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1.
ACS Appl Mater Interfaces ; 12(52): 57686-57694, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-33331759

RESUMO

In recent years, hydrogels as an attractive class of intelligent soft materials have been applied in various advanced fields, including electronic materials, wearable devices, and wound dressing materials. However, it still remains a critical challenge to integrate information encryption transmission capability, antibacterial activity, high mechanical performance, adhesiveness, and self-healable ability into one material and achieve the synergistic characteristics through a simple method. In our study, a facile strategy of a plant-inspired hydrogel was proposed, which provides a novel initiator-free photo-cross-linked hydrogel system by simply mixing the coumarin derivative Pho-CA and the monomer in water, and then obtaining the hydrogel Gel-C-Am under the irradiation of UV light without adding any other cross-linking agents and initiators, and this process is very similar to the growth process of plants in nature. This novel hydrogel presents desirable mechanical properties (including twist, stretchability, and recoverability), which exhibits elongation of approximately 1600%. More interestingly, Gel-C-Am hydrogel displays reversible adhesiveness to various substrates (such as glass, paper, leaves, and rubber), and its adhesion properties can be regulated by water: the viscosity disappears when its surface becomes wet, and the viscosity will recover after the water evaporates. In addition, the developed hydrogel has certain self-healable ability. Two pieces of the Gel-C-Am hydrogel can combine together and reshape into one piece in water, and the fused hydrogel has uniform and interconnected pores under SEM. Based on the characteristic of Pho-CA whose fluorescence get recovery after UV irradiation, the hydrogel can be used in the field of encryption and decryption. Also, the resulting Gel-C-Am hydrogel shows an effective antibacterial activity and can potentially be addressed as antibacterial coatings. Taken together, the formation of the novel fluorescent hydrogel system is just like the growth of a plant in the presence of water and light, Pho-CA and the monomer will form a highly stretchable and recoverable self-healing hydrogel with water-controlled adhesiveness. The developed Gel-C-Am hydrogel shows favorable attributes and is suitable for applications in antibacterial polymeric coatings and information encryption transmission.


Assuntos
Biomimética , Segurança Computacional , Corantes Fluorescentes/química , Hidrogéis/química , Hidrogéis/farmacologia , Plantas , Água/química , Acrilamida/química , Adesividade , Antibacterianos/química , Antibacterianos/farmacologia , Cumarínicos/química , Escherichia coli/efeitos dos fármacos , Ligação de Hidrogênio , Propriedades de Superfície
2.
PLoS One ; 15(9): e0239145, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32941495

RESUMO

Turn-on fluorescent probes show enhanced emission upon DNA binding, advocating their importance in imaging cellular DNA. We have probed the DNA binding mode of thiazole-coumarin (TC) conjugate, a recently reported hemicyanine-based turn-on red fluorescent probe, using a number of biophysical techniques and a series of short oligonucleotides. TC exhibited increased fluorescence anisotropy and decreased absorbance (~50%) at low [DNA]/[TC] ratio. Although the observed hypochromicity and the saturating value of [DNA base pair]:[TC] ratio is consistent with a previous study that suggested intercalation to be the DNA binding mode of TC, a distinctly different and previously unreported binding mode was observed at higher ratios of [DNA]:[TC]. With further addition of DNA, only oligonucleotides containing AnTn or (AT)n stretches showed further change-decreased hypochromicity, red shifted absorption peaks and concomitant fluorescence enhancement, saturating at about 1:1 [DNA]: [TC]. 1H-NMR chemical shift perturbation patterns and H1'-H6/H8 NOE cross-peaks of the 1:1 complex indicated minor groove binding by TC. ITC showed the 1:1 DNA binding event to be endothermic (ΔH° ~ 2 kcal/mol) and entropy driven (ΔS° ~ 32 cal/mol/K). Taken together, the experimental data suggest a dual DNA binding mode by TC. At low [DNA]/[TC] ratio, the dominant mode is intercalation. This switches to minor groove binding at higher [DNA]/[TC], only for sequences containing AnTn or (AT)n stretches. Turn-on fluorescence results only in the previously unreported minor groove bound state. Our results allow a better understanding of DNA-ligand interaction for the newly reported turn-on probe TC.


