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1.
Food Chem ; 351: 129273, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-33662907

RESUMO

Heat processing of ready-to-drink beverages is required to ensure a microbiologically safe product, however, this can result in the loss of bioactive compounds responsible for functionality. The objective of this study was to establish the thermal stability of a novel dihydrochalcone, 3',5'-di-ß-d-glucopyranosyl-3-hydroxyphloretin (2), 3',5'-di-ß-d-glucopyranosylphloretin (3) and other Cyclopia subternata phenolic compounds, in model solutions with or without citric acid and ascorbic acid. The solutions were heated at 93, 121 and 135 °C, relevant to pasteurisation, commercial sterilisation and ultra-high temperature (UHT) pasteurisation, respectively. For most compounds, the acids decreased the second order reaction rate constants, up to 27 times. Compound 2 (46.29 ± 0.53 (g/100 g)-1 h-1), and to a lesser extent compound 3 (5.94 ± 0.01 (g/100 g)-1 h-1) were the most thermo-unstable compounds when treated at 135 °C without added acids. Even though differential effects were observed for compounds at different temperatures and formulations, overall, the phenolic compounds were most stable under UHT pasteurisation conditions.


Assuntos
Bebidas/análise , Chalconas/química , Fabaceae/química , Extratos Vegetais/química , Polifenóis/química , Temperatura , Glicosilação , Pasteurização , Fenóis/análise , Soluções
2.
Molecules ; 26(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652969

RESUMO

Cytotoxic flavonoids of Murraya tetramera were investigated in this study. A novel flavonoid and twelve known flavonoids, including seven flavones (1-7), three flavanones (8-10), and three chalcones (11-13) were isolated from the leaves and twigs of Murraya tetramera. Chemical structures were elucidated by NMR combined with MS spectral analysis, and the new compound (6) was confirmed as 3',5'-dihydroxy-5,6,7,4'-tetramethoxyflavone. Furthermore, all the isolated flavonoids were evaluated for their cytotoxicities against murine melanoma cells (B16), and human breast cancer cells (MDA-MB-231) by CCK-8 assay. Among them, compounds 7, 13, and 5 exhibited potent cytotoxic activities against B16 cell lines (IC50 = 3.87, 7.00 and 8.66 µg/mL, respectively). Compounds 5, 13, and 12 displayed potent cytotoxicities against MDA-MB-231 cell lines (IC50 = 3.80, 5.95 and 7.89 µg/mL, respectively). According to the correlation of the structure and activity analysis, 5-hydroxyl and 8-methoxyl substituents of the flavone, 8-methoxyl substituent of the flavanone, and 3',5'-methoxyl substituents of the chalcone could be critical factors of the high cytotoxicity. The results indicated that the active flavonoids have potential to be developed as leading compounds for treating cancers.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Flavonoides/farmacologia , Murraya/química , Animais , Antineoplásicos Fitogênicos/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chalconas/química , Chalconas/farmacologia , Feminino , Flavonoides/química , Humanos , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química
3.
Int J Mol Sci ; 22(2)2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33467209

RESUMO

Skeletal muscle is the most abundant tissue and constitutes about 40% of total body mass. Herein, we report that crude water extract (CWE) of G. uralensis enhanced myoblast proliferation and differentiation. Pretreatment of mice with the CWE of G. uralensis prior to cardiotoxin-induced muscle injury was found to enhance muscle regeneration by inducing myogenic gene expression and downregulating myostatin expression. Furthermore, this extract reduced nitrotyrosine protein levels and atrophy-related gene expression. Of the five different fractions of the CWE of G. uralensis obtained, the ethyl acetate (EtOAc) fraction more significantly enhanced myoblast proliferation and differentiation than the other fractions. Ten bioactive compounds were isolated from the EtOAc fraction and characterized by GC-MS and NMR. Of these compounds (4-hydroxybenzoic acid, liquiritigenin, (R)-(-)-vestitol, isoliquiritigenin, medicarpin, tetrahydroxymethoxychalcone, licochalcone B, liquiritin, liquiritinapioside, and ononin), liquiritigenin, tetrahydroxymethoxychalcone, and licochalcone B were found to enhance myoblast proliferation and differentiation, and myofiber diameters in injured muscles were wider with the liquiritigenin than the non-treated one. Computational analysis showed these compounds are non-toxic and possess good drug-likeness properties. These findings suggest that G. uralensis-extracted components might be useful therapeutic agents for the management of muscle-associated diseases.


