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1.
Int Immunopharmacol ; 130: 111800, 2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38447416

RESUMEN

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. Furthermore, we established that CIA and IIP evoked increases in the mRNA expression levels of Th1/Th17 inflammatory cytokines in the joints and skin, which was again suppressed by NJK14047. NJK14047 reversed the enlargement of spleens induced by CIA and IIP as well as increases in the levels of inflammatory cytokine in spleens following induction by CIA and IIP. In human SW982 synovial cells, NJK14047 was found to suppress lipopolysaccharide-induced increases in the mRNA expression of proinflammatory cytokines. NJK14047 inhibition of p38 MAPK suppressed the differentiation of naïve T cells to Th17 and Th1 cells. Our findings in this study provide convincing evidence indicating the therapeutic efficacy of the p38 MAPK inhibitor NJK14047 against CIA and IIP, which we speculate could be associated with the suppression on T-cell differentiation.


Asunto(s)
Artritis Experimental , Artritis Reumatoide , Inhibidores de Proteínas Quinasas , Psoriasis , Proteínas Quinasas p38 Activadas por Mitógenos , Animales , Humanos , Ratones , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Diferenciación Celular , Citocinas/genética , Citocinas/metabolismo , Imiquimod , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , ARN Mensajero/metabolismo , Células Th17 , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Ratones Endogámicos DBA , Masculino , Línea Celular
2.
J Org Chem ; 89(5): 3102-3110, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38364274

RESUMEN

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.

3.
Life Sci ; 340: 122424, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38242497

RESUMEN

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.


Asunto(s)
Colitis , Flavonas , Enfermedades Inflamatorias del Intestino , Sulfatos , Ratones , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Dextranos/metabolismo , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Flavonas/farmacología , Flavonas/uso terapéutico , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/metabolismo , Sulfato de Dextran/toxicidad , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Colon/metabolismo
4.
Appl Microbiol Biotechnol ; 108(1): 86, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38189951

RESUMEN

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. The bacterial strain Acinetobacter nosocomialis was isolated from PE-containing landfills and characterized using low-density PE (LDPE) surface oxidation when incubated with LDPE. We optimized culture conditions to generate catalytic pseudo-resting cells of A. nosocomialis that are capable of degrading LDPE films in a bioreactor. After 28 days of bioreactor operation using pseudo-resting cells of A. nosocomialis, we observed the formation of holes on the PE film (39 holes per 217 cm2, a maximum diameter of 1440 µm). This study highlights the potential of bacteria as biocatalysts for the development of PE degradation processes. KEY POINTS: • New bioprocess has been proposed to degrade polyethylene (PE). • Process with pseudo-resting cells results in the formation of holes in PE film. • We demonstrated PE degradation using A. nosocomialis as a biocatalyst.


Asunto(s)
Acinetobacter , Polietileno , Reactores Biológicos , Catálisis
5.
Bioorg Med Chem ; 100: 117588, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38295487

RESUMEN

Microsatellite instability (MSI) is a hypermutable condition caused by DNA mismatch repair system defects, contributing to the development of various cancer types. Recent research has identified Werner syndrome ATP-dependent helicase (WRN) as a promising synthetic lethal target for MSI cancers. Herein, we report the first discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for MSI cancer therapy. Initial computational analysis and biological evaluation identified a new scaffold for a WRN inhibitor. Subsequent SAR study led to the discovery of a highly potent WRN inhibitor. Furthermore, we demonstrated that the optimal compound induced DNA damage and apoptotic cell death in MSI cancer cells by inhibiting WRN. This study provides a new pharmacophore for WRN inhibitors, emphasizing their therapeutic potential for MSI cancers.


Asunto(s)
Inestabilidad de Microsatélites , Neoplasias , Tiofenos , Humanos , Ciclohexanonas , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Helicasa del Síndrome de Werner/antagonistas & inhibidores , Helicasa del Síndrome de Werner/metabolismo , Tiofenos/química , Tiofenos/farmacología
6.
J Med Chem ; 66(22): 15141-15170, 2023 11 23.
Artículo en Inglés | MEDLINE | ID: mdl-37963811

RESUMEN

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). To improve the ICI response rate, we developed 29f, a novel ENPP1 inhibitor with phthalazin-1(2H)-one as the core scaffold. 29f inhibited the cGAMP hydrolysis by ENPP1 in vitro (IC50 = 68 nM) and enhanced the STING-mediated type I interferon response in both immune and tumor cells. 29f demonstrated excellent metabolic stability and bioavailability (F = 65%). Orally administered 29f promoted tumor growth inhibition in a CT26 syngeneic model and increased the anti-PD-L1 response. Furthermore, 29f-induced immunological memory prevented the tumor relapse against tumor rechallenge, suggesting the promising therapeutic potential of 29f.


