RESUMEN
Bacterial testicular inflammation is one of the important causes of male infertility. Using plant-derived compounds to overcome the side effects of antibiotics is an alternative treatment strategy for many diseases. Schizandrin B (SchB) is a bioactive compound of herbal medicine Schisandra chinensis which has multiple pharmacological effects. However its effect and the mechanism against testicular inflammation are unknown. Here we tackled these questions using models of lipopolysaccharide (LPS)-induced mice and -Sertoli cells (SCs). Histologically, SchB ameliorated the LPS-induced damages of the seminiferous epithelium and blood-testicular barrier, and reduced the production of pro-inflammatory mediators in mouse testes. Furthermore, SchB decreased the levels of pro-inflammatory mediators and inhibited the nuclear factor kB (NF-κB) and MAPK (especially JNK) signaling pathway phosphorylation in LPS-induced mSCs. The bioinformatics analysis based on receptor prediction and the molecular docking was further conducted. We targeted androgen receptor (AR) and illustrated that AR might bind with SchB in its function. Further experiments indicate that the AR expression was upregulated by LPS stimulation, while SchB treatment reversed this phenomenon; similarly, the expression of the JNK-related proteins and apoptotic-related protein were also reversed after AR activator treatment. Together, SchB mitigates LPS-induced inflammation and apoptosis by inhibiting the AR-JNK pathway.
Asunto(s)
Apoptosis , Ciclooctanos , Lignanos , Lipopolisacáridos , Compuestos Policíclicos , Células de Sertoli , Animales , Masculino , Ciclooctanos/farmacología , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/uso terapéutico , Lignanos/farmacología , Lignanos/uso terapéutico , Apoptosis/efectos de los fármacos , Ratones , Células de Sertoli/efectos de los fármacos , Células de Sertoli/metabolismo , Receptores Androgénicos/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Simulación del Acoplamiento Molecular , Testículo/efectos de los fármacos , Testículo/metabolismo , Testículo/patología , FN-kappa B/metabolismoRESUMEN
Platensilin, platensimycin, and platencin are potent inhibitors of ß-ketoacyl-acyl carrier protein synthase (FabF) in the bacterial and mammalian fatty acid synthesis system, presenting promising drug leads for both antibacterial and antidiabetic therapies. Herein, a bioinspired skeleton reconstruction approach is reported, which enables the unified synthesis of these three natural FabF inhibitors and their skeletally diverse analogs, all stemming from a common ent-pimarane core. The synthesis features a diastereoselective biocatalytic reduction and an intermolecular Diels-Alder reaction to prepare the common ent-pimarane core. From this intermediate, stereoselective Mn-catalyzed hydrogen atom-transfer hydrogenation and subsequent Cu-catalyzed carbenoid C-H insertion afford platensilin. Furthermore, the intramolecular Diels-Alder reaction succeeded by regioselective ring opening of the newly formed cyclopropane enables the construction of the bicyclo[3.2.1]-octane and bicyclo[2.2.2]-octane ring systems of platensimycin and platencin, respectively. This skeletal reconstruction approach of the ent-pimarane core facilitates the preparation of analogs bearing different polycyclic scaffolds. Among these analogs, the previously unexplored cyclopropyl analog 47 exhibits improved antibacterial activity (MIC80 = 0.0625 µg/mL) against S. aureus compared to platensimycin.
Asunto(s)
Adamantano , Aminobenzoatos , Aminofenoles , Anilidas , Compuestos Policíclicos , Aminofenoles/química , Aminofenoles/farmacología , Aminofenoles/síntesis química , Compuestos Policíclicos/química , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/síntesis química , Adamantano/química , Adamantano/farmacología , Adamantano/síntesis química , Adamantano/análogos & derivados , Anilidas/farmacología , Anilidas/química , Anilidas/síntesis química , Aminobenzoatos/farmacología , Aminobenzoatos/química , Aminobenzoatos/síntesis química , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Staphylococcus aureus/efectos de los fármacos , Estructura Molecular , Reacción de Cicloadición , Pruebas de Sensibilidad Microbiana , Estereoisomerismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/químicaRESUMEN
Early NMR studies of several heterohelicenes containing an annular nitrogen atom and a thiophene ring in their structure suggested the possibility of the lengthening of the carbon-carbon bonds in the interior of the helical turn of the molecule based on the progressive upfield shift of 13C resonances toward the center of the helical turn. We now report a comprehensive analysis of the optimized geometry and a comparison of the calculated vs. observed 1H and 13C NMR chemical shifts of nineteen representative benzothienoquinoline heterohelicenes. As was initially hypothesized on the basis of the progressive upfield shift of carbon resonances toward the center of the interior helical turn, the present computational study has demonstrated that carbon-carbon bonds indeed have more sp3 character and are longer than normal sp2 bonds to accommodate the helical twist of the molecule, as expected.