Assuntos
Glycyrrhiza uralensis/química , Atrofia Muscular/tratamento farmacológico , Extratos Vegetais/química , Animais , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Chalconas/química , Chalconas/farmacologia , Chalconas/uso terapêutico , Flavanonas/química , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mioblastos/citologia , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Miostatina/genética , Miostatina/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Tirosina/análogos & derivados , Tirosina/metabolismo
4.
Molecules ; 26(2)2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33419109

RESUMO

Bidens pilosa L. (Asteraceae) has been used historically in traditional Asian medicine and is known to have a variety of biological effects. However, the specific active compounds responsible for the individual pharmacological effects of Bidens pilosa L. (B. pilosa) extract have not yet been made clear. This study aimed to investigate the anti-inflammatory phytochemicals obtained from B. pilosa. We isolated a flavonoids-type phytochemical, isookanin, from B. pilosa through bioassay-guided fractionation based on its capacity to inhibit inflammation. Some of isookanin's biological properties have been reported; however, the anti-inflammatory mechanism of isookanin has not yet been studied. In the present study, we evaluated the anti-inflammatory activities of isookanin using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We have shown that isookanin reduces the production of proinflammatory mediators (nitric oxide, prostaglandin E2) by inhibiting the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-stimulated macrophages. Isookanin also inhibited the expression of activator protein 1 (AP-1) and downregulated the LPS-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-jun NH2-terminal kinase (JNK) in the MAPK signaling pathway. Additionally, isookanin inhibited proinflammatory cytokines (tumor necrosis factor-a (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-1ß (IL-1ß)) in LPS-induced THP-1 cells. These results demonstrate that isookanin could be a potential therapeutic candidate for inflammatory disease.


Assuntos
Anti-Inflamatórios , Bidens/química , Bioensaio , Chalconas , Macrófagos/metabolismo , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Chalconas/química , Chalconas/isolamento & purificação , Chalconas/farmacologia , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Monocinas/metabolismo , Células RAW 264.7 , Células THP-1
5.
J Agric Food Chem ; 69(1): 555-567, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33356228

RESUMO

Dihydrochalcones are a subclass of flavonoids. There has been growing interest in dihydrochalcones for their health benefits and potential to modulate flavor, but their comprehensive profile in diverse plant species is lacking. Star fruit is a tropical fruit rich in dihydrochalcones. In this study, a systematic annotation using UHPLC/Q-Orbitrap-MS and molecular networking was established to rapidly identify dihydrochalcones in 12 star fruit cultivars. A total of 53 dihydrochalcones were characterized within a short retention time including one novel compound (phloretin-3'-C-(2-O-trans-p-coumaroyl)-ß-d-fucopyranoside) and 23 compounds identified from the Averrhoa genus for the first time. 3-Hydroxyphloretin was the most abundant dihydrochalcone in star fruit. All the identified dihydrochalcones had a higher abundance in leaves compared to fruits. This is the first report that systematically investigates dihydrochalcones in star fruit of multiple cultivars, and the results could provide a useful reference for the future development and utilization of plant genetic resources.


Assuntos
Averrhoa/química , Chalconas/química , Cromatografia Líquida de Alta Pressão/métodos , Frutas/química , Espectrometria de Massas/métodos , Extratos Vegetais/química , Estrutura Molecular
6.
Eur J Pharmacol ; 886: 173448, 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-32768503

