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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 324: 124974, 2025 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-39151399

RESUMO

Alcoholic liver disease (ALD) is a chronic toxic liver injury caused by long-term heavy drinking. Due to the increasing incidence, ALD is becoming one of important medical tasks. Many studies have shown that the main mechanism of liver damage caused by large amounts of alcohol may be related to antioxidant stress. As an important antioxidant, cysteine (Cys) is involved in maintaining the normal redox balance and detoxifying metabolic function of the liver, which may be closely related to the pathogenesis of ALD. Therefore, it is necessary to develop a simple non-invasive method for rapid monitoring of Cys in liver. Thus, a near-infrared (NIR) fluorescent probe DCI-Ac-Cys which undergoes Cys triggered cascade reaction to form coumarin fluorophore is developed. Using the DCI-Ac-Cys, decreased Cys was observed in the liver of ALD mice. Importantly, different levels of Cys were monitored in the livers of ALD mice taking silybin and curcumin with the antioxidant effects, indicating the excellent therapeutic effect on ALD. This study provides the important references for the accurate diagnosis of ALD and the pharmacodynamic evaluation of silybin and curcumin in the treatment of ALD, and support new ideas for the pathogenesis of ALD.


Assuntos
Cumarínicos , Cisteína , Corantes Fluorescentes , Hepatopatias Alcoólicas , Animais , Cisteína/análise , Cisteína/metabolismo , Cumarínicos/química , Corantes Fluorescentes/química , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Masculino , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Curcumina/farmacologia , Espectrometria de Fluorescência , Silibina/farmacologia , Silibina/química
2.
ACS Appl Bio Mater ; 7(9): 5795-5809, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39279416

RESUMO

Narrow band red-emitting phosphors based on organo-Eu(III) complexes prove their energetic features with surprising performance in smart red/white LEDs, sensing, and biological fields. In this report, a series of unique Eu(III) complexes have been synthesized with coumarin integrated with a class of phenanthroline(Phen)/thiabendazole(TBZ) based ancillary ligands and dibenzoyl methane (DBM)/2-theonyl trifluoroacetone (TTA) as an anionic ligand. The computational study reveals that the TBZ/Phen-based neutral ligands are superior energy harvesters to those other reported analogue neutral ligands. All the Eu-complexes demonstrated outstanding red emission due to electric dipole (ED) transition (5D0 → 7F2) in solid, solution, and thin film with high quantum yield (QY). Theoretical analysis (TD-DFT) and experimental findings describe that the energy transfer (ET) from the ligand's triplet level to the Eu(III) ion is completely occurring. The Eu(III) complexes can potentially be used to fabricate intense hybrid white and red LEDs. All of the fabricated red LEDs revealed high luminous efficiency of radiation (LER) values. The fabricated blue LED based hybrid white LEDs displayed remarkable performance with a low correlated color temperature (5634 K), high color rendering index 88%, and CIE values (x = 0.33; y = 0.342) for 3Eu. By interaction with acid-base vapors, Eu-complexes displayed effectively alterable on-off-on luminescence. Further, cellular imaging shows that Eu-complexes can be a potential biomarker for cancer cell lines.


Assuntos
Cumarínicos , Európio , Teste de Materiais , Fenantrolinas , Európio/química , Cumarínicos/química , Humanos , Fenantrolinas/química , Estrutura Molecular , Materiais Biocompatíveis/química , Materiais Biocompatíveis/síntese química , Tamanho da Partícula , Imagem Óptica , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Medições Luminescentes , Substâncias Luminescentes/química , Substâncias Luminescentes/síntese química
3.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(8): 1589-1598, 2024 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-39276055

RESUMO

OBJECTIVE: To investigate the mechanism underlying the neuroprotective effect of linarin (LIN) against microglia activation-mediated inflammation and neuronal apoptosis following spinal cord injury (SCI). METHODS: Fifty C57BL/6J mice (8- 10 weeks old) were randomized to receive sham operation, SCI and linarin treatment at 12.5, 25, and 50 mg/kg following SCI (n=10). Locomotor function recovery of the SCI mice was assessed using the Basso Mouse Scale, inclined plane test, and footprint analysis, and spinal cord tissue damage and myelination were evaluated using HE and LFB staining. Nissl staining, immunofluorescence assay and Western blotting were used to observe surviving anterior horn motor neurons in injured spinal cord tissue. In cultured BV2 cells, the effects of linarin against lipopolysaccharide (LPS)­induced microglia activation, inflammatory factor release and signaling pathway changes were assessed with immunofluorescence staining, Western blotting, RT-qPCR, and ELISA. In a BV2 and HT22 cell co-culture system, Western blotting was performed to examine the effect of linarin against HT22 cell apoptosis mediated by LPS-induced microglia activation. RESULTS: Linarin treatment significantly improved locomotor function (P < 0.05), reduced spinal cord damage area, increased spinal cord myelination, and increased the number of motor neurons in the anterior horn of the SCI mice (P < 0.05). In both SCI mice and cultured BV2 cells, linarin effectively inhibited glial cell activation and suppressed the release of iNOS, COX-2, TNF-α, IL-6, and IL-1ß, resulting also in reduced neuronal apoptosis in SCI mice (P < 0.05). Western blotting suggested that linarin-induced microglial activation inhibition was mediated by inhibition of the TLR4/NF- κB signaling pathway. In the cell co-culture experiments, linarin treatment significantly decreased inflammation-mediated apoptosis of HT22 cells (P < 0.05). CONCLUSION: The neuroprotective effect of linarin is medicated by inhibition of microglia activation via suppressing the TLR4/NF­κB signaling pathway, which mitigates neural inflammation and reduce neuronal apoptosis to enhance motor function of the SCI mice.


