benzotropones via Palladium(II)-Catalyzed Aerobic Dehydrogenation from 1-Benzosuberones and Sequential Diels-Alder Reaction to Yield Benzobicyclo[3.2.2]nonenones.

An approach to 2,3-benzotropone from 1-benzosuberone via palladium(II)-catalyzed aerobic dehydrogenation was developed. This method first provided a catalytic route to various 2,3-benzotropones from their corresponding 1-benzosuberones in good yields. In addition, the reaction could be applied to a one-pot Diels-Alder reaction with maleimide, providing a complex benzobicyclo[3.2.2]nonenone in ≤90% yield. Kinetic analysis supporting our proposed mechanism was also performed, underscoring the robustness of the developed synthetic pathway.

Dextran sodium sulfate (DSS)-induced colitis is alleviated in mice after administration of flavone-derived NRF2-activating molecules.

Inflammatory Bowel Disease (IBD) is a chronic and relapsing inflammatory condition characterized by severe symptoms such as diarrhea, fatigue, and weight loss. Growing evidence underscores the direct involvement of the nuclear factor-erythroid 2-related factor 2 (NRF2) in the development and progression of IBD, along with its associated complications, including colorectal cancer. The NRF2 pathway plays a crucial role in cellular responses to oxidative stress, and dysregulation of this pathway has been implicated in IBD. Flavones, a significant subclass of flavonoids, have shown pharmacological impacts in various diseases including IBD, through the NRF2 signaling pathway. In this study, we conducted a screening of compounds with a flavone structure and identified NJK15003 as a promising NRF2 activator. NJK15003 demonstrated potent NRF2 activation, as evidenced by the upregulation of downstream proteins, promoter activation, and NRF2 nuclear translocation in IBD cellular models. Treatment with NJK15003 effectively restored the protein levels of tight junctions in cells treated with dextran sodium sulfate (DSS) and in DSS-treated mice, suggesting its potential to protect cells from barrier integrity disruption in IBD. In DSS-treated mice, the administration of NJK15003 resulted in the prevention of body weight loss, a reduction in colon length shortening, and a decrease in the disease activity index. Furthermore, NJK15003 treatment substantially alleviated inflammatory responses and apoptotic cell death in the colon of DSS-treated mice. Taken together, this study proposes the potential utility of NRF2-activating flavone compounds, exemplified by NJK15003, for the treatment of IBD.

3',4'-Dihydroxyflavone mitigates inflammatory responses by inhibiting LPS and TLR4/MD2 interaction.

BACKGROUND: We previously reported the potential inhibitory activity of 3',4'-dihydroxyflavone (DHF) on nitric oxide (NO) and prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-stimulated macrophages. PURPOSE: We investigated the underlying molecular mechanisms of DHF in LPS-activated macrophages and evaluated its effect on LPS-induced septic shock in mice. METHODS: To explore the anti-inflammatory effect of DHF, nitrite, PGE2, and cytokines were measured in vitro and in vivo experiments. In addition, to verify the molecular signaling pathway, quantitative real time-PCR, luciferase assay, nuclear extraction, electrophoretic mobility shift assay, immunocytochemistry, immunoprecipitation, molecular docking analysis, and myeloid differentiation 2 (MD2)-LPS binding assay were conducted. RESULTS: DHF suppressed the LPS-induced expression of proinflammatory mediators through nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and interferon regulatory factor 3 (IRF3) inactivation pathways in RAW 264.7 macrophages. Importantly, molecular docking analysis and in vitro binding assays showed that DHF interacts with the hydrophobic pocket of MD2 and then interferes with the interaction between LPS and toll-like receptor 4 (TLR4). DHF inhibited LPS-induced oxidative stress by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2). Treatment of LPS-induced endotoxemia mice with DHF reduced the expression levels of pro-inflammatory mediators via the inactivation of NF-κB, AP-1, and signal transducer and activator of transcription 1 (STAT1) in the lung tissue, thus increasing the survival rate. CONCLUSION: Taken together, our data first time revealed the underlying mechanism of the DHF-dependent anti-inflammatory effect by preventing LPS from binding to the TLR4/MD2 complex. Therefore, DHF may be a possible anti-inflammatory agent for the treatment of LPS-mediated inflammatory diseases.

Synthesis of Xanthones via Copper(II)-Catalyzed Dehydrogenative Cyclization and Successive Aromatization in a One-Step Sequence.