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is distinctly infective and there is an ongoing effort to find a cure for this pandemic. Flavonoids exist in many diets as well as in traditional medicine, and their modern subset, indole-chalcones, are effective in fighting various diseases. Hence, these flavonoids and structurally similar indole chalcones derivatives were studied in silico for their pharmacokinetic properties including absorption, distribution, metabolism, excretion, toxicity (ADMET) and anti-SARS-CoV-2 properties against their proteins, namely, RNA dependent RNA polymerase (rdrp), main protease (Mpro) and Spike (S) protein via homology modelling and docking. Interactions were studied with respect to biology and function of SARS-CoV-2 proteins for activity. Functional/structural roles of amino acid residues of SARS-CoV-2 proteins and, the effect of flavonoid and indole chalcone interactions which may cause disease suppression are discussed. The results reveal that out of 23 natural flavonoids and 25 synthetic indole chalcones, 30 compounds are capable of Mpro deactivation as well as potentially lowering the efficiency of Mpro function. Cyanidin may inhibit RNA polymerase function and, Quercetin is found to block interaction sites on the viral spike. These results suggest flavonoids and their modern pharmaceutical cousins, indole chalcones are capable of fighting SARS-CoV-2. The in vitro anti-SARS-CoV-2 activity of these 30 compounds needs to be studied further for complete understanding and confirmation of their inhibitory potential.


Assuntos
Betacoronavirus/efeitos dos fármacos , Chalconas/química , Chalconas/farmacologia , Flavonoides/farmacologia , Indóis/química , Simulação de Acoplamento Molecular , Proteínas Virais/metabolismo , Betacoronavirus/metabolismo , Chalconas/metabolismo , Chalconas/farmacocinética , Simulação por Computador , Flavonoides/metabolismo , Flavonoides/farmacocinética , Conformação Proteica , Segurança , Distribuição Tecidual , Proteínas Virais/química
7.
Chem Biol Interact ; 324: 109084, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32289290

RESUMO

INTRODUCTION: An imbalance between oxidants and antioxidants in favour of oxidants, potentially leading to damage, is termed oxidative stress. Antioxidants (AO), either enzymatic or non-enzymatic, are the ones that can reduce diverse effects of pro-oxidants such as DNA, proteins and lipids damage. Chalcones (1,3-diaryl-2-propen-1-ones) are open chain flavonoids that are widely biosynthesized in plants. Aim of this study was to test antioxidative potency of 15 chalcones (Chs) in in vitro model in serum (native conditions), so as with exogenously induced oxidative stress. MATERIAL AND METHODS: Oxidative stress was induced in serum samples of healthy individuals with 0.25 mmol/L terc-buthyl-hydroperoxide (TBH), and then we monitored the effects of various concentrations of chalcones on oxidative stress parameters: total antioxidative status (TAS), total oxidative status (TOS), total concentration of sulfhydryl group (SHG) and prooxidative-antioxidative balance (PAB), and calculated prooxidative score, antioxidative score, and oxy score (OS). Nonparametric repeated measures ANOVA (Friedman's test) was used for comparison of antioxidative potency of samples with 15 different chalcones, in a native state and upon TBH influence. Spearman's nonparametric correlation analysis was used for estimation of relation between different parameters. RESULTS: Negative Oxy Score (OS) values for Chs11-15 showed significantly stronger antioxidative potency compared to other investigated chalcones (p < 0.05). Ch11, Ch13 and Ch14 remained with negative OS even after TBH addition, whereas OS of Ch12 and Ch15 became positive, with small nominal values. Samples with Ch11 and Ch13 showed significant negative correlation between TAS and TOS (p < 0.05 for both), but in Ch14 sample the negative correlation existed between TAS and PAB (p < 0.05). CONCLUSION: Lower value of OS (i.e. better antioxidative potency) was noticed in samples with Ch11-Ch15. Electron-donor effects of substituent groups as a structural part of these chalcones could explain its antioxidative capability. Phenolic and methyl groups are responsible for antioxidative ability enhancement of five chalcones with the best activity.


Assuntos
Antioxidantes/farmacologia , Sangue/metabolismo , Chalconas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/síntese química , Antioxidantes/química , Sangue/efeitos dos fármacos , Chalconas/síntese química , Chalconas/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , terc-Butil Hidroperóxido/farmacologia
8.
Eur J Med Chem ; 193: 112216, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32208222