Assuntos
Benzotiazóis/química , Carbocianinas/química , Cumarínicos/química , DNA/análise , Corantes Fluorescentes/química , Sítios de Ligação , Conformação de Ácido Nucleico , Termodinâmica
3.
Molecules ; 25(17)2020 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-32842606

RESUMO

Presently, there are no approved drugs or vaccines to treat COVID-19, which has spread to over 200 countries and at the time of writing was responsible for over 650,000 deaths worldwide. Recent studies have shown that two human proteases, TMPRSS2 and cathepsin L, play a key role in host cell entry of SARS-CoV-2. Importantly, inhibitors of these proteases were shown to block SARS-CoV-2 infection. Here, we perform virtual screening of 14,011 phytochemicals produced by Indian medicinal plants to identify natural product inhibitors of TMPRSS2 and cathepsin L. AutoDock Vina was used to perform molecular docking of phytochemicals against TMPRSS2 and cathepsin L. Potential phytochemical inhibitors were filtered by comparing their docked binding energies with those of known inhibitors of TMPRSS2 and cathepsin L. Further, the ligand binding site residues and non-covalent interactions between protein and ligand were used as an additional filter to identify phytochemical inhibitors that either bind to or form interactions with residues important for the specificity of the target proteases. This led to the identification of 96 inhibitors of TMPRSS2 and 9 inhibitors of cathepsin L among phytochemicals of Indian medicinal plants. Further, we have performed molecular dynamics (MD) simulations to analyze the stability of the protein-ligand complexes for the three top inhibitors of TMPRSS2 namely, qingdainone, edgeworoside C and adlumidine, and of cathepsin L namely, ararobinol, (+)-oxoturkiyenine and 3α,17α-cinchophylline. Interestingly, several herbal sources of identified phytochemical inhibitors have antiviral or anti-inflammatory use in traditional medicine. Further in vitro and in vivo testing is needed before clinical trials of the promising phytochemical inhibitors identified here.


Assuntos
Antivirais/química , Betacoronavirus/efeitos dos fármacos , Catepsina L/química , Compostos Fitoquímicos/química , Inibidores de Proteases/química , Receptores Virais/química , Serina Endopeptidases/química , Sequência de Aminoácidos , Antivirais/isolamento & purificação , Antivirais/farmacologia , Betacoronavirus/patogenicidade , Sítios de Ligação , Catepsina L/antagonistas & inibidores , Catepsina L/genética , Catepsina L/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/virologia , Cumarínicos/química , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia , Expressão Gênica , Ensaios de Triagem em Larga Escala , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Índia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Monossacarídeos/química , Monossacarídeos/isolamento & purificação , Monossacarídeos/farmacologia , Pandemias , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/enzimologia , Pneumonia Viral/virologia , Inibidores de Proteases/isolamento & purificação , Inibidores de Proteases/farmacologia , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Quinazolinas/química , Quinazolinas/isolamento & purificação , Quinazolinas/farmacologia , Receptores Virais/antagonistas & inibidores , Receptores Virais/genética , Receptores Virais/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Termodinâmica , Internalização do Vírus/efeitos dos fármacos
4.
Food Chem ; 332: 127404, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32623127

RESUMO

Coumarins, derivatives of cinnamic acid, are found in wines aged in wooden barrels. The lab-made molecularly imprinted polymers (MIP), selective for simple coumarins, were used in three forms, as sorbents in solid phase extraction (SPE) cartridge or pipette tip and coated on to the surface of magnetite for magnetic extraction. MIP-7-hydroxycoumarin had greater selectivity and extraction efficiency (recoveries above 75%, RSDs less than 6%) compared with conventional SPE sorbents (C18 and styrene-divinylbenzene polymeric types). Batch extraction with MIP coated on to magnetic particles was relatively time-consuming compared with conventional and pipette tip SPE. The advantage of pipette tip SPE was reduced solvent volumes. LOQs for MISPE offline coupled with HPLC were less than 1.5 µg mL-1 and 12 ng mL-1 for UV and fluorescence detectors, respectively. 6-Methoxy-7-hydroxycoumarin and 4-methyl-7-hydroxycoumarin were detected in Slovak Tokaj wines using method with coumarin-specific sorbents.


