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/químicaRESUMO
Oligonucleotides, including DNA and RNA, can be functionalized by chemical modification based on synthetic organic chemistry. For example, ligand-oligonucleotide conjugates have a wide variety of applications. Conjugates of functional ligands and oligonucleotides have attracted attention in recent years as a drug delivery system (DDS) for improving the efficacy of oligonucleotide therapeutics. In addition, oligonucleotide conjugates with drug candidate compounds as ligands have been applied to drug screening using DNA-encoded libraries (DELs). Against this background, we have focused on the development of practical synthetic methods for ligand-oligonucleotide conjugates. Recently, we have developed a new synthetic method to construct oligonucleotides conjugated with coumarins and dipeptides, which are expected to have bioactivity, for application to DDS research of oligonucleotide therapeutics and drug discovery research using DEL. In this review, we will discuss the details, including how to construct a coumarin scaffold on oligonucleotides based on Knoevenagel condensation.
Assuntos
Cumarínicos , Sistemas de Liberação de Medicamentos , Descoberta de Drogas , Oligonucleotídeos , Cumarínicos/síntese química , Cumarínicos/química , Oligonucleotídeos/síntese química , Oligonucleotídeos/química , Ligantes , DNA , Dipeptídeos/síntese química , Dipeptídeos/química , Biblioteca Gênica , Avaliação Pré-Clínica de MedicamentosRESUMO
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 MúltiplaRESUMO
Central nervous system(CNS) disorders can significantly impact patients' daily lives, impairing their ability to work and imposing a substantial financial burden on their families. In recent years, the incidence of CNS diseases has shown a significant increase with the continuous improvement of the quality of life and the aging problem. Therefore, the search for new preventive and curative drugs has been a research hotspot for this group of diseases. Osthole(OST), isolated from Umbelliferae such as Cnidium monnieri, Angelica sinensis, and Heracleum hemsleyanum, possesses a variety of pharmacological effects such as neuroprotective, antioxidant, anti-inflammatory, and antithrombotic effects. There is increasing evidence that OST has demonstrated significant preventive and curative effects in various CNS disease models. This paper systematically reviewed the research progress of OST in preventing and treating CNS diseases by reviewing domestic and international literature to provide more in-depth theoretical support for the future clinical application of OST in the prevention and treatment of CNS diseases.
Assuntos
Doenças do Sistema Nervoso Central , Cumarínicos , Cumarínicos/uso terapêutico , Humanos , Doenças do Sistema Nervoso Central/tratamento farmacológico , Doenças do Sistema Nervoso Central/prevenção & controle , Animais , Medicamentos de Ervas Chinesas/uso terapêutico , Fármacos Neuroprotetores/uso terapêuticoRESUMO
A novel coumarin-naphthalimide-based ratiometric fluorescent probe, called XPT, was synthesized with the aim of achieving high sensitivity and anti-interference for N2H4 detection. The probe XPT consists of coumarin species and naphthalimide species, which act as the energy donor and acceptor, respectively. The phthalimide group functions as the recognition unit for N2H4. Without the presence of hydrazine, the naphthalimide remains in a non-fluorogenic phthalimide mode, disrupting the FRET signal. However, the phthalimide group undergoes the Gabriel reaction to an amine, which induces FRET and consequently causes a shift in the emitted fluorescence from 468 to 528 nm when N2H4 was added. The results of the study demonstrated that XPT exhibits high sensitivity with a limit of detection 2.2 µM, as well as selectivity. Furthermore, it is remarkable that the distribution of N2H4 in real water samples can be monitored by XPT.