In this study, an unprecedented approach to the xanthone scaffold from cyclohexyl(2-hydroxyphenyl)methanone via dehydrogenative cyclization and a successive aromatization cascade is reported. This methodology affords a novel route to the privileged structure with a wide substrate scope (a total of 29 compounds, ≤96% yield) in a highly atom-economic manner.

Syntheses of 1H-Indoles, Quinolines, and 6-Membered Aromatic N-Heterocycle-Fused Scaffolds via Palladium(II)-Catalyzed Aerobic Dehydrogenation under Alkoxide-Free Conditions.

Aromatic N-heterocycle-fused scaffolds such as indoles and quinolines are important core structures found in various bioactive natural products and synthetic compounds. Recently, various dehydrogenation methods with the help of alkoxides, known to significantly promote dihydro- or tetrahydro-heterocycles to be oxidized, were developed for the heterocycle synthesis. However, these approaches are sometimes unsuitable due to resulting undesired side reactions such as reductive dehalogenation. Herein, expedient syntheses of 1H-indoles, quinolines, and 6-membered N-heterocycle-fused scaffolds from their hydrogenated forms through palladium(II)-catalyzed aerobic dehydrogenation under alkoxide-free conditions are reported. A total of 48 compounds were successfully synthesized with a wide range of functional groups including halogens (up to 99% yield). These methodologies provide facile routes for various privileged structures possessing aromatic N-heterocycles without the help of alkoxides, in highly efficient manners.

Synthesis of meta-(Indol-3-yl)phenols from Indoles and Cyclohexenone via Palladium(II)-Catalyzed Oxidative Heck Reaction and Dehydrogenative Aromatization in a One-Step Sequence.

Facile construction of a meta-(indol-3-yl)phenol framework with a wide substrate scope (a total of 25 compounds) via a palladium(II)-catalyzed oxidative Heck reaction and dehydrogenative aromatization in a one-step sequence is reported. This methodology affords a novel route for the privileged structures that are challenging to access via a direct link between indole and phenol, in a highly efficient and atom-economical manner.

Identification of ortho catechol-containing isoflavone as a privileged scaffold that directly prevents the aggregation of both amyloid ß plaques and tau-mediated neurofibrillary tangles and its in vivo evaluation.

In this study, polyhydroxyisoflavones that directly prevent the aggregation of both amyloid ß (Aß) and tau were expediently synthesized via divergent Pd(0)-catalyzed Suzuki-Miyaura coupling and then biologically evaluated. By preliminary structure-activity relationship studies using thioflavin T (ThT) assays, an ortho-catechol containing isoflavone scaffold was proven to be crucial for preventing both Aß aggregation and tau-mediated neurofibrillary tangle formation. Additional TEM experiment confirmed that ortho-catechol containing isoflavone 4d significantly prevented the aggregation of both Aß and tau. To investigate the mode of action (MOA) of 4d, which possesses an ortho-catechol moiety, 1H-15N HSQC NMR analysis was thoroughly performed and the result indicated that 4d could directly inhibit both the formation of Aß42 fibrils and the formation of tau-derived neurofibrils, probably through the catechol-mediated nucleation of tau. Finally, 4d was demonstrated to alleviate cognitive impairment and pathologies related to Alzheimer's disease in a 5XFAD transgenic mouse model.

Chemical Degradation of Androgen Receptor (AR) Using Bicalutamide Analog-Thalidomide PROTACs.

A series of PROTACs (PROteolysis-TArgeting Chimeras) consisting of bicalutamide analogs and thalidomides were designed, synthesized, and biologically evaluated as novel androgen receptor (AR) degraders. In particular, we found that PROTAC compound 13b could successfully demonstrate a targeted degradation of AR in AR-positive cancer cells and might be a useful chemical probe for the investigation of AR-dependent cancer cells, as well as a potential therapeutic candidate for prostate cancers.

Divergent synthesis of flavones and flavanones from 2'-hydroxydihydrochalcones via palladium(ii)-catalyzed oxidative cyclization.

Divergent and versatile synthetic routes to flavones and flavanones via efficient Pd(ii) catalysis are disclosed. These Pd(ii) catalyses expediently provide a variety of flavones and flavanones from 2'-hydroxydihydrochalcones as common intermediates, depending on oxidants and additives, via discriminate oxidative cyclization sequences involving dehydrogenation, respectively, in a highly atom-economic manner.

Identification of 3',4',5'-trihydroxyflavone as an mammalian target of rapamycin inhibitor and its suppressive effects on dextran sulfate sodium-induced ulcerative colitis.