Assuntos
Apoptose , Camundongos Endogâmicos C57BL , Microglia , NF-kappa B , Transdução de Sinais , Traumatismos da Medula Espinal , Receptor 4 Toll-Like , Animais , Camundongos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Receptor 4 Toll-Like/metabolismo , Apoptose/efeitos dos fármacos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Cumarínicos/farmacologia , Inflamação/metabolismo , Lipopolissacarídeos , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/etiologia , Glicosídeos
4.
Molecules ; 29(17)2024 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-39274880

RESUMO

Lamellarins are natural products with a [3,4]-fused pyrrolocoumarin skeleton possessing interesting biological properties. More than 70 members have been isolated from diverse marine organisms, such as sponges, ascidians, mollusks, and tunicates. There is a continuous interest in the synthesis of these compounds. In this review, the synthetic strategies for the synthesis of the title compounds are presented along with their biological properties. Three routes are followed for the synthesis of lamellarins. Initially, pyrrole derivatives are the starting or intermediate compounds, and then they are fused to isoquinoline or a coumarin moiety. Second, isoquinoline is the starting compound fused to an indole moiety. In the last route, coumarins are the starting compounds, which are fused to a pyrrole moiety and an isoquinoline scaffold. The synthesis of isolamellarins, azacoumestans, isoazacoumestans, and analogues is also described. The above synthesis is achieved via metal-catalyzed cross-coupling, [3 + 2] cycloaddition, substitution, and lactonization reactions. The title compounds exhibit cytotoxic, multidrug resistance (MDR), topoisomerase I-targeted antitumor, anti-HIV, antiproliferative, anti-neurodegenerative disease, and anti-inflammatory activities.


Assuntos
Cumarínicos , Cumarínicos/química , Cumarínicos/síntese química , Cumarínicos/farmacologia , Humanos , Animais , Produtos Biológicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/farmacologia , Isoquinolinas/química , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Pirróis/química , Pirróis/síntese química , Pirróis/farmacologia , Estrutura Molecular , Compostos Heterocíclicos de 4 ou mais Anéis
5.
Front Cell Infect Microbiol ; 14: 1403219, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39253327

RESUMO

Introduction: Despite years of efforts to develop new antibiotics for eradicating multidrug-resistant (MDR) and multi-virulent Methicillin-Resistant Staphylococcus aureus (MRSA) and Vancomycin-Resistant Staphylococcus aureus (VRSA) infections, treatment failures and poor prognoses in most cases have been common. Therefore, there is an urgent need for new therapeutic approaches targeting virulence arrays. Our aim is to discover new anti-virulence therapies targeting MRSA and VRSA virulence arrays. Methodology: We employed phenotypic, molecular docking, and genetic studies to screen for anti-virulence activities among selected promising compounds: Coumarin, Simvastatin, and Ibuprofen. Results: We found that nearly all detected MRSA and VRSA strains exhibited MDR and multi-virulent profiles. The molecular docking results aligned with the phenotypic and genetic assessments of virulence production. Biofilm and hemolysin productions were inhibited, and all virulence genes were downregulated upon treatment with sub-minimum inhibitory concentration (sub-MIC) of these promising compounds. Ibuprofen was the most active compound, exhibiting the highest inhibition and downregulation of virulence gene products. Moreover, in vivo and histopathological studies confirmed these results. Interestingly, we observed a significant decrease in wound area and improvements in re-epithelialization and tissue organization in the Ibuprofen and antimicrobial treated group compared with the group treated with antimicrobial alone. These findings support the idea that a combination of Ibuprofen and antimicrobial drugs may offer a promising new therapy for MRSA and VRSA infections. Conclusion: We hope that our findings can be implemented in clinical practice to assist physicians in making the most suitable treatment decisions.