Assuntos
Cumarínicos/isolamento & purificação , Extração em Fase Sólida/métodos , Adsorção , Cromatografia Líquida de Alta Pressão , Cumarínicos/química , Impressão Molecular , Polímeros/síntese química , Polímeros/química , Solventes/química , Estireno/química
5.
Int J Nanomedicine ; 15: 2841-2858, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32425521

RESUMO

Introduction: Osthole (Ost) is a coumarin compound that strengthens hippocampal neurons and neural stem cells against Aß oligomer-induced neurotoxicity in mice, and is a potential drug for the treatment of Alzheimer's disease (AD). However, the effectiveness of the drug is limited by its solubility and bioavailability, as well as by the low permeability of the blood-brain barrier (BBB). In this study, a kind of transferrin-modified Ost liposomes (Tf-Ost-Lip) was constructed, which could improve the bioavailability and enhance brain targeting. Methods: Tf-Ost-Lip was prepared by thin-film hydration method. The ability of liposomal formulations to translocate across BBB was investigated using in vitro BBB model. And the protective effect of Tf-Ost-Lip was evaluated in APP-SH-SY5Y cells. In addition, we performed pharmacokinetics study and brain tissue distribution analysis of liposomal formulations in vivo. We also observed the neuroprotective effect of the varying formulations in APP/PS-1 mice. Results: In vitro studies reveal that Tf-Ost-Lip could increase the intracellular uptake of hCMEC/D3 cells and APP-SH-SY5Y cells, and increase the drug concentration across the BBB. Additionally, Tf-Ost-Lip was found to exert a protective effect on APP-SH-SY5Y cells. In vivo studies of pharmacokinetics and the Ost distribution in brain tissue indicate that Tf-Ost-Lip prolonged the cycle time in mice and increased the accumulation of Ost in the brain. Furthermore, Tf-Ost-Lip was also found to enhance the effect of Ost on the alleviation of Alzheimer's disease-related pathology. Conclusion: Transferrin-modified liposomes for delivery of Ost has great potential for AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Barreira Hematoencefálica/efeitos dos fármacos , Cumarínicos/farmacologia , Lipossomos/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/patologia , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Linhagem Celular , Cumarínicos/química , Cumarínicos/farmacocinética , Humanos , Lipossomos/química , Lipossomos/farmacocinética , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Polietilenoglicóis/química , Presenilina-1/genética , Ratos Sprague-Dawley , Distribuição Tecidual , Transferrina/química
6.
Biochim Biophys Acta Proteins Proteom ; 1868(9): 140445, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32405284

RESUMO

Coumarins represent well-established structures to introduce fluorescence into tool compounds for biochemical investigations. They are valued for their small size, chemical stability and accessibility as well as their tunable photochemical properties. As components of fluorophore/quencher pairs or FRET donor/acceptor pairs, coumarins have frequently been applied in substrate mapping approaches for serine and cysteine proteases. This review also focuses on the incorporation of coumarins into the side chain of amino acids and the exploitation of the resulting fluorescent amino acids for the positional profiling of protease substrates. The protease-inhibiting properties of certain coumarin derivatives and the utilization of coumarin moieties to assemble activity-based probes for serine and cysteine proteases are discussed as well.


Assuntos
Cumarínicos/química , Cumarínicos/metabolismo , Cisteína Proteases/metabolismo , Serina Proteases/metabolismo , Domínio Catalítico , Cumarínicos/farmacologia , Cisteína Proteases/efeitos dos fármacos , Fluorescência , Transferência Ressonante de Energia de Fluorescência/métodos , Corantes Fluorescentes/química , Serina/metabolismo , Serina Proteases/efeitos dos fármacos , Especificidade por Substrato
7.
J Med Chem ; 63(11): 5723-5733, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32374603

RESUMO

The serine protease kallikrein-related peptidase 7 (KLK7) is a member of the human tissue kallikreins. Its dysregulation leads to pathophysiological inflammatory processes in the skin. Furthermore, it plays a role in several types of cancer. For the treatment of KLK7-associated diseases, coumarinic esters have been developed as small-molecule enzyme inhibitors. To characterize the inhibition mode of these inhibitors, we analyzed structures of the inhibited protease by X-ray crystallography. Electron density shows the inhibitors covalently attached to His57 of the catalytic triad. This confirms the irreversible character of the inhibition process. Upon inhibitor binding, His57 undergoes an outward rotation; thus, the catalytic triad of the protease is disrupted. Besides, the halophenyl moiety of the inhibitor was absent in the final enzyme-inhibitor complex due to the hydrolysis of the ester linkage. With these results, we analyze the structural basis of KLK7 inhibition by the covalent attachment of aromatic coumarinic esters.