RESUMO

Inflammation is a complex biological response to stimuli. Activated macrophages induced excessively release of pro-inflammatory cytokines and mediators such as endogenous radical nitric oxide (NO) play a significant role in the progression of multiple inflammatory diseases. Both natural and synthetic chalcones possess a wide range of bioactivities. In this work, thirty-nine chalcones and three related compounds, including several novel ones, based on bioactive kava chalcones were designed, synthesized and their inhibitory effects on NO production in RAW 264.7 cells were evaluated. The novel compound (E)-1-(2'-hydroxy-4',6'-dimethoxyphenyl)-3-(3-methoxy-4-(3-morpholinopropoxy)phenyl)prop-2-en-1-one (53) exhibited a better inhibitory activity (84.0%) on NO production at 10 µM (IC50 = 6.4 µM) with the lowest cytotoxicity (IC50 > 80 µM) among the tested compounds. Besides, western blot analysis indicated that compound 53 was a potent down-regulator of inducible nitric oxide synthase (iNOS) protein. Docking study revealed that compound 53 also can dock into the active site of iNOS. Furthermore, at the dose of 10 mg/kg/day, compound 53 could both significantly suppress the progression of inflammation on collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) models. In addition, the structure-activity relationship (SAR) of the kava chalcones based analogs was also depicted.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite/tratamento farmacológico , Chalconas/farmacologia , Desenvolvimento de Medicamentos , Inflamação/tratamento farmacológico , Óxido Nítrico/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Artrite/induzido quimicamente , Artrite/metabolismo , Células Cultivadas , Chalconas/síntese química , Chalconas/química , Doença Crônica , Colágeno , Relação Dose-Resposta a Droga , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos DBA , Estrutura Molecular , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-Atividade
9.
Biochem Pharmacol ; 175: 113848, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32044354

RESUMO

The enhancement of drug efflux caused by ATP-binding cassette (ABC) transporters (including ABCG2 and ABCB1) overexpression is an important factor for multidrug resistance (MDR) in cancers. After testing the reversal activities of 19 chalcone and bis-chalcone derivatives on MDR cancer cell lines, we found that non-basic chalcone CYB-2 exhibited the most potent reversal activities against both ABCG2- and ABCB1-mediated MDR. The mechanistic studies show that this compound can increase the accumulation of anticancer drugs in both ABCG2- and ABCB1-overexpressing cancer cell lines, resulting from the blocked efflux function of the MDR cancer cell lines. This inhibition is due to the barred ABCG2 and ABCB1 ATPase activities rather than altering the expression or localization of ABCG2 or ABCB1 transporters. The previous studies showed that non-basic chalcones were ABCG2-specific inhibitors; however, we found that non-basic chalcone CYB-2 can be developed as an ABCG2/ABCB1 dual inhibitor to overcome MDR in cancers that co-express both ABCG2 and ABCB1. Moreover, non-basic chalcone CYB-2 has synthetic tractability compared to other chalcone-based derivatives.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Chalconas/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Neoplasias/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/química , Linhagem Celular Tumoral , Chalconas/química , Humanos , Simulação de Acoplamento Molecular , Proteínas de Neoplasias/genética
10.
Molecules ; 25(3)2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32033283

RESUMO

To elucidate the mechanism of anti-ferroptosis and examine structural optimization in natural phenolics, cellular and chemical assays were performed with 2'-hydroxy chalcone butein and dihydroflavone (S)-butin. C11-BODIPY staining and flow cytometric assays suggest that butein more effectively inhibits ferroptosis in erastin-treated bone marrow-derived mesenchymal stem cells than (S)-butin. Butein also exhibited higher antioxidant percentages than (S)-butin in five antioxidant assays: linoleic acid emulsion assay, Fe3+-reducing antioxidant power assay, Cu2+-reducing antioxidant power assay, 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide radical (PTIO•)-trapping assay, and α,α-diphenyl-ß-picrylhydrazyl radical (DPPH•)-trapping assay. Their reaction products with DPPH• were further analyzed using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC-ESI-Q-TOF-MS). Butein and (S)-butin produced a butein 5,5-dimer (m/z 542, 271, 253, 225, 135, and 91) and a (S)-butin 5',5'-dimer (m/z 542, 389, 269, 253, and 151), respectively. Interestingly, butein forms a cross dimer with (S)-butin (m/z 542, 523, 433, 419, 415, 406, and 375). Therefore, we conclude that butein and (S)-butin exert anti-ferroptotic action via an antioxidant pathway (especially the hydrogen atom transfer pathway). Following this pathway, butein and (S)-butin yield both self-dimers and cross dimers. Butein displays superior antioxidant or anti-ferroptosis action to (S)-butin. This can be attributed the decrease in π-π conjugation in butein due to saturation of its α,ß-double bond and loss of its 2'-hydroxy group upon biocatalytical isomerization.