Assuntos
Antibacterianos , Biofilmes , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Infecções Estafilocócicas , Staphylococcus aureus Resistente à Vancomicina , Fatores de Virulência , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Staphylococcus aureus Resistente à Meticilina/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Biofilmes/efeitos dos fármacos , Fatores de Virulência/genética , Staphylococcus aureus Resistente à Vancomicina/efeitos dos fármacos , Animais , Virulência/efeitos dos fármacos , Ibuprofeno/farmacologia , Ibuprofeno/uso terapêutico , Humanos , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Camundongos , Modelos Animais de Doenças , Proteínas Hemolisinas/antagonistas & inibidores , Proteínas Hemolisinas/metabolismo , Proteínas Hemolisinas/genética , Farmacorresistência Bacteriana Múltipla
6.
Carbohydr Res ; 544: 109244, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39180880

RESUMO

Sugars are vital biomolecules widely found in nature, playing an indispensable role in a plethora of biological processes. Similarly, coumarins are heterocycles with an effective pharmacophore skeleton, making them crucial in drug design and development. Coupling carbohydrate moieties to the small biologically active molecules creates a vast library of glycoconjugates with impressive structural diversity. The potential of coumarin glycosides is being extensively explored due to their broad spectrum of applications, including antibacterial, anticancer, and anticoagulant properties, etc. This review highlights various chemical methodologies for synthesizing diverse coumarin glycohybrids with distinct linkages and explores their immense biological potential, making a significant contribution to the field of organic synthesis.


Assuntos
Cumarínicos , Cumarínicos/química , Cumarínicos/síntese química , Humanos , Açúcares/química , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Estrutura Molecular
7.
Int Immunopharmacol ; 140: 112854, 2024 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-39116494

RESUMO

The inflammation causes the destroyed osseointegration at the implant-bone interface, significantly increasing the probability of implant loosening in osteoporotic patients. Currently, inhibiting the differentiation of M1 macrophages and the inflammatory response could be a solution to stabilize the microenvironment of implants. Interestingly, some natural products have anti-inflammatory and anti-polarization effects, which could be a promising candidate for stabilizing the implants' microenvironment in osteoporotic patients. This research aims to explore the inhibitory effect of Urolithin B(UB) on macrophage M1 polarization, which ameliorates inflammation, thus alleviating implant instability. We established an osteoporosis mouse model of implant loosening. The mouse tissues were taken out for morphological analysis, staining analysis, and bone metabolic index analysis. In in vitro experiments, RAW264.7 cells were polarized to M1 macrophages using lipopolysaccharide (LPS) and analyzed by immunofluorescence (IF) staining, Western blot (WB), and flow cytometry. The CSP100 plus chip experiments were used to explore the potential mechanisms behind the inhibiting effects of UB. Through observation of these experiments, UB can improve the osseointegration between the implants and femurs in osteoporotic mice and enhance the stability of implants. The UB can inhibit the differentiation of M1 macrophages and local inflammation via inhibiting the phosphorylation of VEGFR2, which can be further proved by the weakened inhibited effects of UB in macrophages with lentivirus-induced overexpression of VEGFR2. Overall, UB can specifically inhibit the activation of VEGFR2, alleviate local inflammation, and improve the stability of implants in osteoporotic mice.


Assuntos
Diferenciação Celular , Cumarínicos , Macrófagos , Osteoporose , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Animais , Camundongos , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células RAW 264.7 , Fosforilação/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Osteoporose/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Feminino , Camundongos Endogâmicos C57BL , Regulação para Baixo/efeitos dos fármacos , Osseointegração/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Modelos Animais de Doenças , Próteses e Implantes
8.
Int Immunopharmacol ; 140: 112839, 2024 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-39126737

RESUMO

OBJECTIVES: Treatment of hemorrhagic shock (HS) induced multi-organ injury remains a challenge. Bergapten (BeG) is a bioactive coumarin-derived compound, and previous articles have suggested that BeG may serve as a prospective therapeutic modality for HS. This study was designed to investigate the efficacy of BeG in the treatment of HS and its underlying mechanisms. METHODS: In this research, we established a rat model of HS, following which we assessed the protective effects of BeG on HS induced multi-organ injury. Subsequently, we scrutinized the activation of NLRP3 inflammasomes and pyroptosis in damaged organs. Additionally, we conducted examinations of AMPK and the downstream mitophagy pathway in damaged organs. Finally, we established a hypoxia/reoxygenation (H/R) model in HK-2 cells to simulate the in vitro HS process. Following AMPK inhibition with compound C, we evaluated the levels of mitophagy and cellular pyroptosis in BeG-treated HK-2 cells subjected to H/R. RESULTS: BeG treatment alleviated HS induced multi-organ injury. Subsequent analyses indicated that the therapeutic effects of BeG were related to the attenuation of NLRP3 inflammasome activation and pyroptosis. Additionally, we found BeG treatment stimulated the phosphorylation of AMPK, thereby enhancing mitophagy. Lastly, we found that the inhibition of AMPK in vitro attenuates BeG's enhancement of mitophagy and its suppression of pyroptosis. CONCLUSION: Our research indicates that BeG has the potential to alleviate multi-organ injury induced by HS. The protective effect of BeG is likely associated with its promotion of mitophagy through AMPK activation, thereby inhibiting NLRP3 inflammasome-mediated pyroptosis.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Ratos Sprague-Dawley , Choque Hemorrágico , Choque Hemorrágico/tratamento farmacológico , Choque Hemorrágico/complicações , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose/efeitos dos fármacos , Humanos , Masculino , Inflamassomos/metabolismo , Linhagem Celular , Ratos , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Mitofagia/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Modelos Animais de Doenças , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/prevenção & controle , Insuficiência de Múltiplos Órgãos/etiologia
9.
Bioorg Chem ; 151: 107682, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39137597