Assuntos
Cumarínicos/química , Calicreínas/antagonistas & inibidores , Inibidores de Proteases/química , Sítios de Ligação , Domínio Catalítico , Cumarínicos/metabolismo , Cristalografia por Raios X , Ésteres/química , Humanos , Calicreínas/genética , Calicreínas/metabolismo , Simulação de Dinâmica Molecular , Inibidores de Proteases/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Espectrometria de Massas em Tandem
8.
Chem Pharm Bull (Tokyo) ; 68(3): 216-219, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115528

RESUMO

A turn-on fluorescent traceable linker based on N-sulfanylethylcoumarinyl amide (SECmide) has been developed as an advanced cleavable linker. It was successfully employed for the enrichment and selective visualization of a target protein in cell lysate. The results demonstrated that the SECmide-based traceable linker is potentially applicable to the identification of low molecular weight target proteins, a factor which has been problematic for a previously developed N-sulfanylethylanilide-based traceable linker.


Assuntos
Amidas/química , Cumarínicos/química , Fluorescência , Corantes Fluorescentes/química , Proteínas/análise , Corantes Fluorescentes/síntese química , Estrutura Molecular
9.
Mar Drugs ; 18(3)2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32110865

RESUMO

Aspergillus terreus has been reported to produce many secondary metabolites that exhibit potential bioactivities, such as antibiotic, hypoglycemic, and lipid-lowering activities. In the present study, two new thiodiketopiperazines, emestrins L (1) and M (2), together with five known analogues (3-7), and five known dihydroisocoumarins (8-12), were obtained from the marine-derived fungus Aspergillus terreus RA2905. The structures of the new compounds were elucidated by analysis of the comprehensive spectroscopic data, including high-resolution electrospray ionization mass spectrometry (HRESIMS), one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR), and electronic circular dichroism (ECD) data. This is the first time that the spectroscopic data of compounds 3, 8, and 9 have been reported. Compound 3 displayed antibacterial activity against Pseudomonas aeruginosa (minimum inhibitory concentration (MIC) = 32 µg/mL) and antifungal activity against Candida albicans (MIC = 32 µg/mL). In addition, compound 3 exhibited an inhibitory effect on protein tyrosine phosphatase 1 B (PTP1B), an important hypoglycemic target, with an inhibitory concentration (IC)50 value of 12.25 µM.


Assuntos
Antibacterianos/farmacologia , Aspergillus/química , Animais , Candida albicans/efeitos dos fármacos , Cumarínicos/química , Testes de Sensibilidade Microbiana , Oceanos e Mares , Piperazinas/química , Pseudomonas aeruginosa/efeitos dos fármacos
10.
Chem Biol Interact ; 322: 109053, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32198085

RESUMO

Notopterol (NOT) is a major bioactive ingredient extracted from the rhizomes of either Notopterygium incisum Ting ex H. T. Chang or N. forbesii Boiss (Qianghuo in Chinese), a botanical drug that was adopted as a traditional Chinese medicine. NOT is suggested to show analgesic and anti-inflammatory effects in clinical practice. The inhibitory effects of NOT on human cytochrome P450 enzymes were investigated in the present study. Our results indicate that NOT inhibited the activity of CYP2D6 in a time-, concentration- and NADPH-dependent manner. The values of KI and kinact were 10.8 µM and 0.62 min-1, respectively. The calculated kobs at 10 µM was 0.29 min-1, above the 0.02 min-1 risk level. After incubation with NOT at 10 µM for 9 min, approximately 92% of CYP2D6 activity was inhibited. Such loss of enzyme activity was not restored through dialysis, which indicates that the observed enzyme inhibition was irreversible. Partition ratio of the inactivation was approximately 29. Quinidine, a competitive CYP2D6 inhibitor, demonstrated protection on enzymes against the NOT-induced inactivation, but such protection was not found in incubation systems fortified with glutathione or catalase/superoxide dismutase. Additionally, CYP3A4 was observed to function as an enzyme mainly involved in the biotransformation of NOT. Taken together, these findings indicate that NOT served as a mechanism-based inactivator of CYP2D6, meanwhile, those observed effects may induce the latent drug-drug interactions. The metabolic activation of NOT may be the key to trigger the inactivation of the enzyme.