Flavone derivatives have been shown to possess anti-inflammatory properties in various inflammation model systems; however, their underlying molecular mechanisms remain elusive. In this study, a flavone derivative 3',4',5'-trihydroxyflavone (THF; NJK16003) was synthesized, and its anti-inflammatory effects and molecular targets were investigated using in vitro systems and an in vivo colitis model. NJK16003 showed potent anti-inflammatory activities in cell-based assays using macrophages. In vitro enzyme activity assays using various inflammation-related kinases revealed the mammalian target of rapamycin (mTOR) as a possible molecular target. Treatment of RAW264.7 cells with NJK16003 resulted in an increase in light chain 3B protein lipidation and a decrease in p62 protein levels and ribosomal S6 kinase phosphorylation, indicating that NJK16003 induces autophagy through mTOR inhibition. NJK16003 treatment resulted in significant induction of autophagy and suppression of inflammatory responses in intestinal epithelial cells. Autophagy induction has been shown to alleviate colitis by suppressing inflammatory responses and apoptotic cell death of intestinal epithelial cells. Indeed, inflammatory responses and intestinal epithelial cell death in our DSS-induced colitis mouse model were significantly suppressed by NJK16003 treatment. Our results indicate that NJK16003 could suppress inflammation by inducing autophagy through its mTOR inhibitory activity. These results suggest that NJK16003 could be a possible therapeutic agent for the treatment of inflammatory bowel diseases including colitis.

Ginger and 6-shogaol protect intestinal tight junction and enteric dopaminergic neurons against 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine in mice.

Objective: Ginger and its compound, 6-shogaol, have been known for improving gastrointestinal (GI) function and reducing inflammatory responses in GI tract. Recently, the treatment of GI dysfunction has been recognized as an important part of the management of neurodegenerative diseases, especially for Parkinson's disease (PD). In this study, we investigated whether ginger and 6-shogaol attenuate disruptions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the intestinal barrier and the enteric dopaminergic neurons.Methods: C57BL/6J mice received MPTP (30 mg/kg) for 5 days to induce GI alterations. Ginger (30, 100, 300 mg/kg) and 6-shogaol (10 mg/kg) were treated by gavage feeding for 15 days including the period of MPTP injection.Results: Ginger and 6-shogaol protected intestinal tight junction proteins disrupted by MPTP in mouse colon. In addition, ginger and 6-shogaol suppressed the increase of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α and IL-1ß activated by macrophage. Moreover, ginger and 6-shogaol suppressed the MPTP-induced enteric dopaminergic neuronal damage via increasing the cell survival signaling pathway.Conclusion: These results indicate that ginger and 6-shogaol restore the disruption of intestinal integrity and enteric dopaminergic neurons in an MPTP-injected mouse PD model by inhibiting the processes of inflammation and apoptosis, suggesting that they may attenuate the GI dysfunction in PD patients.

Synthesis of Flavanones via Palladium(II)-Catalyzed One-Pot ß-Arylation of Chromanones with Arylboronic Acids.

A total of 47 flavanones were expediently synthesized via one-pot ß-arylation of chromanones, a class of simple ketones possessing chemically unactivated ß sites, with arylboronic acids via tandem palladium(II) catalysis. This reaction provides a novel route to various flavanones, including natural products such as naringenin trimethyl ether, in yields up to 92%.

Synthetic 3',4'-Dihydroxyflavone Exerts Anti-Neuroinflammatory Effects in BV2 Microglia and a Mouse Model.

Neuroinflammation is an immune response within the central nervous system against various proinflammatory stimuli. Abnormal activation of this response contributes to neurodegenerative diseases such as Parkinson disease, Alzheimer's disease, and Huntington disease. Therefore, pharmacologic modulation of abnormal neuroinflammation is thought to be a promising approach to amelioration of neurodegenerative diseases. In this study, we evaluated the synthetic flavone derivative 3',4'-dihydroxyflavone, investigating its anti-neuroinflammatory activity in BV2 microglial cells and in a mouse model. In BV2 microglial cells, 3',4'-dihydroxyflavone successfully inhibited production of chemokines such as nitric oxide and prostaglandin E2 and proinflammatory cytokines such as tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 in BV2 microglia. It also inhibited phosphorylation of mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB activation. This indicates that the anti-inflammatory activities of 3',4'-dihydroxyflavone might be related to suppression of the proinflammatory MAPK and NF-κB signaling pathways. Similar anti-neuroinflammatory activities of the compound were observed in the mouse model. These findings suggest that 3',4'-dihydroxyflavone is a potential drug candidate for the treatment of microglia-related neuroinflammatory diseases.