RESUMO

c-MET and STAT-3 are significant targets for cancer treatments. Here, we describe a class of very effective dual STAT-3 and c-MET inhibitors with coumarin-based thiazoles (3a-o) as its scaffold. Spectroscopic evidence (NMR, HRMS, and HPLC) validated the structural discoveries of the new compounds. The cytotoxic activity of these compounds was also tested against a panel of cancer cells in accordance with US-NCI guidelines. Compound 3g proved to be active at 10 µM, thus it was automatically scheduled to be tested at five doses. Towards SNB-75 (CNS cancer cell line), compound 3g showed notable in vitro anti-cancer activity with GI50 = 1.43 µM. For the molecular targets, compound 3g displayed potent activity towards STAT-3 and c-MET having IC50 of 4.7 µM and 12.67, respectively, compared to Cabozantinib (IC50 = 15 nM of c-MET) and STAT-3-IN-3 (IC50 = 2.1 µM of STAT-3). Moreover, compound 3g significantly induced apoptosis in SNB-75 cells, causing a 3.04-fold increase in apoptotic cell death (treated cells exhibited 11.53 % overall apoptosis, against 3.04 % in reference cells) and a 3.58-fold increase in necrosis. Moreover, it arrests cells at the G2 phase. Dual inhibition of c-MET and STAT-3 protein kinase was further validated using RT-PCR. The target compound's binding mechanism was determined by the application of molecular docking.


Assuntos
Antineoplásicos , Proliferação de Células , Cumarínicos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas Proto-Oncogênicas c-met , Fator de Transcrição STAT3 , Tiazóis , Humanos , Cumarínicos/farmacologia , Cumarínicos/química , Cumarínicos/síntese química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Tiazóis/farmacologia , Tiazóis/química , Tiazóis/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Simulação de Acoplamento Molecular
10.
Int J Mol Sci ; 25(15)2024 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-39125817

RESUMO

Recent studies confirmed that pyroptosis is involved in the progression of pulmonary hypertension (PH), which could promote pulmonary artery remodeling. Urolithin A (UA), an intestinal flora metabolite of ellagitannins (ETs) and ellagic acid (EA), has been proven to possess inhibitory effects on pyroptosis under various pathological conditions. However, its role on PH remained undetermined. To investigate the potential of UA in mitigating PH, mice were exposed to hypoxia (10% oxygen, 4 weeks) to induce PH, with or without UA treatment. Moreover, in vitro experiments were carried out to further uncover the underlying mechanisms. The in vivo treatment of UA suppressed the progression of PH via alleviating pulmonary remodeling. Pyroptosis-related genes were markedly upregulated in mice models of PH and reversed after the administration of UA. In accordance with that, UA treatment significantly inhibited hypoxia-induced pulmonary arterial smooth muscle cell (PASMC) pyroptosis via the AMPK/NF-κB/NLRP3 pathway. Our results revealed that UA treatment effectively mitigated PH progression through inhibiting PASMC pyroptosis, which represents an innovative therapeutic approach for PH.


Assuntos
Proteínas Quinases Ativadas por AMP , Cumarínicos , Hipertensão Pulmonar , Hipóxia , Miócitos de Músculo Liso , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Artéria Pulmonar , Piroptose , Transdução de Sinais , Animais , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Piroptose/efeitos dos fármacos , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Hipóxia/metabolismo , Hipóxia/complicações , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/etiologia , Masculino , Proteínas Quinases Ativadas por AMP/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
11.
Int J Mol Sci ; 25(15)2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39125898