Assuntos
Cumarínicos/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Ativação Metabólica , Apiaceae/química , Apiaceae/metabolismo , Cumarínicos/química , Citocromo P-450 CYP2D6/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Glutationa/antagonistas & inibidores , Glutationa/metabolismo , Humanos , Cinética , NADP/química , NADP/metabolismo , Superóxido Dismutase/antagonistas & inibidores , Superóxido Dismutase/metabolismo
11.
Nature ; 579(7799): 421-426, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32188939

RESUMO

Bioorthogonal chemistry capable of operating in live animals is needed to investigate biological processes such as cell death and immunity. Recent studies have identified a gasdermin family of pore-forming proteins that executes inflammasome-dependent and -independent pyroptosis1-5. Pyroptosis is proinflammatory, but its effect on antitumour immunity is unknown. Here we establish a bioorthogonal chemical system, in which a cancer-imaging probe phenylalanine trifluoroborate (Phe-BF3) that can enter cells desilylates and 'cleaves' a designed linker that contains a silyl ether. This system enabled the controlled release of a drug from an antibody-drug conjugate in mice. When combined with nanoparticle-mediated delivery, desilylation catalysed by Phe-BF3 could release a client protein-including an active gasdermin-from a nanoparticle conjugate, selectively into tumour cells in mice. We applied this bioorthogonal system to gasdermin, which revealed that pyroptosis of less than 15% of tumour cells was sufficient to clear the entire 4T1 mammary tumour graft. The tumour regression was absent in immune-deficient mice or upon T cell depletion, and was correlated with augmented antitumour immune responses. The injection of a reduced, ineffective dose of nanoparticle-conjugated gasdermin along with Phe-BF3 sensitized 4T1 tumours to anti-PD1 therapy. Our bioorthogonal system based on Phe-BF3 desilylation is therefore a powerful tool for chemical biology; our application of this system suggests that pyroptosis-induced inflammation triggers robust antitumour immunity and can synergize with checkpoint blockade.


Assuntos
Preparações de Ação Retardada/administração & dosagem , Neoplasias Mamárias Experimentais/imunologia , Piroptose/imunologia , Animais , Cumarínicos/administração & dosagem , Cumarínicos/química , Cumarínicos/metabolismo , Cumarínicos/farmacocinética , Preparações de Ação Retardada/química , Preparações de Ação Retardada/metabolismo , Preparações de Ação Retardada/farmacocinética , Feminino , Proteínas de Fluorescência Verde/administração & dosagem , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Fluorescência Verde/farmacocinética , Células HeLa , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/química , Imunoconjugados/metabolismo , Imunoconjugados/farmacocinética , Inflamassomos/imunologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Oligopeptídeos/administração & dosagem , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Oligopeptídeos/farmacocinética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Proteínas/administração & dosagem , Proteínas/química , Proteínas/metabolismo , Proteínas/farmacocinética , Silanos/administração & dosagem , Silanos/química , Silanos/metabolismo , Silanos/farmacocinética , Linfócitos T/imunologia , Trastuzumab/administração & dosagem , Trastuzumab/química , Trastuzumab/metabolismo , Trastuzumab/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Oxid Med Cell Longev ; 2020: 2432918, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215169

RESUMO

The present study was directed to investigate the effect of precotreatment with (E)-N'-(1-(7-hydroxy-2-oxo-2H-chromen-3-yl) ethylidene) benzohydrazide (7-hyd.HC), a novel potent synthesized coumarin, on isoproterenol- (ISO-) induced myocardial infarction (MI) in rats. The hydrazone compound was characterized by IR, 1D, and 2D NMR analyses. Experimental induction of MI in rats was established by ISO (85 mg/kg/day, s.c) for two consecutive days (6th and 7th days). 7-hyd.HC or sintrom was given for 7 days prior and simultaneous to ISO injection. 7-hyd.HC offered a cardiopreventive effect by preventing heart injury marker leakage (LDH, ALT, AST, CK-MB, and cTn-I) from cardiomyocytes and normalizing cardiac function and ECG pattern, as well as improving lipid profile (TC, TG, LDL-C, and HDL-C), which were altered by ISO administration. Moreover, 7-hyd.HC precotreatment significantly mitigated the oxidative stress biomarkers, as evidenced by the decrease of lipid peroxidation and the increased level of the myocardial GSH level together with the SOD, GSH-Px, and catalase activities. 7-hyd.HC inhibited the cardiac apoptosis by upregulating the expression of Bcl-2 and downregulating the expression of Bax and caspase-3 genes. In addition, 7-hyd.HC reduced the elevated fibrinogen rate and better prevented the myocardial necrosis and improved the interstitial edema and neutrophil infiltration than sintrom. Overall, 7-hyd.HC ameliorated the severity of ISO-induced myocardial infarction through improving the oxidative status, attenuating apoptosis, and reducing fibrinogen production. The 7-hyd.HC actions could be mediated by its antioxidant, antiapoptotic, and anti-inflammatory capacities.