Asunto(s)
Neoplasias , Hidrolasas Diéster Fosfóricas , Humanos , Hidrolasas Diéster Fosfóricas/metabolismo , Neoplasias/terapia , Pirofosfatasas , Inmunoterapia , Microambiente Tumoral
7.
ACS Cent Sci ; 9(3): 417-426, 2023 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-36968534

RESUMEN

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. Given that the activation of p38 MAPK plays pivotal roles in the pathophysiology of Alzheimer's disease (AD), selective degradation of p-p38 may provide an attractive therapeutic option for the treatment of AD. In the 5xFAD transgenic mice model of AD, intranasal treatment of PRZ-18002 reduces p-p38 levels and alleviates microglia activation and amyloid beta (Aß) deposition, leading to subsequent improvement of spatial learning and memory. Collectively, our findings suggest that PRZ-18002 ameliorates AD pathophysiology via selective degradation of p-p38, highlighting a novel therapeutic TPD modality that targets a specific PTM to induce selective degradation of neurodegenerative disease-associated protein.

8.
Phytomedicine ; 109: 154553, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36610153

RESUMEN

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.


Asunto(s)
Lipopolisacáridos , FN-kappa B , Animales , Ratones , Lipopolisacáridos/farmacología , FN-kappa B/metabolismo , Receptor Toll-Like 4/metabolismo , Factor de Transcripción AP-1/metabolismo , Simulación del Acoplamiento Molecular , Antiinflamatorios/farmacología
9.
Biomol Ther (Seoul) ; 31(2): 183-192, 2023 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-36171179

RESUMEN

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. NJK14047 inhibited antigen-induced degranulation of RBL-2H3 mast cells. NJK14047 administration both before OVA sensitization and challenge strongly inhibited the increase in eosinophil and lymphocyte counts in the bronchoalveolar lavage fluid. In addition, NJK14047 administration inhibited the increase in the levels of Th2 cytokines. Moreover, NJK14047 reduced the inflammatory score and the number of periodic acid-Schiff-stained cells in the lungs. Further, OVA-induced increase in the levels of C16:0 and C24:1 ceramides was not altered by NJK14047. These results suggest that p38 MAPK plays crucial roles in activation of dendritic and mast cells during sensitization and challenge periods, but not in ORMDL3 and sphingolipid biosynthesis.

10.
Org Lett ; 24(50): 9216-9221, 2022 12 23.
Artículo en Inglés | MEDLINE | ID: mdl-36512443

RESUMEN

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.


Asunto(s)
Cobre , Xantonas , Ciclización , Cobre/química , Catálisis , Xantonas/química , Estructura Molecular
11.
J Enzyme Inhib Med Chem ; 37(1): 2434-2451, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36069240

RESUMEN

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 18p possessed high potency (IC50 = 25.0 nM) against ENPP1, and activated STING pathway in a concentration dependent manner. Also, in response to STING pathway activation, cytokines such as IFN-ß and IP-10 were induced by 18p in a concentration dependent manner. Finally, we discovered that 18p causes inhibition of tumour growth in 4T1 syngeneic mouse model. This study provides new insight into the designing of novel ENPP1 inhibitors and warrants further development of small molecule immune modulators for cancer immunotherapy.


Asunto(s)
Hidrolasas Diéster Fosfóricas , Pirofosfatasas , Animales , Ratones , Hidrolasas Diéster Fosfóricas/metabolismo , Pirimidinas , Pirofosfatasas/genética , Pirofosfatasas/metabolismo , Pirroles/farmacología , Relación Estructura-Actividad
12.
Biomol Ther (Seoul) ; 30(6): 501-509, 2022 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-35788499

RESUMEN

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. This study examined the effect of NJK14047, an inhibitor of p38 MAPKs, on AD-like skin lesions induced in BALB/c mice by sensitization and challenges with 1-chloro-2,4-dinitrobenzene (CDNB) on dorsal skin and ears, respectively. After induction of AD, NJK14047 (2.5 mg/kg) or dexamethasone (10 mg/kg) was administrated for 3 weeks via intraperitoneal injection. Following its administration, NJK14047 suppressed CDNB-induced AD-like symptoms such as skin hypertrophy and suppressed mast cell infiltration into the skin lesions. It also reduced CDNB-induced increase in TH2 cytokine (IL-13) and TH1 cytokines (interferon-γ and IL-12A) levels but did not decrease serum IgE level. Furthermore, NJK14047 blocked CDNB-induced lymph node enlargement. These results suggest that NJK14047, a p38 MAPK inhibitor, might be an optimal therapeutic option with unique modes of action for AD treatment.

13.
J Med Chem ; 65(7): 5407-5432, 2022 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-35315650

RESUMEN

Stimulator of interferon genes (STING) is an endoplasmic reticulum-membrane protein that plays important roles in cancer immunotherapy by activating innate immune responses. We designed and synthesized STING modulators and characterized compounds 4a and 4c that share a crucial amidobenzimidazole moiety. In vitro STING binding and cell-based activity assays demonstrated the potency and efficacy of the compounds that function as direct STING agonists by stimulating STING downstream signaling and promoting type I interferon immune responses. In vitro metabolic studies and the pharmacokinetic properties of the compounds led us to investigate their anticancer activity in an in vivo syngeneic model. Intravenous injection of compounds 4a and 4c significantly decreased tumor volume in a CT26 murine colorectal carcinoma model, and the immunological memory-derived cancer inhibition was observed in 4c-treated mouse models. The present results suggest the therapeutic potential of the compounds for cancer immunotherapy via STING-mediated immune activation.