Identification and structure activity relationship of novel flavone derivatives that inhibit the production of nitric oxide and PGE2 in LPS-induced RAW 264.7 cells.

In an effort to identify novel anti-inflammatory compounds, a series of flavone derivatives were synthesized and biologically evaluated for their inhibitory effects on the production of nitric oxide (NO) and prostaglandin E2 (PGE2), representative pro-inflammatory mediators, in LPS-induced RAW 264.7 cells. Their structure-activity relationship was also investigated. In particular, we found that compound 3g displayed more potent inhibitory activities on PGE2 production, similar inhibitory activities on NO production and less weak cytotoxicity than luteolin, a natural flavone known as a potent anti-inflammatory agent.

The Neurological Safety of an Epidurally Administered Lipo-PGE1 Agonist in Rats.

BACKGROUND AND OBJECTIVE: Liposomal prostaglandin E1 (Lipo-PGE1) can inhibit platelet aggregation and vasodilatation and has been found to be therapeutic in ischemia and spinal diseases including stenosis. However, the neurologic safety of epidural administration of lipo-PGE1 requires further study. We investigated the neurotoxicity of epidurally administered lipo-PGE1 agonist in rats. METHODS: Twenty-seven rats were randomly divided into three groups: Epidural isotonic sodium chloride solution administration (negative control, group N, n = 9); epidural lipo-PGE1 agonist (group L, n = 9); and epidural alcohol (positive control, group A, n = 9). A single 3-mL injection of lipo-PGE1 agonist (0.3 mL, 0.15 µg/kg), 40% ethanol, or isotonic sodium chloride solution was administered. Neurologic assessments were performed 3, 7, and 21 days after the injection. Histopathologic data were evaluated by one pathologist via light microscopy. RESULTS: All rats in groups N and L, except one rat in group L, demonstrated normal response to neurologic assessments. Histopathologic findings showed no evidence of degenerative myelopathy, chromatolysis, or myelin loss in group N or L at any time point. However, all rats in group A revealed sensory and motor deficits as well as histopathologic abnormalities. CONCLUSION: Liposomal prostaglandin E1 agonist did not cause any apparent neurologic abnormalities in the spinal cord or dorsal root ganglion, suggesting it is neurologically safe for epidural injection in this species. Additional mammalian study is warranted.

Early thoracic sympathetic block improves the treatment effect for upper extremity neuropathic pain.

BACKGROUND: The sympathetic nervous system has important roles in mediating many neuropathic pain conditions. A thoracic sympathetic block (TSB) is a useful therapeutic procedure for neuropathic pain in the upper extremities and thorax. However, no studies have examined the factors related to an improved therapeutic effect of TSB. In this study, we evaluated the influence of potential prognostic factors for a better TSB effect and identified clinically important prognostic factors. METHODS: Percutaneous TSB was performed in 51 patients, under fluoroscopic guidance. Data collected for each patient included age, gender, body mass index, diagnosis, pain intensity, and symptom duration. The adjusted odds ratios and 95% confidence intervals for each variable were calculated by logistic regression. RESULTS: TSB was more effective in patients with symptom durations of ≤1 year compared with >1 year (P = 0.006; odds ratio, 8.037; 95% confidence interval, 1.808-35.729). Patient age, gender, body mass index, diagnosis, and intensity of pre-TSB pain were not associated with TSB effectiveness. CONCLUSION: The results showed that an earlier TSB produced a better outcome for patients with chronic pain syndrome. Thus, early TSB should be performed in patients with chronic pain in the upper extremities.

Pregnancy in woman with spinal cord stimulator for complex regional pain syndrome: a case report and review of the literature.

Spinal cord stimulation (SCS) is used to manage chronic pain syndromes and it is accepted a cost-effective therapy. Child-bearing women who had SCS become or choose to become pregnant despite these policies pregnancy is a relative contraindication. A 32-year-old woman had SCS as a treatment for the CRPS I of the left lower extremity. During various check up tests, we happen to find out that her serum beta-hCG was positive and confirmed pregnancy. SCS is not recommended in pregnancy because the effects of SCS on pregnancy and nursing mothers had not been confirmed. However, many female patients suffering from chronic pain may expect future pregnancy and we think that they must be informed about the possibility of pregnancy and the effects of SCS device implantation in the course of pregnancy. First of all, a good outcome requires a multidisciplinary team approach, including obstetrics, neonatology, pain medicine and anesthesia, as was used from an early pregnancy. Unfortunately, she had a misabortrion after 6 weeks.