Asunto(s)
Espectroscopía de Resonancia Magnética , Quinolinas , Espectroscopía de Resonancia Magnética/métodos , Quinolinas/química , Compuestos Policíclicos/química , Modelos Moleculares , Estructura Molecular , Tiofenos/químicaRESUMEN
Abnormal proliferation, migration, and foam cell formation of Vascular smooth muscle cells (VSMCs) each play a role in the development of atherosclerosis (AS). Schisandrin (Sch) is the active lignan ingredient with broad-spectrum pharmacological effects. However, the role of Sch in the AS process is not clear. Therefore, this study was proposed to explore the therapeutic effect and potential mechanism of Sch on VSMCs. Ox-LDL was selected to create an atherosclerosis injury environment for VSMCs and macrophages. The MTT assay, Oil red O staining, wound healing, transwell experiments and ELISA were used to investigate the phenotype effects of Sch. Network pharmacology, molecular docking, flow cytometry, and western blot were used to investigate the underlying mechanisms of Sch on AS progression. Our findings implied that Sch treatment inhibited the proliferation and migration of VSMCs, and suppressed the ROS production and inflammatory cytokines up-regulation of VSMCs and macrophages. Moreover, Sch reduced lipid uptake and foam cell formation through downregulating LOX-1. Mechanistically, we found that Sch can inhibit the activation of JAK2/STAT3 signaling by targeting JAK2, and arrest cell cycle in GO/G1 phase. In summary, Sch can inhibit VSMCs proliferation and migration by arresting cell cycle and targeting JAK2 to regulating the JAK2/STAT3 pathway. Sch may serve as a potential drug for patients with AS.
Asunto(s)
Movimiento Celular , Proliferación Celular , Ciclooctanos , Janus Quinasa 2 , Lignanos , Músculo Liso Vascular , Compuestos Policíclicos , Factor de Transcripción STAT3 , Transducción de Señal , Janus Quinasa 2/metabolismo , Factor de Transcripción STAT3/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/citología , Lignanos/farmacología , Transducción de Señal/efectos de los fármacos , Ciclooctanos/farmacología , Compuestos Policíclicos/farmacología , Humanos , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Animales , Aterosclerosis/patología , Aterosclerosis/metabolismo , Aterosclerosis/tratamiento farmacológicoRESUMEN
A novel class of pleuromutilin derivatives possessing 1,2,3-triazole as the linker connected to phenyl analogues were designed. The antibacterial properties of the prepared compounds were assessed in vitro against five strains (E. coli, S. aureus, S. epidermidis, and E. faecalis). Most of the tested compounds displayed potent antibacterial activities against gram-positive bacteria and 14-O-[2-(4-((2,4-dinitrophenoxy)-methyl-1H-1,2,3-triazol-1-yl) acetamide)-2-methylpropan-2-yl) thioacetyl]mutilin (7c) exerted antibacterial activities against S. aureus, MRSA and S. epidermidis with MIC values 0.0625 µg/mL, representing 64-fold, 4-fold and 8-fold higher than tiamulin respectively. Compound 6e, 7c and 8c were chosen to carry out killing kinetics, which exhibited concentration-dependent effect. Subsequently, molecular modeling was conducted to further explore the binding of compound 6e, 7a, 7c, 8c and tiamulin with 50S ribosomal subunit from deinococcus radiodurans. The investigation revealed that the main interactions between compound 7c and the ribosomal residues were three hydrogen bonds, π-π, and p-π conjugate effects. Additionally, the free binding energy and docking score of 7c with the ribosome demonstrated the lowest values of -11.90 kcal/mol and -7.97 kcal/mol, respectively, consistent with its superior antibacterial activities.
Asunto(s)
Antibacterianos , Diterpenos , Pruebas de Sensibilidad Microbiana , Pleuromutilinas , Compuestos Policíclicos , Triazoles , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Compuestos Policíclicos/química , Compuestos Policíclicos/farmacología , Diterpenos/farmacología , Diterpenos/química , Diterpenos/síntesis química , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Relación Estructura-Actividad , Bacterias Grampositivas/efectos de los fármacos , Simulación del Acoplamiento Molecular , Estructura Molecular , Escherichia coli/efectos de los fármacos , Staphylococcus epidermidis/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Descubrimiento de DrogasRESUMEN
The development of new antibiotics continues to pose challenges, particularly considering the growing threat of multidrug-resistant Staphylococcus aureus. Structurally diverse natural products provide a promising source of antibiotics. Herein, we outline a concise approach for the collective asymmetric total synthesis of polycyclic xanthene myrtucommulone D and five related congeners. The strategy involves rapid assembly of the challenging benzopyrano[2,3-a]xanthene core, highly diastereoselective establishment of three contiguous stereocenters through a retro-hemiketalization/double Michael cascade reaction, and a Mitsunobu-mediated chiral resolution approach with high optical purity and broad substrate scope. Quantum mechanical calculations provide insight into stereoselective construction mechanism of the three contiguous stereocenters. Additionally, this work leads to the discovery of an antibacterial agent against both drug-sensitive and drug-resistant S. aureus. This compound operates through a unique mechanism that promotes bacterial autolysis by activating the two-component sensory histidine kinase WalK. Our research holds potential for future antibacterial drug development.