RESUMO

The first example of applying salicylaldehyde derivatives, as well as coumarin with the formyl group at the C8 position in its structure, as carbonyl partners in a three-component Passerini reaction, is presented. As a result of research on the conditions of the Passerini reaction, the important role of the hydroxyl group in the salicylaldehyde used in the course of the multicomponent reaction was revealed. When an aldehyde with an unprotected hydroxyl group is used, only two-component α-hydroxy amide products are obtained. In contrast, the use of acylated aldehyde results in three-component α-acyloxy amide products with high efficiency. The developed protocol gives access to structurally diversified peptidomimetics with good yield. The compounds were also evaluated as antimicrobial agents against selected strains of nosocomial pathogenic bacteria. The structure-activity relationship revealed that inhibitory activity is strongly related to the presence of the trifluoromethyl group (CF3) or the methyl group at the C4 position in an unsaturated lactone ring of the coumarin scaffold. MIC and MBC studies were carried out on eight selected pathogenic bacteria strains (Gram-positive pathogenic Staphylococcus aureus strain (ATCC 23235), as well as on Gram-negative E. coli (K12 (ATCC 25404), R2 (ATCC 39544), R3 (ATCC 11775), and R4 (ATCC 39543)), Acinetobacter baumannii (ATCC 17978), Pseudomonas aeruginosa (ATCC 15442), and Enterobacter cloacae (ATCC 49141) have shown that the tested compounds show a strong bactericidal effect at low concentrations. Among all agents investigated, five exhibit higher antimicrobial activity than those observed for commonly used antibiotics. It should be noted that all the compounds tested showed very high activity against S. aureus, which is the main source of nosocomial infections that cause numerous fatalities. Additionally, the cytotoxicity of sixteen derivatives was measured with the use of the MTT test on BALB/c3T3 mouse fibroblast cell lines. The cytotoxicity studies revealed that the tested substances exert a similar or lower effect on cell proliferation than that observed for commonly used antibiotics within the range of therapeutic doses. A parallel MTT assay using ciprofloxacin, bleomycin, and cloxacillin showed that these antibiotics are more cytotoxic when tested in mammalian cells, and cell viability is in the range of 85.0-89.9%. Furthermore, we have shown that the studied coumarin-based peptidomimetics, depending on their structural characteristics, are nonselective and act efficiently against various Gram-positive and Gram-negative pathogens, which is of great importance for hospitalised patients.


Assuntos
Antibacterianos , Testes de Sensibilidade Microbiana , Peptidomiméticos , Peptidomiméticos/farmacologia , Peptidomiméticos/química , Peptidomiméticos/síntese química , Animais , Camundongos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Relação Estrutura-Atividade , Cumarínicos/farmacologia , Cumarínicos/química , Cumarínicos/síntese química , Staphylococcus aureus/efeitos dos fármacos , Aldeídos/química , Aldeídos/farmacologia , Infecção Hospitalar/microbiologia , Infecção Hospitalar/tratamento farmacológico
12.
Ecotoxicol Environ Saf ; 282: 116836, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39097417

RESUMO

Since the onset of the SARS-CoV-2 pandemic in early 2020, there has been a notable rise in sodium hypochlorite disinfectants. Sodium hypochlorite undergoes hydrolysis to generate hypochlorous acid for virus eradication. This chlorine-based disinfectant is widely utilized for public disinfection due to its effectiveness. Although sodium hypochlorite disinfection is convenient, its excessive and indiscriminate use can harm the water environment and pose a risk to human health. Hypochlorous acid, a reactive oxygen species, plays a crucial role in the troposphere, stratospheric chemistry, and oxidizing capacity. Additionally, hypochlorous acid is vital as a reactive oxygen species in biological systems, and its irregular metabolism and level is associated with several illnesses. Thus, it is crucial to identify hypochlorous acid to comprehend its environmental and biological functions precisely. Here, we constructed a new fluorescent probe, utilizing the twisted intramolecular charge transfer mechanism to quickly and accurately detect hypochlorous acid in environmental water and biosystems. The probe showed a notable increase in fluorescence when exposed to hypochlorous acid, demonstrating its excellent selectivity, fast response time (less than 10 seconds), a large Stokes shift (∼ 102 nm), and a low detection limit of 15.5 nM.


Assuntos
Cumarínicos , Corantes Fluorescentes , Ácido Hipocloroso , Poluentes Químicos da Água , Ácido Hipocloroso/química , Corantes Fluorescentes/química , Cumarínicos/química , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/química , Poluentes Químicos da Água/toxicidade , Animais , Desinfetantes/química , Desinfetantes/análise , Desinfetantes/toxicidade , Limite de Detecção
13.
Mol Pharm ; 21(9): 4708-4725, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39115967

RESUMO

This study investigates the interaction between daphnetin and ovalbumin (OVA) as well as its potential to inhibit OVA fibrillation using both spectroscopic and computational analysis. A moderate binding affinity of 1 × 104 M-1 was observed between OVA and daphnetin, with a static quenched mechanism identified during the fluorescence quenching processes. Metal ions' (Cu2+ and Zn2+) presence led to an increase in the binding affinities of daphnetin toward OVA, mirroring a similar trend observed with the pH variation. Synchronous and 3D fluorescence studies indicated an increase in the polarity of the microenvironment surrounding the Trp residues during binding. Interestingly, circular dichroism and Fourier transform infrared studies showed a significant change in the secondary structure of OVA upon binding with daphnetin. The efficacy of daphnetin in inhibiting protein fibrillation was confirmed through thioflavin T and Congo Red binding assays along with fluorescence microscopic imaging analysis. The thermodynamic assessment showed positive ΔH° [+(29.34 ± 1.526) kJ mol-1] and ΔS° [+(181.726 ± 5.465) J mol-1] values, indicating the presence of the hydrophobic forces, while negative ΔG° signifies spontaneous binding interactions. These experimental findings were further correlated with computational analysis, revealing daphnetin dynamics within the binding site of OVA.


