One-Step Synthesis of 2-Arylquinolin-4(1)-Ones from 1-(2-Aminoaryl)-3-Arylpropan-1-Ones via Pd(II)-Catalyzed Dehydrogenative Cyclization.

In this study, we developed palladium-catalyzed dehydrogenative cyclization to transform 1-(2-aminoaryl)-3-arylpropan-1-ones into 2-arylquinolin-4(1)-ones, also known as aza-flavones which are the bioisosteres of flavones, in an atom-economic manner. This method exhibited excellent chemical compatibility with a broad substrate scope, accommodating up to 25 derivatives. Additionally, kinetic studies were performed to elucidate the reaction mechanism.

sp. nov., a novel actinobacterium isolated from flowerpot soil.

Strain CJN36-1N, a Gram-stain-positive, non-flagellated, strictly aerobic and short rod-shaped bacterium, was isolated from flowerpot soil sampled in the Jeonju region of the Republic of Korea. Based on 16S rRNA gene sequences and the resulting phylogenetic tree, the strain belonged to the genus . Strain CJN36-1N contained a chromosome of 3.

NJK14047 inhibition of p38 MAPK ameliorates inflammatory immune diseases by suppressing T cell differentiation.

p38 MAPK has been implicated in the pathogenesis of rheumatoid arthritis and psoriasis. To assess the therapeutic efficacy of the p38 MAPK inhibitor NJK14047 in the treatment of rheumatoid arthritis and psoriasis, we developed mouse models of collagen-induced rheumatoid arthritis (CIA) and imiquimod-induced psoriasis (IIP). NJK14047 was found to suppress arthritis development and psoriasis symptoms and also suppressed histopathological changes induced by CIA and IIP.

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.

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.

Enhancing polyethylene degradation: a novel bioprocess approach using Acinetobacter nosocomialis pseudo-resting cells.

Despite the discovery of several bacteria capable of interacting with polymers, the activity of the natural bacterial isolates is limited. Furthermore, there is a lack of knowledge regarding the development of bioprocesses for polyethylene (PE) degradation. Here, we report a bioprocess using pseudo-resting cells for efficient degradation of PE.

Discovery of Orally Bioavailable Phthalazinone Analogues as an ENPP1 Inhibitor for STING-Mediated Cancer Immunotherapy.

A lack of the T cell-inflamed tumor microenvironment limits the efficacy of immune checkpoint inhibitors (ICIs). Activation of stimulator of interferon genes (STING)-mediated innate immunity has emerged as a novel therapeutic approach in cancer therapy. 2',3'-Cyclic GMP-AMP (cGAMP) is a natural STING agonist; however, cGAMP is subjected to endogenous degradation by ecto-nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1).

Chemical Knockdown of Phosphorylated p38 Mitogen-Activated Protein Kinase (MAPK) as a Novel Approach for the Treatment of Alzheimer's Disease.

Targeted protein degradation (TPD) provides unique advantages over gene knockdown in that it can induce selective degradation of disease-associated proteins attributed to pathological mutations or aberrant post-translational modifications (PTMs). Herein, we report a protein degrader, PRZ-18002, that selectively binds to an active form of p38 MAPK. PRZ-18002 induces degradation of phosphorylated p38 MAPK (p-p38) and a phosphomimetic mutant of p38 MAPK in a proteasome-dependent manner.

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 E (PGE) 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, PGE, and cytokines were measured in vitro and in vivo experiments.

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.

NJK14047 Suppression of the p38 MAPK Ameliorates OVA-Induced Allergic Asthma during Sensitization and Challenge Periods.

p38 MAPK has been implicated in the pathogenesis of asthma as well as pro-allergic Th2 cytokines, orosomucoid-like protein isoform 3 (ORMDL3), regulation of sphingolipid biosynthesis, and regulatory T cell-derived IL-35. To elucidate the role of p38 MAPK in the pathogenesis of asthma, we examined the effect of NJK14047, an inhibitor of p38 MAPK, against ovalbumin (OVA)-induced allergic asthma; we administrated NJK14047 before OVA sensitization or challenge in BALB/c mice. As ORMDL3 regulation of sphingolipid biosynthesis has been implicated in childhood asthma, ORMDL3 expression and sphingolipids contents were also analyzed.