Asunto(s)
Antibacterianos , Staphylococcus aureus Resistente a Meticilina , Xantenos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Xantenos/síntesis química , Xantenos/farmacología , Xantenos/química , Pruebas de Sensibilidad Microbiana , Estereoisomerismo , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/química , Descubrimiento de Drogas , Estructura MolecularRESUMEN
Cardiac tissue remodeling is characterized by altered heart tissue architecture and dysfunction, leading to heart failure. Sustained activation of the renin-angiotensin-aldosterone system (RAAS) greatly promotes the development of myocardial remodeling. Angiotensin II (Ang II), which is the major component of RAAS, can directly lead to cardiac remodeling by inducing an inflammatory response. Schisandrin B (Sch B), the active component extracted from the fruit of Schisandra chinensis (Turcz.) Baill has been shown to exhibit anti-inflammatory activity through its ability to target TLR4 and its adaptor protein, MyD88. In this study, we explored whether Sch B alleviates Ang II-induced myocardial inflammation and remodeling via targeting MyD88. Sch B significantly suppressed Ang II-induced inflammation as well as increased the expression of several genes of tissue remodeling (ß-Mhc, Tgfb, Anp, α-Ska) both in vivo and in vitro. These protective effects of Sch B were due to the inhibition of recruitment of MyD88 to TLR2 and TLR4, suppressing the Ang II-induced NF-κB activation and reducing the following inflammatory responses. Moreover, the knockdown of Myd88 in cardiomyocytes abrogated the Ang II-induced increases in the production of inflammatory cytokines and expression of remodeling genes. These findings provide new evidence that the mechanism of Sch B protection was attributed to selective inhibition of MyD88 signaling. This finding could pave the way for novel therapeutic strategies for myocardial inflammatory diseases.
Asunto(s)
Angiotensina II , Ciclooctanos , Lignanos , Ratones Endogámicos C57BL , Factor 88 de Diferenciación Mieloide , Miocitos Cardíacos , Compuestos Policíclicos , Receptor Toll-Like 4 , Animales , Ciclooctanos/farmacología , Ciclooctanos/uso terapéutico , Lignanos/farmacología , Lignanos/uso terapéutico , Factor 88 de Diferenciación Mieloide/metabolismo , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/uso terapéutico , Angiotensina II/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Ratones , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 2/genética , Remodelación Ventricular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Células Cultivadas , FN-kappa B/metabolismoRESUMEN
Epidemiological studies consistently link environmental toxicant exposure with increased Type 2 diabetes risk. Our study investigated the diabetogenic effects of a widely used flame retardant, Dechlorane Plus (DP), on pancreatic ß-cells using rodent and human model systems. We first examined pancreas tissues from male mice exposed daily to oral gavage of either vehicle (corn oil) or DP (10, 100, or 1000 µg/kg per day) and fed chow or high fat diet for 28-days in vivo. DP exposure did not affect islet size or endocrine cell composition in either diet group. Next, we assessed the effect of 48-hour exposure to vehicle (DMSO) or DP (1, 10, or 100 nM) in vitro using immortalized rat ß-cells (INS-1 832/3), primary mouse and human islets, and human stem-cell derived islet-like cells (SC-islets). In INS-1 832/3 cells, DP did not impact glucose-stimulated insulin secretion (GSIS) but significantly decreased intracellular insulin content. DP had no effect on GSIS in mouse islets or SC-islets but had variable effects on GSIS in human islets depending on the donor. DP alone did not affect insulin content in mouse islets, human islets, or SC-islets, but mouse islets co-exposed to DP and glucolipotoxic (GLT) stress conditions (28.7 mM glucose + 0.5 mM palmitate) had reduced insulin content compared to control conditions. Co-exposure of mouse islets to DP + GLT amplified the upregulation of Slc30a8 compared to GLT alone. Our study highlights the importance and challenges of using different in vitro models for studying chemical toxicity.