Assuntos
Anti-Inflamatórios/uso terapêutico , Benzopiranos/uso terapêutico , Cumarínicos/uso terapêutico , Hidrazonas/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Apoptose/efeitos dos fármacos , Benzopiranos/síntese química , Benzopiranos/química , Biomarcadores/metabolismo , Cumarínicos/síntese química , Cumarínicos/química , Hidrazonas/síntese química , Hidrazonas/química , Inflamação/metabolismo , Isoproterenol/toxicidade , Masculino , Estrutura Molecular , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Resultado do Tratamento
13.
Biomater Sci ; 8(8): 2274-2282, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32162618

RESUMO

Because of their excellent capacity to significantly improve the bioavailability and solubility of chemotherapy drugs, block copolymer micelles are widely utilized for chemotherapy drug delivery. In order to further improve the anti-tumor ability and reduce unwanted side effects of drugs, tumor-targeting peptides were used to functionalize the surface of polymer micelles so that the micelles can target tumor tissues. Herein, we synthesized a kind of PEG-PLA that is maleimide-terminated and then conjugated with a specific peptide F3 which revealed specific capacity binding to nucleolin that is overexpressed on the surface of many tumor cells. Then, F3 conjugated, paclitaxel loaded nanoparticles (F3-NP-PTX) were prepared as stable micelles that displayed an enhanced accumulation via a peptide-mediated cellular association in human breast cancer cells (MCF-7). Furthermore, F3-NP-PTX showed a prominent anti-tumor efficacy compared with non-targeting nanoparticles (NP-PTX) both in vitro and in vivo, and showed great potential as an efficacious targeting drug delivery system for breast cancer treatment.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Cumarínicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Micelas , Paclitaxel/administração & dosagem , Peptídeos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Tiazóis/administração & dosagem , Animais , Antineoplásicos Fitogênicos/sangue , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/química , Liberação Controlada de Fármacos , Feminino , Humanos , Células MCF-7 , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos Endogâmicos ICR , Paclitaxel/sangue , Paclitaxel/química , Paclitaxel/farmacocinética , Peptídeos/química , Peptídeos/farmacocinética , Polietilenoglicóis/química , Esferoides Celulares/efeitos dos fármacos , Tiazóis/química , Carga Tumoral/efeitos dos fármacos
14.
Chem Commun (Camb) ; 56(29): 4098-4101, 2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32163053

RESUMO

We detail a heterobifunctional, 7-aminocoumarin photocleavable (PC) linker with unique properties to covalently attach Abs to surfaces and subsequently release them with visible light (400-450 nm). The PC linker allowed rapid (2 min) and efficient (>90%) release of CTCs and EVs without damaging their molecular cargo.


Assuntos
Anticorpos Monoclonais/química , Cumarínicos/química , Vesículas Extracelulares , Células Neoplásicas Circulantes , Anticorpos Monoclonais/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular , Cumarínicos/efeitos da radiação , Humanos , Luz , Biópsia Líquida , Microfluídica
15.
J Fluoresc ; 30(2): 317-327, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016910

RESUMO

Herein, we report the preparation of a fluorescent sensor based on coumarin derivative for copper (II) ion sensing in CH3CN/HEPES media. 6,7-dihydroxy-3-(4-(trifluoro)methylphenyl)coumarin (HMAC) sensor was fabricated and analyzed by spectroscopic techniques. The sensor demonstrates "turn on-off" fluorescence quenching in the presence of copper (II) ions at 458 nm. A clear complex between the chemosensor HMAC and copper (II) ions was characterized by ESI-MS as well as the Job's method. Also, the limit of detection (LOD, 3σ/k) value was determined as 24.5 nM in CH3CN/HEPES (95/5, v/v) buffer media (pH = 7.0). This value is lower than the admissible level of copper (II) ions in drinking water (maximum 31.5 µM) reported by EU Water Framework Directive (WFD) and World Health Organization (WHO) guidelines. The theoretical calculations (density functional theory, DFT) have been performed for the geometric optimized structures. As a final stage, real sample analyses have successfully been performed by using HMAC, as well as ICP-OES method. The relative standard deviation for copper (II) in mineral and drinking water samples has been determined to be below 0.15% and recovery values are in the range of 95.48-109.20%.