Identification of novel pyrrolopyrimidine and pyrrolopyridine derivatives as potent ENPP1 inhibitors.

In an effort to discover novel scaffolds of non-nucleotide-derived Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors to stimulate the Stimulator of Interferon Genes (STING) pathway, we designed and synthesised pyrrolopyrimidine and pyrrolopyridine derivatives and performed structure-activity relationship (SAR) study. We found possessed high potency (IC = 25.0 nM) against ENPP1, and activated STING pathway in a concentration dependent manner.

p38 MAPK Inhibitor NJK14047 Suppresses CDNB-Induced Atopic Dermatitis-Like Symptoms in BALB/c Mice.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder. Suppression of MAPKs and NF-κB is implicated as a vital mechanism of action of several traditional Chinese medicines for AD therapy. Although overexpression of MAPK mRNA in the skin tissue has been shown in the AD model, the roles of each MAPK in AD pathogenesis have rarely been studied.

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

Divergent and versatile synthetic routes to flavones and flavanones 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, discriminate oxidative cyclization sequences involving dehydrogenation, respectively, in a highly atom-economic manner.

Eugenitol ameliorates memory impairments in 5XFAD mice by reducing Aβ plaques and neuroinflammation.

Alzheimer's disease (AD) is caused by various pathological mechanisms; therefore, it is necessary to develop drugs that simultaneously act on multiple targets. In this study, we investigated the effects of eugenitol, which has anti-amyloid β (Aβ) and anti-neuroinflammatory effects, in an AD mouse model. We found that eugenitol potently inhibited Aβ plaque and oligomer formation.

Synthesis of -(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 -(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.

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.

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

In this study, polyhydroxyisoflavones that directly prevent the aggregation of both amyloid β (Aβ) 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 Aβ aggregation and tau-mediated neurofibrillary tangle formation. Additional TEM experiment confirmed that ortho-catechol containing isoflavone 4d significantly prevented the aggregation of both Aβ and tau.

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 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.

15-Deoxy-Δ-prostaglandin J Upregulates VEGF Expression via NRF2 and Heme Oxygenase-1 in Human Breast Cancer Cells.

There is a plethora of evidence to support that inflammation is causally linked to carcinogenesis. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the biosynthesis of prostaglandins, is inappropriately overexpressed in various cancers and hence recognized as one of the hallmarks of chronic inflammation-associated malignancies. However, the mechanistic role of COX-2 as a link between inflammation and cancer remains largely undefined.

Development of Free Fatty Acid Receptor 4 (FFA4/GPR120) Agonists in Health Science.

Till the 21 century, fatty acids were considered as merely building blocks for triglycerides, phospholipids, or cholesteryl esters. However, the discovery of G protein-coupled receptors (GPCRs) for free fatty acids at the beginning of the 21 century challenged that idea and paved way for a new field of research, merged into the field of receptor pharmacology for intercellular lipid mediators. Among the GPCRs for free fatty acids, free fatty acid receptor 4 (FFA4, also known as GPR120) recognizes long-chain polyunsaturated fatty acids such as DHA and EPA.

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.

A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse.

Background: Chronic neuroinflammation, aggressive amyloid beta (Aβ) deposition, neuronal cell loss, and cognitive impairment are pathological presentations of Alzheimer's disease (AD). Therefore, resolution of neuroinflammation and inhibition of Aβ-driven pathology have been suggested to be important strategies for AD therapy. Previous efforts to prevent AD progression have identified p38 mitogen-activated protein kinases (MAPKs) as a promising target for AD therapy.