Asunto(s)
Hidrocarburos Clorados , Células Secretoras de Insulina , Compuestos Policíclicos , Animales , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Humanos , Ratones , Masculino , Compuestos Policíclicos/farmacología , Hidrocarburos Clorados/toxicidad , Ratas , Insulina/metabolismo , Retardadores de Llama/toxicidad , Secreción de Insulina/efectos de los fármacos , Ratones Endogámicos C57BL , Células CultivadasRESUMEN
Mastitis, one of the most significant problems in women, is commonly caused by pathogens, especially Staphylococcus aureus (S.aureus). Schisandrin B (SCB), the main abundant derivatives from Schisandra chinensis, has been proven to have the ability to inhibiting inflammation and bacteria. However, few relevant researches systematically illustrate the role SCB in the treatment of mastitis. The aim of the present study is to demonstrate the mechanism that SCB functions in reducing pathological injury to the mammary gland in treating S.aureus-induced mastitis. H&E staining was used to identify pathological changes and injuries in mastitis. The levels of cytokines associated with inflammation were detected by ELISA. Key signals relevant to ferroptosis and Nrf2 signaling pathway were tested by western blot analysis and iron assay kit. Compared with the control group, inflammation-associated factors, such as IL-1ß, TNF-α, MPO activity, increased significantly in S. aureus-treated mice. However, these changes were inhibited by SCB. Ferroptosis-associated factors Fe2+ and MDA increased significantly, and GSH, GPX4 and ferritin expression decreased markedly in S. aureus-treated mice. SCB treatment could attenuate S.aureus-induced ferroptosis. Furthermore, SCB increase SIRT1 and SLC7A11 expression and down-regulated p53 expression and NF-κB activation. In conclusion, SCB alleviates S.aureus-induced mastitis via up-regulating SIRT1/p53/SLC7A11 signaling pathway, attenuating the activation of inflammation-associated cytokines and ferroptosis in the mammary gland tissues.
Asunto(s)
Ciclooctanos , Ferroptosis , Lignanos , Mastitis , Compuestos Policíclicos , Transducción de Señal , Sirtuina 1 , Infecciones Estafilocócicas , Staphylococcus aureus , Proteína p53 Supresora de Tumor , Animales , Lignanos/farmacología , Lignanos/uso terapéutico , Ciclooctanos/farmacología , Ciclooctanos/uso terapéutico , Ferroptosis/efectos de los fármacos , Mastitis/tratamiento farmacológico , Mastitis/inducido químicamente , Mastitis/inmunología , Mastitis/metabolismo , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/uso terapéutico , Femenino , Sirtuina 1/metabolismo , Transducción de Señal/efectos de los fármacos , Ratones , Staphylococcus aureus/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/inmunología , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Glándulas Mamarias Animales/efectos de los fármacos , Glándulas Mamarias Animales/patología , Glándulas Mamarias Animales/inmunología , Citocinas/metabolismo , Inflamación/tratamiento farmacológico , HumanosRESUMEN
Acquired resistance represents a critical clinical challenge to molecular targeted therapies such as tyrosine kinase inhibitors (TKIs) treatment in hepatocellular carcinoma (HCC). Therefore, it is urgent to explore new mechanisms and therapeutics that can overcome or delay resistance. Here, a US Food and Drug Administration (FDA)-approved pleuromutilin antibiotic is identified that overcomes sorafenib resistance in HCC cell lines, cell line-derived xenograft (CDX) and hydrodynamic injection mouse models. It is demonstrated that lefamulin targets interleukin enhancer-binding factor 3 (ILF3) to increase the sorafenib susceptibility of HCC via impairing mitochondrial function. Mechanistically, lefamulin directly binds to the Alanine-99 site of ILF3 protein and interferes with acetyltransferase general control non-depressible 5 (GCN5) and CREB binding protein (CBP) mediated acetylation of Lysine-100 site, which disrupts the ILF3-mediated transcription of mitochondrial ribosomal protein L12 (MRPL12) and subsequent mitochondrial biogenesis. Clinical data further confirm that high ILF3 or MRPL12 expression is associated with poor survival and targeted therapy efficacy in HCC. Conclusively, this findings suggest that ILF3 is a potential therapeutic target for overcoming resistance to TKIs, and lefamulin may be a novel combination therapy strategy for HCC treatment with sorafenib and regorafenib.