Assuntos
Cumarínicos , Corantes Fluorescentes , Hidrazinas , Naftalimidas , Hidrazinas/análise , Hidrazinas/química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Naftalimidas/química , Cumarínicos/química , Cumarínicos/síntese química , Poluentes Químicos da Água/análise , Estrutura Molecular , Água/química , Espectrometria de Fluorescência , Transferência Ressonante de Energia de FluorescênciaRESUMO
Staphylococcus aureus infections are the primary causes of morbidity, and mortality, particularly in immuno-compromised individuals. S. aureus associated infections are acquired from community, as well as hospital settings, and difficult to treat because of the emerging resistance against available antibiotics. One of the key factors of its resistance is the biofilm formation, which can be targeted to treat S. aureus-induced infections. Currently, there is no drug available that function by targeting the biofilm. This unmet need demands the discovery of drug candidates against S. aureus biofilm. The present study was designed to evaluate coumarin derivatives 1-21 against S. aureus biofilm. The 96-well plate crystal violet assay was employed for the quantification of biofilm. Results showed that the coumarin derivatives 2-4, 10, and 17 possess potent antibiofilm activity, with MBIC values between 25-100 µg/mL. The results were further confirmed through atomic force microscopy (AFM), scanning electron (SEM), and fluorescence microscopic studies. The quantitative RT-PCR analysis revealed the downregulation of biofilm associated genes, icaA and icaD. These coumarin derivatives were also found to be non-cytotoxic to fibroblasts. This study, therefore, identifies the antibiofilm potential of coumarin derivatives that will pave the way for further research on these derivatives.
Assuntos
Antibacterianos , Biofilmes , Cumarínicos , Testes de Sensibilidade Microbiana , Staphylococcus aureus , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Cumarínicos/farmacologia , Cumarínicos/química , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Humanos , Microscopia de Força AtômicaRESUMO
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 , GlicosídeosRESUMO
Targeted delivery systems combined with the stimuli-responsive release of drug molecules hold noteworthy promise for precision medicine, enabling treatments with enhanced effectiveness and reduced adverse effects. An ideal drug delivery platform with versatile targeting moieties, the capability of combinational payloads, and simple preparation is highly desirable. Herein, we developed pH-sensitive fluorescent self-assembled complexes (SACs) of a galactose-functionalized G-quadruplex (G4) and a coumarin carboxamidine derivative as a targeted delivery platform through the nanoprecipitation method. These SACs selectively targeted hepatocellular carcinoma (HepG2) cells in fluorescence imaging after a short incubation and exerted specific anticancer effects in an appropriate dose range. Co-delivery of 1 µM prodrug floxuridine oligomers and 16 µg/mL SACs (minimal hemolytic effect) significantly reduced the cytotoxicity of the nucleoside anticancer drug on normal cells (NIH/3T3), kept up to 70% alive after 72-h incubation, and improved anticancer efficacy compared to SACs alone. This strategy can be extended to ratiometric multidrug delivery through self-assembly for targeted combinational therapy.
Assuntos
Quadruplex G , Humanos , Quadruplex G/efeitos dos fármacos , Células Hep G2 , Camundongos , Animais , Células NIH 3T3 , Corantes Fluorescentes/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Floxuridina/química , Floxuridina/farmacologia , Galactose/química , Cumarínicos/química , Cumarínicos/farmacologiaRESUMO
Leonurus japonicus Houtt is an exceptional medicinal herb used to treat obstetrical and gynecological diseases in traditional Chinese medicine, and it has significant effects on the treatment of dysmenorrhea and postpartum hemorrhage. This study investigated the effects of coumarins with diverse substituent groups from L. japonicus on isolated uterine smooth muscle and the preliminary mechanism of the most effective compound. Eight coumarins isolated from L. japonicus were assessed for their effects on the isolated uterine smooth muscle of nonpregnant rats in vitro. Coumarins 1 and 2 significantly promoted the contraction of rat uterine smooth muscle strips, whereas coumarins 3-5 showed remarkable relaxing effects against oxytocin (OT)-induced rat uterine smooth muscle contraction. Further mechanism investigations revealed that bergapten (coumarin 1) significantly increased the level of Ca2+ in uterine tissues by promoting extracellular Ca2+ influx and intracellular Ca2+ release, which were related to the activation of L-type Ca2+ channels and α-receptors. By contrast, osthole (coumarin 5), an α receptor antagonist, inhibited OT-induced uterine smooth muscle contraction by decreasing the level of Ca2+ in uterine tissues via inhibition of extracellular Ca2+ influx and intracellular Ca2+ release. This study demonstrates that the coumarins from L. japonicus are effective substances for regulating uterine smooth muscle contraction, but different coumarins with diverse substituent groups have different, even opposite effects. It can be inferred that coumarins are closely related to the efficacy of L. japonicus in the treatment of dysmenorrhea and postpartum hemorrhage.