Assuntos
Cumarínicos , Ovalbumina , Umbeliferonas , Ovalbumina/metabolismo , Umbeliferonas/química , Umbeliferonas/metabolismo , Concentração de Íons de Hidrogênio , Cumarínicos/química , Cumarínicos/metabolismo , Dicroísmo Circular , Ligação Proteica , Termodinâmica , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Simulação de Acoplamento Molecular , Zinco/química , Zinco/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Espectrometria de Fluorescência , Sítios de Ligação , Cobre/química , Estrutura Secundária de Proteína
14.
Biomed Mater ; 19(5)2024 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-39121891

RESUMO

Polymer nanomicelles have the advantages of small particle size, improved drug solubility, retention effect and enhanced permeability, so they can be used in the treatment of tumour diseases. The aim of this study was to prepare and optimise a nanomicelle which can improve the solubility of insoluble drugs. Firstly, the carboxyl group of cholesterol succinic acid monoester was grafted with the side chain amino group of O-carboxymethyl chitosan-g-cholesterol succinic acid monoester (CCMC), and its structure was characterized by fourier transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance (1H-NMR). Particle size has an important impact on tissue distribution, cell uptake, permeability and inhibition of tumour tissue. In this study, particle size and polydispersity index (PDI) were selected as indexes to optimise the preparation process of CCMC nanomicelles through single factor experiment, Plackett-Burman experiment, the steepest climbing experiment and response surface design experiment. The optimised CCMC nanomicelles showed an average particle size of 173.9 ± 2.3 nm and a PDI of 0.170 ± 0.053. The Cell Counting Kit-8 assay showed no significant effect on cell viability in the range of 0-1000 µg ml-1concentration. Coumarin-6 (C6) was used as a fluorescent probe to investigate the drug-carrying ability of CCMC nanomicelles. C6-CCMC showed 86.35 ± 0.56% encapsulation efficiency with a drug loading of 9.18 ± 0.32%. Both CCMC and C6-CCMC demonstrated excellent stability in different media. Moreover, under the same conditions, the absorption effect of C6 in C6-CCMC nanomicelles was significantly higher than that of free C6 while also exhibiting good sustained-release properties. Therefore, this study demonstrates CCMC nanomicelles as a promising new drug carrier that can significantly improve insoluble drug absorption.


Assuntos
Quitosana , Colesterol , Micelas , Tamanho da Partícula , Quitosana/química , Quitosana/análogos & derivados , Humanos , Colesterol/química , Colesterol/análogos & derivados , Espectroscopia de Infravermelho com Transformada de Fourier , Nanopartículas/química , Solubilidade , Polímeros/química , Portadores de Fármacos/química , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/química , Linhagem Celular Tumoral , Tiazóis/química , Tiazóis/farmacologia
15.
Bioorg Med Chem ; 111: 117863, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39096786

RESUMO

We designed and synthesized two novel photocaged peroxide compounds, N5TBHP and N6TBHP, featuring nitrogen-containing fused ring coumarin skeletons. Notably, a tetrahydroquinoline fused coumarin derivative, N6TBHP demonstrated significantly higher photocleavage efficiency under visible light at 455 nm compared to N5TBHP, which contains an indoline fused coumarin. This process effectively releases the oxidative stress inducer tert-butylhydroperoxide (TBHP). Additionally, N6TBHP exhibits high resistance to glutathione (GSH), and its UV spectral analysis suggests enhanced intracellular stability due to reduced reactivity with GSH through self-assembly. Furthermore, N6TBHP can release an optimal amount of TBHP into cells under visible light irradiation with minimal cell damage. These properties position N6TBHP as a promising tool for advancing research in intracellular redox signaling.