Asunto(s)
Carcinoma Hepatocelular , Resistencia a Antineoplásicos , Neoplasias Hepáticas , Mitocondrias , Proteínas del Factor Nuclear 90 , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Humanos , Animales , Ratones , Resistencia a Antineoplásicos/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Proteínas del Factor Nuclear 90/metabolismo , Proteínas del Factor Nuclear 90/genética , Línea Celular Tumoral , Diterpenos/farmacología , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/uso terapéutico , Homeostasis/efectos de los fármacos , Sorafenib/farmacología , Modelos Animales de Enfermedad , Limoninas/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Benzofuranos , NaftoquinonasRESUMEN
Lefamulin is a first-in-class systemic pleuromutilin antimicrobial and potent inhibitor of bacterial translation, and the most recent novel antimicrobial approved for the treatment of community-acquired pneumonia (CAP). It exhibits potent antibacterial activity against the most prevalent bacterial pathogens that cause typical and atypical pneumonia and other infectious diseases. Early studies indicate additional anti-inflammatory activity. In this study, we further investigated the immune-modulatory activity of lefamulin in the influenza A/H1N1 acute respiratory distress syndrome (ARDS) model in BALB/c mice. Comparators included azithromycin, an anti-inflammatory antimicrobial, and the antiviral oseltamivir. Lefamulin significantly decreased the total immune cell infiltration, specifically the neutrophils, inflammatory monocytes, CD4+ and CD8+ T-cells, NK cells, and B-cells into the lung by Day 6 at both doses tested compared to the untreated vehicle control group (placebo), whereas azithromycin and oseltamivir did not significantly affect the total immune cell counts at the tested dosing regimens. Bronchioalveolar lavage fluid concentrations of pro-inflammatory cytokines and chemokines including TNF-α, IL-6, IL-12p70, IL-17A, IFN-γ, and GM-CSF were significantly reduced, and MCP-1 concentrations were lowered (not significantly) by lefamulin at the clinically relevant 'low' dose on Day 3 when the viral load peaked. Similar effects were also observed for oseltamivir and azithromycin. Lefamulin also decreased the viral load (TCID50) by half a log10 by Day 6 and showed positive effects on the gross lung pathology and survival. Oseltamivir and lefamulin were efficacious in the suppression of the development of influenza-induced bronchi-interstitial pneumonia, whereas azithromycin did not show reduced pathology at the tested treatment regimen. The observed anti-inflammatory and immune-modulatory activity of lefamulin at the tested treatment regimens highlights a promising secondary pharmacological property of lefamulin. While these results require confirmation in a clinical trial, they indicate that lefamulin may provide an immune-modulatory activity beyond its proven potent antibacterial activity. This additional activity may benefit CAP patients and potentially prevent acute lung injury (ALI) and ARDS.
Asunto(s)
Modelos Animales de Enfermedad , Diterpenos , Subtipo H1N1 del Virus de la Influenza A , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae , Animales , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Ratones , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/virología , Diterpenos/farmacología , Diterpenos/uso terapéutico , Citocinas/metabolismo , Azitromicina/farmacología , Azitromicina/uso terapéutico , Oseltamivir/farmacología , Oseltamivir/uso terapéutico , Femenino , Pulmón/inmunología , Pulmón/virología , Pulmón/efectos de los fármacos , Pulmón/patología , Antivirales/farmacología , Antivirales/uso terapéutico , Tetrahidronaftalenos/farmacología , Tetrahidronaftalenos/uso terapéutico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/virología , Agentes Inmunomoduladores/farmacología , Agentes Inmunomoduladores/uso terapéutico , Líquido del Lavado Bronquioalveolar/inmunología , Compuestos Policíclicos , TioglicolatosRESUMEN
This paper reports the design, synthesis, and antibacterial activity study of pleuromutilin derivatives with 2-methyl-4-nitroaniline and 2-methoxy-4-nitroaniline side chains at the C22 position. The structures of the new compounds were characterized by 1H-NMR, 13C-NMR and HRMS. The inhibitory activity of the compounds against MSSA, pyogeniccoccus, streptococcus, and MRSA strains was determined using the micro broth dilution method. The results showed that the compounds exhibited certain activity against Gram-positive bacteria, among which compounds A8a, A8b, A8c, A8d, and A7 demonstrated superior antibacterial activity against MSSA, MRSA, and pyogeniccoccus compared to tiamulin, although the derivatives showed lower antibacterial activity against streptococcus compared to the control drug. Based on the favorable in vitro activity of A8c, the time-kill kinetics against MRSA were evaluated, revealing that compound A8c could inhibit bacterial proliferation in a concentration-dependent manner.