Assuntos
Cálcio , Cumarínicos , Leonurus , Músculo Liso , Contração Uterina , Útero , Animais , Feminino , Cumarínicos/farmacologia , Cumarínicos/química , Leonurus/química , Ratos , Cálcio/metabolismo , Contração Uterina/efeitos dos fármacos , Útero/efeitos dos fármacos , Útero/metabolismo , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Contração Muscular/efeitos dos fármacos , Ratos Sprague-Dawley , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Canais de Cálcio Tipo L/metabolismo , Ocitocina/farmacologiaRESUMO
Intracellular biothiols, including cysteine (Cys), glutathione (GSH), and homocysteine (Hcy), play a critical role in many physiological and pathological processes. Among them, GSH is the most abundant non-protein mercaptan (1-10 mM) in cells, and the change in GSH concentration level is closely related to the occurrence of many diseases, such as Parkinson's disease, Alzheimer's disease, and neurological diseases. Fluorescent probes have attracted much attention due to their advantages of high specificity, high sensitivity, high selectivity, low cost, and high quantum yield. Methods that use optical probes for selective detection of GSH in vitro and in vivo are in high demand. In this paper, we reviewed the most recent five years of research on fluorescence probes for the detection of GSH, including the specific detection of GSH, dual-channel identification of GSH and other substances, and the detection of GSH and other biothiols. According to the type of fluorophore, we classified GSH fluorescent probes into eight classes, including BODIPY, 1,8-Naphthalimide, coumarin, xanthene, rhodamine, cyanine, benzothiazoles, and others. In addition, we roundly discuss the synthesis, detection mechanism, photophysical properties, and biological applications of fluorescent probes. We hope that this review will inspire the exploration of new fluorescent probes for GSH and other related analyses.
Assuntos
Corantes Fluorescentes , Glutationa , Corantes Fluorescentes/química , Glutationa/análise , Humanos , Animais , Cumarínicos/químicaRESUMO
Lonicerae japonicae flos (LJF) and Lonicerae flos (LF) are traditional Chinese herbs that are commonly used and widely known for their medicinal properties and edibility. Although they may have a similar appearance and vary slightly in chemical composition, their effectiveness as medicine and their use in clinical settings vary significantly, making them unsuitable for substitution. In this study, a novel 2 × 3 six-channel fluorescent sensor array is proposed that uses machine learning algorithms in combination with the indicator displacement assay (IDA) method to quickly identify LJF and LF. This array comprises two coumarin-based fluorescent indicators (ES and MS) and three diboronic acid-substituted 4,4'-bipyridinium cation quenchers (Q1-Q3), forming six dynamic complexes (C1-C6). When these complexes react with the ortho-dihydroxy groups of phenolic acid compounds in LJF and LF, they release different fluorescent indicators, which in turn causes distinct fluorescence recovery. By optimizing eight machine learning algorithms, the model achieved 100% and 98.21% accuracy rates in the testing set and the cross-validation predictions, respectively, in distinguishing between LJF and LF using Linear Discriminant Analysis (LDA). The integration of machine learning with this fluorescent sensor array shows great potential in analyzing and detecting foods and pharmaceuticals that contain polyphenols.
Assuntos
Lonicera , Lonicera/química , Corantes Fluorescentes/química , Espectrometria de Fluorescência/métodos , Aprendizado de Máquina , Cumarínicos/química , Cumarínicos/análise , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/análise , Extratos Vegetais/química , Extratos Vegetais/análiseRESUMO
In the present study, a series of coumarins, including eight undescribed bis-isoprenylated ones Spinifoliumin A-H, were isolated and identified from the aerial parts of Zanthoxylum dimorphophyllum var. spinifolium (ZDS), a plant revered in traditional Chinese medicine, particularly for treating rheumatoid arthritis (RA). The structures of the compounds were elucidated using 1D and 2D NMR spectroscopy, complemented by ECD, [Rh2(OCOCF3)4]-induced ECD, Mo2(OAc)4 induced ECD, IR, and HR-ESI-MS mass spectrometry. A network pharmacology approach allowed for predicting their anti-RA mechanisms and identifying the MAPK and PI3K-Akt signaling pathways, with EGFR as a critical gene target. A CCK-8 method was used to evaluate the inhibition activities on HFLS-RA cells of these compounds. The results demonstrated that Spinifoliumin A, B, and D-H are effective at preventing the abnormal proliferation of LPS-induced HFLS-RA cells. The results showed that compounds Spinifoliumin A, D, and G can significantly suppress the levels of IL-1ß, IL-6, and TNF-α. Moreover, molecular docking methods were utilized to confirm the high affinity between Spinifoliumin A, D, and G and EGFR, SRC, and JUN, which were consistent with the results of network pharmacology. This study provides basic scientific evidence to support ZDS's traditional use and potential clinical application.