Assuntos
Cobre/análise , Cumarínicos/química , Teoria da Densidade Funcional , Água Potável/química , Corantes Fluorescentes/química , Minerais/química , Cumarínicos/síntese química , Fluorescência , Corantes Fluorescentes/síntese química , Íons/análise , Estrutura Molecular , Espectrometria de Fluorescência
16.
PLoS One ; 15(2): e0228543, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32045426

RESUMO

Two molecules, 7-(diethylamino)coumarin-3-carbohydrazide (DCCH) and fluorescein-5-thiosemicarbazide (FTSC) were investigated in different solvents, under varying pH conditions regarding their spectroscopic properties for the usage as a Förster Resonance Energy Transfer (FRET) pair to study the molecular interaction between cellulosic surfaces. All the relevant spectroscopic properties to determine the Förster distance were measured and the performance as a FRET system was checked. From the results, it is clear that the environmental conditions need to be accurately controlled as both, but especially the FTSC dyes are sensitive to changes. For high enough concentrations positive FRET systems were observed in DMF, DMSO, H2O, THF and alkaline DMF. However due to the low quantum yield of the unmodified DCCH throughout the investigated parameter range and the strong environmental dependency of FTSC, both dyes are not preferable for being used in a FRET system for studying interaction between cellulosic surfaces.


Assuntos
Cumarínicos/química , Fluoresceínas/química , Transferência Ressonante de Energia de Fluorescência/métodos , Hidrazinas/química , Solventes/química , Análise Espectral/métodos , Transferência de Energia/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Solventes/farmacologia , Espectrometria de Fluorescência/métodos , Espectrofotometria Ultravioleta/métodos
17.
Sci Rep ; 10(1): 1606, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005894

RESUMO

The aim of this study is to devise, prepare and characterize nano encapsulated auraptene (AUR) and evaluate cytotoxic and apoptotic effects on HT-29 colon cancer cells. Herein, AUR nano formulations were prepared by triblock (PCL-PEG-PCL) and pentablock (PLA-PCL-PEG-PCL-PLA) biodegradable copolymers in order to increase AUR bioavailability as an anticancer agent. The preparation of nano particles (NPs) was done with rotor stator homogenization (RSH) and Ultrasonic homogenization (USH) methods. The physicochemical characteristics of prepared nanoparticles (NPs) were studied using HNMR, FTIR, GPC, DLS and SEM techniques. The smaller hydrodynamic size (110 nm) and polydispersity index (PDI: 0.288) as well as higher cellular uptake (89%) were observed in PB NPs rather than TB NPs. The highest cytotoxic and apoptotic effects were observed in AUR loaded PB NPs compared to AUR loaded TB NPs and free AUR obtained by MTT assay, cell cycle arrest, Annexin V-FITC, DAPI staining and RT-PCR techniques. Real time PCR results indicated that Bax /Bcl2 expression ratio as an apoptosis predicting criterion, in free AUR, AUR loaded TB and AUR loaded PB have increased 6, 9 and 13 times, respectively (p value < 0.05). In conclusion, using biodegradable nano-vehicles for sustained delivery of natural anti-cancer compounds may open new perspectives for treatment of cancer patients.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/química , Neoplasias do Colo/tratamento farmacológico , Cumarínicos/química , Cumarínicos/farmacologia , Nanopartículas/química , Linhagem Celular Tumoral , Colo/efeitos dos fármacos , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Excipientes/química , Células HT29 , Humanos , Tamanho da Partícula , Poliésteres/química , Polietilenoglicóis/química
18.
Int J Pharm ; 577: 119095, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32004680

RESUMO

The objective of the study was to assess the effect of enhanced mucoadhesion of a cationic mucoadhesive nanostructured lipid carrier (NLC) on its ocular disposition after topical administration. The NLC was made mucoadhesive by surface coating with chitosan oligosaccharide (COS), a low molecular weight derivate of chitosan which is more suitable for drug delivery applications as compared to the native chitosan. The NLC was characterised by surface evaluating techniques like SANS and XPS for confirming coating of COS over the surface of NLC. In order to assess the effect of COS coating on in vivo ocular mucoadhesion, coumarin loaded NLC were topically administered to rats and the sagittal sections of the eyes were imaged using confocal microscopy. The COS coated NLC were seen to adhere more around the ocular surface than the uncoated NLC during the 4-h study. The improved ocular retention for COS-NLC reflected on the content of Etoposide within the eye, which showed a higher concentration of Etoposide, as compared to the uncoated NLC. The NLC was also assessed for any ocular irritancy in rabbits and repeat dose toxicity in rats and found to be relatively non-irritant and non-toxic as compared to appropriate controls. Thus, the study asserts that to achieve higher concentration of therapeutics within the eye, the formulations like NLC are not just required to be permeating but also retentive on the surface of the eye to achieve appreciable concentrations.