Asunto(s)
Antibacterianos , Diterpenos , Diseño de Fármacos , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Pleuromutilinas , Compuestos Policíclicos , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Diterpenos/farmacología , Diterpenos/química , Diterpenos/síntesis química , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/química , Compuestos Policíclicos/síntesis química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Relación Estructura-Actividad , Streptococcus/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacosRESUMEN
A facile and novel synthetic method for the synthesis of functionalized polycyclic coumarins at the C-4 and C-5 positions is proposed for the first time, which employs copper-catalyzed addition reactions of undiscovered alkenes with difluoromethyl radicals to construct polycyclic coumarins. This strategy is characterized by high regioselectivity, easy availability of raw materials, and simple operation. Additionally, such undiscovered coumarin alkenes can be reacted with a variety of difluoromethyl precursors to obtain a wide range of valuable C-4 and C-5 position functionalized/difluoromethylated polycyclic coumarins. More importantly, some of the products showed significant inhibition of proliferation in vitro against melanoma B16-F10 and lung cancer A549 cell lines with optimal IC50 values of 8.57 and 16.04 µM, respectively.
Asunto(s)
Cobre , Cumarinas , Cumarinas/química , Cumarinas/síntesis química , Catálisis , Cobre/química , Humanos , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Policíclicos/química , Compuestos Policíclicos/síntesis químicaRESUMEN
14 novel pleuromutilin derivatives were designed and synthesized as inhibitors against Staphylococcus aureus (S. aureus). The modification was focused on the C22 position of pleuromutilin. We conducted the characterization, in vitro and in vivo biological assessment of the compounds. Compound 18 exhibited the best antibacterial effect against MRSA (MIC = 0.015 µg/mL, MBC = 0.125 µg/mL). Compound 18 was further studied by time-kill kinetic and post-antibiotic effect (PAE) approaches. Besides, most compounds exhibited low cytotoxicity to RAW 264.7 cells. Compound 18 displayed decent bactericidal activity in vivo (-0.51 log10 CFU/mL). Molecular docking study indicated that compound 18 could be located stably at the ribosome (ΔGb = -7.30 kcal/mol). The results revealed that compound 18 might be further developed into a novel antibiotic.
Asunto(s)
Antibacterianos , Diterpenos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Pleuromutilinas , Compuestos Policíclicos , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Diterpenos/farmacología , Diterpenos/química , Ratones , Animales , Estructura Molecular , Células RAW 264.7 , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Diseño de Fármacos , Staphylococcus aureus/efectos de los fármacos , Infecciones Estafilocócicas/tratamiento farmacológicoRESUMEN
In this study, we designed and synthesized a series of pleuromutilin derivatives containing thiazole. The in vitro antimicrobial efficacy of these synthesized compounds was examined by using four strains. Compared with tiamulin (MIC = 0.25 µg/mL), compound 14 exhibited potency in inhibiting MRSA growth (MIC = 0.0625 µg/mL) in these derivatives. Meanwhile, the time-killing kinetics further demonstrated that compound 14 could efficiently inhibit the MRSA growth. After exposure at 4 × MIC, the postantibiotic effect (PAE) of compound 14 was 1.29 h. Additionally, in thigh-infected mice, compound 14 exhibited a more potent antibacterial efficacy (-1.78 ± 0.28 log10 CFU/g) in reducing MRSA load compared to tiamulin (-1.21 ± 0.23 log10 CFU/g). Moreover, the MTT assay on RAW 264.7 cells demonstrated that compound 14 (8 µg/mL) had no significant cytotoxicity. Docking studies indicated the strong affinity of compound 14 toward the 50S ribosomal subunit, with a binding free energy of -9.63 kcal/mol. Taken together, it could be deduced that compound 14 was a promising candidate for treating MRSA infections.
Asunto(s)
Antibacterianos , Diterpenos , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Pleuromutilinas , Compuestos Policíclicos , Infecciones Estafilocócicas , Tiazoles , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/química , Diterpenos/farmacología , Diterpenos/química , Diterpenos/síntesis química , Animales , Ratones , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Tiazoles/farmacología , Tiazoles/química , Tiazoles/síntesis química , Infecciones Estafilocócicas/tratamiento farmacológico , Diseño de Fármacos , Células RAW 264.7RESUMEN
Cisplatin is an effective chemotherapeutic agent; however, ototoxicity is one of its negative effects that greatly limits the use of cisplatin in clinical settings. Previous research has shown that the most important process cisplatin damage to inner ear cells, such as hair cells (HCs), is the excessive production and accumulation of ROS. Schisandrin B (SchB), is a low-toxicity, inexpensive, naturally occurring antioxidant with a variety of pharmacological effects. Therefore, the potential antioxidant effects of SchB may be useful for cisplatin ototoxicity treatment. In this study, the effects of SchB on cochlear hair cell viability, ROS levels, and expression of apoptosis-related molecules were evaluated by CCK-8, immunofluorescence, flow cytometry, and qRT-PCR, as well as auditory brainstem response (ABR) and dysmorphic product otoacoustic emission (DPOAE) tests to assess the effects on inner ear function. The results showed that SchB treatment increased cell survival, prevented apoptosis, and reduced cisplatin-induced ROS formation. SchB treatment reduced the loss of cochlear HCs caused by cisplatin in exosome culture. In addition, SchB treatment attenuated cisplatin-induced hearing loss and HC loss in mice. This study demonstrates the ability of SchB to inhibit cochlear hair cell apoptosis and ROS generation and shows its potential therapeutic effect on cisplatin ototoxicity.