Comparison of surgical condition in endoscopic sinus surgery using remifentanil combined with propofol, sevoflurane, or desflurane.

BACKGROUND: Various maneuvers are commonly used to achieve the ideal operative field necessary for successful endoscopic sinus surgery (ESS). There are a few contradictory reports on this subject and the consensus is that propofol anesthesia results in a better or similar surgical field and less or similar amount of bleeding than volatile anesthesia. The aim of this study was to compare the surgical field in patients in whom intravenous anesthesia is used as opposed to balanced general anesthesia. METHODS: SIXTY PATIENTS UNDERGOING ESS WERE RANDOMLY ASSIGNED INTO THREE GROUPS, EACH OF WHICH USED A DIFFERENT TYPE OF ANESTHESIA: propofol/remifentanil (PRO/REM) group, sevoflurane/remifentanil (SEV/REM) group, and desflurane/remifentanil (DES/REM) group. We aimed to maintain the intraoperative mean blood pressure (MBP) at 65 mmHg and the heartrate (HR) at about 75 beats per minute. The quality of visibility of the surgical field was graded, using a validated scoring system, 60 minutes after the start of the operation. RESULTS: All groups had a similar MBP and mean HR at 60 minutes after the operation started. There was no significant differences among the three groups for surgical grade score (P = 0.83). CONCLUSIONS: In this comparative study of three anesthetic combinations (PRO/REM, SEV/REM, and DES/REM) in patients undergoing ESS with controlled BP and HR, we did not observe any significant differences in the surgical grade scores.

Paraplegia caused by an epidural hematoma in a patient with unrecognized chronic idiopathic thrombocytopenic purpura following an epidural steroid injection.

STUDY DESIGN: Case report. OBJECTIVES: To report a rare case of complicated paraplegia caused by a spontaneous epidural hematoma following an epidural steroid injection in a patient with unrecognized chronic idiopathic thrombocytopenic purpura (ITP) and to review relevant literature and discuss etiology, pathogenesis, and clinical features. SUMMARY OF BACKGROUND DATA: A spinal epidural hematoma is a rare but potentially catastrophic complication, which could develop in patients without any risk factors. Some patients with chronic ITP are asymptomatic. To our knowledge there has been no previous report of such a complication. METHODS: This is a retrospective review of a case seen at our institution. RESULTS: The authors present a case of a 67-year-old woman who received an epidural steroid injection following complaints of lower back pain and bilateral buttock and leg pain. One day later, the patient had right leg numbness and weakness extending to her right knee; she was taken for emergency surgery. An emergency magnetic resonance imaging revealed an epidural hematoma with high-signal intensity on T2 imaging in the lumbar spinal cord and spinal cord compression with subdural hematoma. One week later, she was progressively developing lower extremity paraplegia with an L1 motor level and no sensory or sphincter activity. She was taken from the emergency room at our institution to the operating room for emergency decompression. After an uneventful course for 1 year, the patient presented with progressive bilateral lower extremity paralysis. CONCLUSION: Epidural steroid therapy is a commonly used conservative therapy; however, complications could develop in patients without any risk factors. Clinicians who plan an epidural steroid injection must perform a rigorous evaluation through a detailed physical examination, simple laboratory tests, and history taking to prevent various risks associated with spinal cord compression.

The effect of forced-air warming during arthroscopic shoulder surgery with general anesthesia.

PURPOSE: The aim of this study was to compare the change in body temperature between the cotton blanket group and forced-air warming blanket group during arthroscopic shoulder surgery. In both groups irrigation fluid at room temperature (22 degrees C) was used. METHODS: We randomly assigned 44 American Society of Anesthesiologists physical status I and II patients scheduled for elective shoulder arthroscopic surgery to receive 1 cotton blanket (group I, n = 22) or a forced-air warming blanket (group II, n = 22). Body temperatures were measured with an esophageal stethoscope, which was inserted immediately after intubation. RESULTS: A significant difference in body temperatures was observed at 60 minutes after induction (P = .0192), 90 minutes after induction (P = .0004), 120 minutes after induction (P = .0003), and 150 minutes after induction (P = .0228). Shivering on arrival in the postanesthesia care unit was found in 15 patients in group I (68.1%) and only 1 patient in group II (4.5%). CONCLUSIONS: We conclude that forced-air warming is significantly more efficient than a cotton blanket alone at maintaining perioperative normothermia during arthroscopic shoulder surgery. LEVEL OF EVIDENCE: Level I, randomized controlled trial.