Assuntos
Quitosana/química , Sistemas de Liberação de Medicamentos , Etoposídeo/administração & dosagem , Nanoestruturas , Administração Tópica , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Cumarínicos/química , Portadores de Fármacos/química , Etoposídeo/farmacocinética , Olho/metabolismo , Lipídeos/química , Mucinas/metabolismo , Oligossacarídeos/química , Coelhos , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , Testes de Toxicidade
19.
J Colloid Interface Sci ; 569: 57-67, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105903

RESUMO

Aiming to prepare oily core pH-sensitive nanocapsules (NCs) for anticancer drugs delivery, the use of a dextran-based transurf (DexN3-τCTAγ) as both stabilizer and macromolecular chain transfer agent in methyl methacrylate/2-(diethylamino)ethyl methacrylate (MMA/DEAEMA) miniemulsion copolymerization was investigated. NCs of about 195 nm with an oily-core of Miglyol 810 (M810) and a dextran coverage covalently linked to the poly(MMA-co-DEAEMA) intern shell have been obtained. Compared to the non-sensitive PMMA-based NCs (prepared in a similar way), these novel objects were shown to swell in acidic media and to trigger Coumarin 1 release in physiological relevant pH range. As a starting point of NCs biological effects, cytotoxicity and NCs-proteins interactions studies were performed with both PMMA and poly(MMA-co-DEAEMA)-based NCs. Finally, free azide functions from dextran-based coverage were successfully exploited to attach fluorescent model dyes to NCs surface. The overall results suggest that this novel NCs platform could be potentially used as drug nanocarriers for intravenous injection.


Assuntos
Antineoplásicos/química , Dextranos/química , Metacrilatos/química , Nanocápsulas/química , Triglicerídeos/química , Albuminas/química , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Emulsões/química , Corantes Fluorescentes/química , Humanos , Concentração de Íons de Hidrogênio , Cinética , Transição de Fase , Polimerização , Polimetil Metacrilato/química , Propriedades de Superfície , Células THP-1
20.
Sci Rep ; 10(1): 2893, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32076009

RESUMO

The incidence of obesity-related diseases like diabetes, cardiovascular diseases, and different types of cancers shed light on the importance of dietary control as preventive and treatment measures. However, long-term dietary control is challenging to achieve in most individuals. The use of energy restriction mimetic agents (ERMAs) as an alternative approach to affect the energy machinery of cancer cells has emerged as a promising approach for cancer therapy. ERMAs limit the high need for energy in rapidly growing tumor cells, with their survival rate strongly dependent on the robust availability of energy. In this context, initial phenotypic screening of an in-house pilot compound library identified a new class of aminothiazole anchored on coumarin scaffold as potent anticancer lead drug candidates with potential activity as ERMA. The identified chemotypes were able to inhibit glucose uptake and increase ROS content in cancer cells. Compounds 9b, 9c, 9i, 11b, and 11c were highly active against colorectal cancer cell lines, HCT116 and HT-29, with half-maximal inhibitory concertation (IC50) range from 0.25 to 0.38 µM. Further biological evaluations of 9b and 9f using Western blotting, caspase activity, glucose uptake, ROS production, and NADPH/NADP levels revealed the ability of these lead drug candidates to induce cancer cell death via, at least in part, energy restriction. Moreover, the assessment of 9b and 9f synergistic activity with cisplatin showed promising outcomes. The current work highlights the significant potential of the lead compounds, 9b, and 9f as potential anticancer agents via targeting the cellular energy machinery in cancer cells.


Assuntos
Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Desenho de Fármacos , Metabolismo Energético/efeitos dos fármacos , Tiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Neoplasias Colorretais/patologia , Cumarínicos/síntese química , Cumarínicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Fase G1/efeitos dos fármacos , Glucose/metabolismo , Células HCT116 , Células HT29 , Humanos , Concentração Inibidora 50 , Espécies Reativas de Oxigênio/metabolismo , Tiazóis/síntese química , Tiazóis/química
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