Assuntos
Desenho de Fármacos , Luz , Peróxidos , Espécies Reativas de Oxigênio , Transdução de Sinais , Espécies Reativas de Oxigênio/metabolismo , Humanos , Transdução de Sinais/efeitos dos fármacos , Peróxidos/química , Peróxidos/farmacologia , Peróxidos/síntese química , Estrutura Molecular , Relação Estrutura-Atividade , terc-Butil Hidroperóxido/farmacologia , terc-Butil Hidroperóxido/química , Cumarínicos/química , Cumarínicos/farmacologia , Cumarínicos/síntese química , Relação Dose-Resposta a Droga , Estresse Oxidativo/efeitos dos fármacos , Processos Fotoquímicos
16.
Int J Biol Macromol ; 278(Pt 4): 134984, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39217046

RESUMO

In this work, self-healing cellulose nanocrystals/fluorinated polyacrylate with dual dynamic networks of photoreversible crosslinking network and high-density hydrogen bonds was prepared by Pickering emulsion polymerization. The main work was to study the effects of 7-(2-methacryloyloxy)-4-methylcoumarin (CMA) and 2-ureido-4[1H]-pyrimidinone methyl methacrylate (UPyMA) monomer dosage on emulsion polymerization and latex film properties. The monomer conversion increased first and then decreased as the CMA and UPyMA monomer dosage increased, while a reverse trend was noted for the particle size and particle size distribution. Incorporating UPyMA allowed the rapid formation of hydrogen bonds at the crosslinking sites, which increased the interaction force between the healing surfaces. Besides, reversible photocrosslinking reaction of coumarin groups provided another support for self-healing performance. Moreover, the influence of self-healing temperature, self-healing time and UV irradiation on the self-healing ability was also systematically investigated The tensile strength of the prepared cellulose nanocrystals/fluorinated polyacrylate latex film exhibited a self-healing efficiency of 91.4 % under 365 nm UV irradiation and 80 °C for 12 h. The latex film had excellent thermal stability as was shown by TG and DTG analyses. The outstanding self-healing capability of latex film was attributed to the reversible photodimerization of coumarin groups and multiple hydrogen bonds. In addition, the water-oil repellent and mechanical properties of the latex films were improved as the CMA and UPyMA monomer dosage increased.


Assuntos
Resinas Acrílicas , Celulose , Cumarínicos , Ligação de Hidrogênio , Nanopartículas , Celulose/química , Cumarínicos/química , Nanopartículas/química , Resinas Acrílicas/química , Polimerização , Tamanho da Partícula , Raios Ultravioleta , Resistência à Tração , Temperatura
17.
Bioorg Chem ; 152: 107759, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39213797

RESUMO

In the present study, the design and synthesis of novel coumarin derivatives 8a-h, 11a-d and 16a-c as potential selective inhibitors for the tumor associated human carbonic anhydrase isoforms (hCA IX and XII) was reported. All the newly synthesized derivatives showed potent to mild activity against the targeted CA IX (KI = 0.08-9.57 µM), with selectivity indices over CA I (SI = 2.0-21.9) and over CA II (SI = 1.1-15.7). They showed similar activities against CA XII (KI = 0.06-9.48 µM) with selectivity indices over CA I (SI = 1.4-21.2) and CA II (SI = 0.9-15.5). Compound 16b featuring sulfonamide function possessed promising inhibitory activities against the targeted isoforms CA IX and XII with KI values of 0.08 and 0.06 µM, respectively. Interestingly, it was found that using compound 16b at a nontoxic concentration as an adjuvant with Doxorubicin against MCF-7 cells enhanced the cytotoxicity under hypoxia by almost 3.5 folds; IC50 decreased from 25.74 to 7.43 µM. Therefore, compound 16b restored the cytotoxicity of Doxorubicin against MCF-7 cells under hypoxia, almost as normoxia. Furthermore, flow cytometry analysis of a combination treatment of compound 16b and Doxorubicin to the MCF7 cell line revealed an increase in cell cycle arrest at the G2/M phase and a more efficient apoptotic effect than Doxorubicin alone. Furthermore, compound 16b showed no cytotoxicity against normal breast MCF-10A cell line (IC50 = 296.25 µM).


Assuntos
Anidrase Carbônica IX , Inibidores da Anidrase Carbônica , Anidrases Carbônicas , Proliferação de Células , Cumarínicos , Relação Dose-Resposta a Droga , Doxorrubicina , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/síntese química , Cumarínicos/farmacologia , Cumarínicos/química , Cumarínicos/síntese química , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/metabolismo , Doxorrubicina/farmacologia , Células MCF-7 , Anidrases Carbônicas/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Antígenos de Neoplasias/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacos
18.
Colloids Surf B Biointerfaces ; 244: 114173, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39191111

RESUMO

The quantification of cysteine (Cys) levels in the organisms holds paramount significance in biological research and disease diagnosis, which can give the correlation between abnormal Cys levels and diseases. In this study, two fluorescent probes, designated as DEA-OH and DEA-AC, featuring a coumarin-aurone backbone specifically engineered for Cys detection, were meticulously designed and synthesized. The diethylamino coumarin-aurone probe DEA-OH and the acrylate-substituted probe DEA-AC demonstrated remarkable sensitivity in detecting cysteine by means of copper displacement (DEA-OH) and acrylate hydrolysis mechanisms (DEA-AC) with fluorescence detection limits of 7.25 µM and 1.65 µM, respectively. Moreover, the fluorescence peak wavelength of the two probes displayed a linear relationship with solvent polarity in the ET (30) range of 30-65 kcal•mol-1, indicating the potential for monitoring changes in environmental polarity within this ET (30) range. The outstanding attributes exhibited by DEA-AC including superior photostability, remarkable selectivity, and swift response (kinetic rate constant: 0.00747 s-1), coupled with the exceptional anti-interference ability, have significantly broadened its scope of applications, for example detecting alterations in Cys within biological systems.