Assuntos
Artrite Reumatoide , Cumarínicos , Zanthoxylum , Zanthoxylum/química , Artrite Reumatoide/tratamento farmacológico , Humanos , Cumarínicos/química , Cumarínicos/farmacologia , Cumarínicos/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Simulação de Acoplamento MolecularRESUMO
Secondary polyphenol metabolites, urolithins (UROs), have anti-oxidative, anti-inflammatory, and antidiabetic properties. Therefore, their biological activity relies on blood transport via human serum albumin (HSA) and tissue distribution. The main goal we set was to investigate the interaction between HSA and different URO (URO A, URO B, URO C, URO D, and glucuronidated URO A and B) using a combination of multi-spectroscopic instrumental and in silico approaches. The fluorescence spectroscopy revealed that URO can quench the naturally occurring fluorescence of HSA in a concentration-dependent manner. The HSA fluorescence was quenched by both a static and dynamic mechanism. The results showed that free UROs bind to HSA with higher affinity than their conjugated forms. CD spectroscopy and FTIR revealed that the alpha-helical structure of HSA is preserved. The calculated Gibbs free energy change indicates that the URO-HSA complex forms spontaneously. There is a single binding site on the HSA surface. The molecular docking results indicated that unconjugated Uro binds to Sudlow I, while their conjugation affects this binding site, so in the conjugated form, they bind to the cleft. Docking experiments indicate that all UROs are capable of binding to both thyroxine recognition sites of ligand-bound HSA proteins. Examining interactions under the following conditions (298 K, 303 K, and 310 K, pH 7.4) is of great importance for determining the pharmacokinetics of these bioactive compounds, as the obtained results can be used as a basis for modulating the potential dosing regimen.
Assuntos
Simulação de Acoplamento Molecular , Polifenóis , Ligação Proteica , Albumina Sérica Humana , Humanos , Polifenóis/química , Polifenóis/metabolismo , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismo , Sítios de Ligação , Espectrometria de Fluorescência , Dicroísmo Circular , Termodinâmica , Espectroscopia de Infravermelho com Transformada de Fourier , CumarínicosRESUMO
Aim: This research aims to expand the established pharmacological space of tumor-associated carbonic anhydrases (TACAs) by exploring the synthetically accessible chemical space of 3-substituted coumarins, with the help of in silico pharmacology prediction.Materials & methods: 52 novel 3-substituted coumarins were sketched, prioritizing synthetic feasibility. Their pharmacological potentials were estimated using a custom machine-learning approach. 17 compounds were predicted as cytotoxic against HeLa cells by interfering with TACAs. Those compounds were synthesized and biologically tested against HeLa cells. The three most potent compounds were assayed against multiple carbonic anhydrases, and their enzyme binding mechanism(s) were studied using molecular docking.Results: Experimental results exhibited pronounced consensus with in silico pharmacology predictions.Conclusion: Novel 3-substituted coumarins are herein dispatched to the cancer therapeutics space.
[Box: see text].