Asunto(s)
Neoplasias , Receptores de Interferón , Animales , Factores Inmunológicos/uso terapéutico , Inmunoterapia/métodos , Interferones , Proteínas de la Membrana/metabolismo , Ratones , Neoplasias/tratamiento farmacológico , Receptores de Interferón/uso terapéutico
14.
Biomed Pharmacother ; 148: 112763, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35240526

RESUMEN

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 ß (Aß) and anti-neuroinflammatory effects, in an AD mouse model. We found that eugenitol potently inhibited Aß plaque and oligomer formation. Moreover, eugenitol dissociated the preformed Aß plaques and reduced Aß-induced nero2a cell death. An in silico docking simulation study showed that eugenitol may interact with Aß1-42 monomers and fibrils. Eugenitol showed radical scavenging effects and potently reduced the release of proinflammatory cytokines from lipopolysaccharide-treated BV2 cells. Systemic administration of eugenitol blocked Aß aggregate-induced memory impairment in the Morris water maze test in a dose-dependent manner. In 5XFAD mice, prolonged administration of eugenitol ameliorated memory and hippocampal long-term potentiation impairment. Moreover, eugenitol significantly reduced Aß deposits and neuroinflammation in the hippocampus of 5XFAD mice. These results suggest that eugenitol, which has anti-Aß aggregation, Aß fibril dissociation, and anti-inflammatory effects, potently modulates AD-like pathologies in 5XFAD mice, and could be a promising candidate for AD therapy.


Asunto(s)
Péptidos beta-Amiloides , Trastornos de la Memoria , Enfermedades Neuroinflamatorias , Animales , Masculino , Ratones , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citocinas/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Depuradores de Radicales Libres/metabolismo , Hipocampo/efectos de los fármacos , Trastornos de la Memoria/patología , Enfermedades Neuroinflamatorias/patología , Especies Reactivas de Oxígeno/metabolismo
15.
Chem Asian J ; 16(21): 3469-3475, 2021 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-34494376

RESUMEN

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.

16.
Org Lett ; 23(19): 7467-7471, 2021 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-34523938

RESUMEN

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.

17.
Bioorg Chem ; 113: 105022, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34098397

RESUMEN

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.


Asunto(s)
Catecoles/química , Isoflavonas/química , Fármacos Neuroprotectores/química , Proteínas tau/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Diseño de Fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Ovillos Neurofibrilares/efectos de los fármacos , Ovillos Neurofibrilares/metabolismo , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/metabolismo , Agregado de Proteínas/efectos de los fármacos , Proteínas tau/antagonistas & inhibidores
18.
Molecules ; 26(9)2021 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-33926033

RESUMEN

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.


Asunto(s)
Antagonistas de Andrógenos/química , Anilidas/química , Nitrilos/química , Receptores Androgénicos/química , Talidomida/química , Compuestos de Tosilo/química , Antagonistas de Andrógenos/síntesis química , Antagonistas de Andrógenos/farmacología , Anilidas/farmacología , Sitios de Unión , Línea Celular , Técnicas de Química Sintética , Humanos , Modelos Biológicos , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Nitrilos/farmacología , Unión Proteica , Proteolisis/efectos de los fármacos , Receptores Androgénicos/metabolismo , Relación Estructura-Actividad , Talidomida/farmacología , Compuestos de Tosilo/farmacología
19.
Cells ; 10(3)2021 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-33801351

RESUMEN

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. In this study, we found that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of the final products of COX-2, induced upregulation of vascular endothelial growth factor (VEGF) and capillary formation and migration through nuclear factor erythroid 2-related factor 2 (NRF2)-dependent heme oxygenase-1 (HO-1) induction in MCF-7 cells. Analysis of the publicly available TCGA data set showed that high mRNA levels of both COX-2 and NRF2 correlated with the poor clinical outcomes in breast cancer patients. Moreover, human tissue analysis showed that the levels of 15d-PGJ2 as well the expression of COX-2, NRF2, and HO-1 were found to be increased in human breast cancer tissues. In conclusion, the elevated levels of 15d-PGJ2 during inflammatory response activate VEGF expression through NRF2-driven induction of HO-1 in human breast cancer cells, proposing a novel mechanism underlying the oncogenic function of 15d-PGJ2.


Asunto(s)
Neoplasias de la Mama/genética , Ciclooxigenasa 2/efectos adversos , Hemo-Oxigenasa 1/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Prostaglandinas/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Neoplasias de la Mama/patología , Femenino , Humanos , Transfección , Regulación hacia Arriba
20.
RSC Adv ; 11(23): 14000-14006, 2021 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-35423945

RESUMEN

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.

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