Assuntos
Cumarínicos , Cisteína , Corantes Fluorescentes , Cisteína/análise , Cisteína/química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Cumarínicos/química , Humanos , Espectrometria de Fluorescência , Células HeLa , Limite de Detecção , Estrutura Molecular
19.
Eur J Med Chem ; 277: 116726, 2024 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-39116535

RESUMO

Structural modification based on natural privileged scaffolds has proven to be an attractive approach to generate potential antitumor candidates with high potency and specific targeting. As a continuation of our efforts to identify potent PARP-1 inhibitors, natural 3-arylcoumarin scaffold was served as the starting point for the construction of novel structural unit for PARP-1 inhibition. Herein, a series of novel 8-carbamyl-3-arylcoumarin derivatives were designed and synthesized. The antiproliferative activities of target compounds against four BRCA-mutated cancer cells (SUM149PT, HCC1937, MDA-MB-436 and Capan-1) were evaluated. Among them, compound 9b exhibited excellent antiproliferative effects against SUM149PT, HCC1937 and Capan-1 cells with IC50 values of 0.62, 1.91 and 4.26 µM, respectively. Moreover, 9b could significantly inhibit the intracellular PARP-1/2 activity in SUM149PT cells with IC50 values of 2.53 nM and 6.45 nM, respectively. Further mechanism studies revealed that 9b could aggravate DNA double-strand breaks, increase ROS production, decrease mitochondrial membrane potential, arrest cell cycle at G2/M phase and ultimately induce apoptosis in SUM149PT cells. In addition, molecular docking study demonstrated that the binding mode of 9b with PARP-1 was similar to that of niraparib, forming multiple hydrogen bond interactions with the active site of PARP-1. Taken together, these findings suggest that 8-carbamyl-3-arylcoumarin scaffold could serve as an effective structural unit for PARP-1 inhibition and offer a valuable paradigm for the structural modification of natural products.


Assuntos
Antineoplásicos , Proliferação de Células , Cumarínicos , Ensaios de Seleção de Medicamentos Antitumorais , Poli(ADP-Ribose) Polimerase-1 , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Cumarínicos/farmacologia , Cumarínicos/química , Cumarínicos/síntese química , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/metabolismo , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Relação Dose-Resposta a Droga , Descoberta de Drogas , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Simulação de Acoplamento Molecular , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/síntese química
20.
Int J Biol Macromol ; 278(Pt 4): 135043, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39182891

RESUMO

Protein bioconjugation has emerged as one of the most valuable tools for the development of protein-based biochemical assays. Herein, we report a fluorescent macromolecular probe RF12_POI, in which the coumarin derivative RF12 is specifically conjugated onto the HaloTag fused protein of interest (POI) to achieve a dual stimuli-mediated fluorescence response. RF12 is first obtained by installing a photo-cleavable 1-ethyl-2-nitrobenzyl group onto the C7 hydroxy moiety of coumarin fluorophore with a HaloTag ligand attaching to the acid-labile 1,3-dioxane moiety. Upon stimulation, RF12_Halo exhibits a sequential fluorescence response to photon/H+ on both liquid and solid interfaces. Through the conjugation of RF12 onto the GFP_Halo protein, RF12_GFP_Halo presents a fluorescence resonance energy transfer (FRET) from photo-cleaved RF12 to GFP in the protein complex. Furthermore, by utilizing the stimuli-responsive fluorescence characteristics of coumarin derivatives RF12 (photon/H+) and RF16 (H2O2/H+), we construct RF12/RF16_POI based protein films and achieve multiple applications of logic circuits, including AND, OR, XOR, INHIBIT, Half-adder or Half-subtractor. In these circuits, the output value of I/I0 is dependent on the input sequence of photon, H2O2, and H+. Additionally, we evaluate the fluorescence labeling ability of RF12 to intracellular IRE1_Halo protein and demonstrate that RF12 containing the HaloTag ligand could be precisely retained in cells to track IRE1_Halo protein. Hence, we provide a unique structural design strategy to construct fluorescence dual-responsive macromolecules for information encryption and cellular protein visualization.


Assuntos
Cumarínicos , Corantes Fluorescentes , Corantes Fluorescentes/química , Humanos , Cumarínicos/química , Transferência Ressonante de Energia de Fluorescência/métodos , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Fluorescência Verde/genética
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