Asunto(s)
Antineoplásicos , Apoptosis , Supervivencia Celular , Cisplatino , Ciclooctanos , Células Ciliadas Auditivas Internas , Lignanos , Estrés Oxidativo , Compuestos Policíclicos , Especies Reactivas de Oxígeno , Cisplatino/toxicidad , Ciclooctanos/farmacología , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/toxicidad , Animales , Apoptosis/efectos de los fármacos , Lignanos/farmacología , Estrés Oxidativo/efectos de los fármacos , Antineoplásicos/toxicidad , Supervivencia Celular/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Células Ciliadas Auditivas Internas/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Sustancias Protectoras/farmacología , Antioxidantes/farmacología , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Masculino , Ototoxicidad/prevención & controlRESUMEN
We established myocardial injury models in vivo and in vitro to investigate the cardioprotective effect of gomisin D obtained from Schisandra chinensis. Gomisin D significantly inhibited isoproterenol-induced apoptosis and hypertrophy in H9C2 cells. Gomisin D decreased serum BNP, ANP, CK-MB, cTn-T levels and histopathological alterations, and inhibited myocardial hypertrophy in mice. In mechanisms research, gomisin D reversed ISO-induced accumulation of intracellular ROS and Ca2+. Gomisin D further improved mitochondrial energy metabolism disorders by regulating the TCA cycle. These results demonstrated that gomisin D had a significant effect on isoproterenol-induced myocardial injury by inhibiting oxidative stress, calcium overload and improving mitochondrial energy metabolism.
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Apoptosis , Isoproterenol , Estrés Oxidativo , Compuestos Policíclicos , Schisandra , Animales , Isoproterenol/farmacología , Ratones , Estructura Molecular , Schisandra/química , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Calcio/metabolismo , Masculino , Especies Reactivas de Oxígeno/metabolismo , Lignanos/farmacología , Lignanos/química , Cardiotónicos/farmacología , Línea Celular , Miocitos Cardíacos/efectos de los fármacos , Ciclooctanos/farmacología , Ciclooctanos/químicaRESUMEN
The crude acetone extract of a marine Micromonospora sp. strain associated with Eudistoma vannnamei was fractioned with hexane and ethyl acetate. The crude extract and both soluble fractions were assayed against several bacteria strains. The new polycyclic quinones 12-hydroxy-9-propyltetracene-6,1-dione (1), 5,12-dihydroxy-4-methoxy-9-propyltetracene-5,12-dione (2), and 4,6-dihydroxy-3-methoxycarbonyl- methyl-6a-(oxobutyl)-5,12-anthraquinone (3), along with the known 4,6-dihydroxy-3-methoxycarbonyl-methyl-6a-(oxo-3-methyl-butyl)-5,12-anthraquinone (4) and 4,6-dihydroxy-3-methoxycarbonyl-methyl-6a-(oxopentyl)-5,12-anthraquinone (5) were isolated from the hexane-soluble fraction, while from the active ethyl acetate fraction were isolated the known 4,6,11-trihydroxy-9-propyltetracene-5,12-dione (6), 4-methoxy-9-propyltetracene-6,11-dione (7), 7,8,9,10-tetrahydro-9-hydroxy-4-methoxy-9-propyltetracene-6,11-dione (8), and 10ß-carbomethoxy-7,8,9,10-tetrahydro-4,6,7α,9α,11-pentahydroxy-9-propyltetracene-5,12-dione (9). The structures of the new compounds were established by interpretation of HRMS and NMR techniques. A study of molecular docking was performed with the compounds from the active ethyl acetate fraction to correlate tentatively with the antimicrobial activity. Molecular docking, RMSD, RMSF, and MM-GBSA evaluations were performed to investigate the inhibitory activity of 6-8 against the protein PDB-codex 1MWT, being considered a promising target for studying drug development responsible for inhibiting replication of Staphylococcus aureus. Penicillin G was used as the standard inhibitory. Anthracyclinones 6-8 were the best hydrolase inhibitor with affinity energy -8.1 to -7.9â kcal/mol compared to penicillin G, which presented -6.9â kcal/mol. Both 8 and 7 present potent inhibitory effects against hydrolase through molecular dynamics simulation and exhibit favorable drug-like properties, promising new hydrolase blockers to fight bacterial infections from Staphylococcus aureus.