Assuntos
Antineoplásicos , Anidrases Carbônicas , Cumarínicos , Simulação de Acoplamento Molecular , Humanos , Cumarínicos/química , Cumarínicos/farmacologia , Cumarínicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Células HeLa , Anidrases Carbônicas/metabolismo , Descoberta de Drogas , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Aprendizado de Máquina , Neoplasias/tratamento farmacológico , Neoplasias/patologiaRESUMO
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 AnéisRESUMO
BACKGROUND: Coumarins, abundantly distributed in a plethora of biologically active compounds, serve as a fundamental motif in numerous natural products, drugs, and therapeutic leads. Despite their small size, they exhibit a diverse range of biological activities, intriguing researchers with their immense pharmacological potential. PURPOSE: This study consolidates the evidence regarding the essential role of coumarins in modern drug discovery, exploring their broad-spectrum pharmaceutical effects, structural versatility, and mechanisms of action across various domains. METHODS: For literature search, we utilized PubMed, Google scholar, and SciFinder databases. Keyword and keyword combinations such as "coumarins", "natural coumarins", "specific natural coumarins for particular diseases", and "therapeutic effects" were employed to retrieve relevant studies. The search encompassed articles published between 2005 and 2023. Selection criteria included studies reporting on the pharmacological activities of natural coumarins against various diseases. RESULTS: The results highlight the therapeutic potential of natural coumarins against various diseases, demonstrating anti-cancer, anti-oxidant, and anti-inflammatory activities. They also act as monoamine oxidase inhibitors and phosphodiesterase inhibitors, and as anti-thrombotic, anti-diabetic, and hepatoprotective agents. They also show efficacy against diabetic nephropathy, neurodegenerative diseases, microbial infections and many other diseases. CONCLUSION: This review underscores the significant role of natural coumarins in medicinal chemistry and drug discovery. Their diverse biological activities and structural versatility make them promising therapeutic agents. This study serves as a catalyst for further research in the field, aiming to address emerging challenges and opportunities in drug development.
Assuntos
Cumarínicos , Cumarínicos/farmacologia , Cumarínicos/química , Humanos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Antioxidantes/farmacologia , Antioxidantes/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Animais , Fitoterapia , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Descoberta de DrogasRESUMO
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 â 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 químicaRESUMO
Osthole, a coumarin compound mainly derived from Cnidium monnieri (L.), has attracted much interest from the scientific community owing to its multiple therapeutic properties. However, its pharmacological mechanism, pharmacokinetics, and toxicological effects are far from clear. Furthermore, the potential drug delivery platforms of osthole remain to be comprehensively delineated. The present review aimed to systematically summarize the most up-to-date information related to pharmacology, pharmacokinetics, and safety issues related to osthole, and discuss the investigations of novel drug delivery platforms. The information herein discussed was retrieved from authoritative databases, including PubMed, Web of Science, Google Scholar, Chinese National Knowledge Infrastructure (CNKI) and so on, reviewing information published up until February of 2024. New evidence shows that osthole induces a sequence of therapeutic actions and has a moderate absorption rate and rapid metabolic characteristics. In addition, this phytoconstituent possesses potential hepatotoxicity, and caution should be exercised against the risk of the drug combination. Furthermore, given its needy solubility in aqueous medium and non-organizational targeting, novel drug delivery methods have been designed to overcome these shortcomings. Given the properties of osthole, its therapeutic benefits ought to be elucidated in a greater array of comprehensive research studies, and the molecular mechanisms underlying these benefits should be explored.
Assuntos
Cnidium , Cumarínicos , Sistemas de Liberação de Medicamentos , Cumarínicos/administração & dosagem , Cumarínicos/farmacocinética , Cnidium/química , Humanos , AnimaisRESUMO
Understanding the spatiotemporal dynamics of formaldehyde (FA) is crucial for elucidating its pathophysiology. In this study, we designed a series of organelle-resolved probes to investigate FA dynamics. By incorporating various organelle anchors into a coumarin hydrazonate, we developed a series of probes with excellent organelle selectivity and FA specificity, enabling rapid and precise sensing of FA in an organelle-resolved way. Leveraging these probes, we captured the spatiotemporal dynamics of native FA in response to exogenous FA or oxidative stress challenges. In particular, we unveiled the distinct responses of various organelles to identical cellular stressors. Moreover, we observed the dynamic response within individual organelles when cells were exposed to stressors for varying durations. We envision these probes will serve as versatile tools for probing FA pathophysiology.
Assuntos
Formaldeído , Organelas , Formaldeído/química , Humanos , Organelas/química , Organelas/metabolismo , Células HeLa , Corantes Fluorescentes/química , Imagem Óptica , Cumarínicos/química , Cumarínicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estrutura MolecularRESUMO
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.