Asunto(s)
Antibacterianos , Pruebas de Sensibilidad Microbiana , Micromonospora , Simulación del Acoplamiento Molecular , Quinonas , Micromonospora/química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Quinonas/química , Quinonas/farmacología , Quinonas/aislamiento & purificación , Estructura Molecular , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/química , Compuestos Policíclicos/aislamiento & purificaciónRESUMEN
The antibiotic heliomycin (resistomycin), which is generated from Streptomyces resistomycificus, has multiple activities, including anticancer effects. Heliomycin was first described in the 1960s, but its clinical applications have been hindered by extremely low solubility. A series of 4-aminomethyl derivatives of heliomycin were synthesized to increase water solubility; studies showed that they had anti-proliferative effects, but the drug targets remained unknown. In this study, we conducted cellular thermal shift assays (CETSA) and molecular docking simulations to identify and validate that heliomycin and its water-soluble derivative, 4-(dimethylaminomethyl)heliomycin (designated compound 4-dmH) engaged and targeted with sirtuin-1 (SIRT1) in p53-functional SAS and p53-mutated HSC-3 oral cancer cells. We further addressed the cellular outcome of SIRT1 inhibition by these compounds and found that, in addition to SIRT1, the water-soluble 4-dmH preferentially targeted a tumor-associated NADH oxidase (tNOX, ENOX2). The direct binding of 4-dmH to tNOX decreased the oxidation of NADH to NAD+ which diminished NAD+-dependent SIRT1 deacetylase activity, ultimately inducing apoptosis and significant cytotoxicity in both cell types, as opposed to the parental heliomycin-induced autophagy. We also observed that tNOX and SIRT1 were both upregulated in tumor tissues of oral cancer patients compared to adjacent normal tissues, suggesting their clinical relevance. Finally, the better therapeutic efficacy of 4-dmH was confirmed in tumor-bearing mice, which showed greater tNOX and SIRT1 downregulation and tumor volume reduction when treated with 4-dmH compared to heliomycin. Taken together, our in vitro and in vivo findings suggest that the multifaceted properties of water-soluble 4-dmH enable it to offer superior antitumor value compared to parental heliomycin, and indicated that it functions through targeting the tNOX-NAD+-SIRT1 axis to induce apoptosis in oral cancer cells.
Asunto(s)
Neoplasias de la Boca , Compuestos Policíclicos , Sirtuina 1 , Humanos , Animales , Ratones , Sirtuina 1/metabolismo , Línea Celular Tumoral , NAD/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Simulación del Acoplamiento Molecular , Apoptosis , Neoplasias de la Boca/tratamiento farmacológicoRESUMEN
Obesity is often accompanied by increased adipose tissue inflammation, a process that is partially driven by adipose tissue-resident macrophages. In this study, we explored the potential for plant-derived dietary compounds to exert anti-inflammatory effects in macrophages that alleviate obesity-associated adipocyte dysfunction. Capsaicin (CAP), schisandrin A (SA), enterodiol (END), and enterolactone (ENL) treatment polarized J774 macrophages to an "M2" or anti-inflammatory phenotype and inhibited responses to stimulation with lipopolysaccharide (LPS). Furthermore, these compounds blocked inflammasome activation when administered just before ATP-induced NLRP3 activation, as evidenced by the abrogation of IL-1ß release in mouse macrophages and human peripheral blood monocytes. The addition of CAP, SA, or ENL during the differentiation of bone marrow-derived macrophages was also sufficient to inhibit LPS-induced IL-6 and TNFα production. Finally, CAP, END, and ENL treatment during differentiation of 3T3-L1 adipocytes induced an adiponectin-high phenotype accompanied by increases in thermogenic gene expression, and conditioned media from these adipocytes inhibited LPS-induced production of IL-1ß, IL-6, and TNFα from J774 macrophages. These polarizing effects were partially mediated by the elevated adiponectin and decreased syndecan-4 in the adipocyte-conditioned media. These results implicate the contribution of plant-derived dietary components to the modulation of macrophages and adipocytes in obesity.NEW & NOTEWORTHY The utility of food-based products to prevent or alleviate chronic conditions such as obesity and its associated comorbidities is an attractive approach. Capsaicin, schisandrin A, enterodiol, and enterolactone, phytochemicals present in traditional medicinal food, decreased proinflammatory cytokine production from macrophages that, in turn, reduced obesity-associated adipocyte dysfunction. These results implicate the contribution of plant-derived dietary components to the modulation of macrophages and adipocytes in obesity.