Assuntos
Antioxidantes/farmacologia , Chalconas/química , Chalconas/farmacologia , Ferroptose/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Antioxidantes/química , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Chalcona/análogos & derivados , Chalcona/química , Cromatografia Líquida de Alta Pressão , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/efeitos dos fármacos , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
11.
Molecules ; 25(3)2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32012805

RESUMO

In folk medicine, Stahlianthus thorelii Gagnep. has been used to treat diseases related to inflammation, ulcers, and cancer. There are no reports concerning the chemical components and bioactivities of S. thorelii; thus, this study aims to explore the phytochemicals, quantify the main compounds, and test the anticancer activity of isolates from S. thorelii. Dried rhizomes were extracted with 95% ethanol and, then, partitioned, fractionated, and isolated. On the basis of the result of the antiproliferative activity of the fractions, seven isolates were yielded and were identified by spectroscopic analyses. The inhibition of cancer proliferation was determined by an MTT assay and the deployed IC50 to value their efficacy. Seven compounds containing one new C-benzylated dihydrochalcone derivative, thorechalcone A (1) and 2-7 were isolated from S. thorelii. In terms of the bioactivity, compounds 1 and 3 displayed promising antiproliferative activity (WiDr, A549, and HepG2), with IC50 values <40 µM. The HPLC-UV method of quantification of two major compounds (3 and 4) was also validated. This study presented the isolations of antiproliferative potentials of new chalcone and known flavonoid derivatives from S. thorelii. The validated simple, accurate, and rapid HPLC method could be deployed for the quality control of herbal drugs.


Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Chalconas/isolamento & purificação , Flavonoides/isolamento & purificação , Zingiberaceae/química , Células A549 , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chalconas/química , Chalconas/farmacologia , Cromatografia Líquida de Alta Pressão , Flavonoides/química , Flavonoides/farmacologia , Células Hep G2 , Humanos , Concentração Inibidora 50 , Células MCF-7 , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia
12.
J Antibiot (Tokyo) ; 73(5): 299-308, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31988484

RESUMO

The swift spread of infections caused by drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), has quickly become a worldwide concern as infections spread from healthcare settings to the wider community. While ferrocenyl chalcones, which are chalcone derivatives with antimicrobial activity, have gained attention from researchers, further study is needed to assess their cytotoxicity. Ten newly developed chalcones, in which ring A was replaced with a ferrocenyl moiety and ring B contained increasing alkyl chain lengths from 1 to 10 carbons, were assessed. Using twofold broth microdilution, the minimum inhibitory concentration (MIC) of five of the ten compounds were lower against Gram-positive organisms (MICs from 0.008 mg ml-1 to 0.063 mg ml-1) than Gram-negative organisms (MICs = 0.125 mg ml-1). These novel ferrocenyl chalcone compounds were effective against three types of clinically isolated drug-resistant S. aureus, including an MRSA, and against other non-resistant clinically isolated and laboratory-adapted Gram-positive bacteria. The same compounds inhibited growth in non-resistant bacteria by potentially obstructing cellular respiration in Gram-positive bacteria. Images obtained through scanning electron microscopy revealed fully lysed bacterial cells once exposed to a selected compound that showed activity. The results indicate that these newly developed compounds could be important antimicrobial agents in the treatment of infections from clinically resistant bacteria.


Assuntos
Antibacterianos/farmacologia , Chalconas/farmacologia , Compostos Ferrosos/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Metalocenos/química , Antibacterianos/síntese química , Antibacterianos/química , Chalconas/síntese química , Chalconas/química , Farmacorresistência Bacteriana , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Relação Estrutura-Atividade
13.
Comput Biol Chem ; 84: 107189, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31891900

RESUMO

A series of indole-derived methoxylated chalcones were described as anti-dermatophyte agents. The in vitro antifungal susceptibility testing against different dermatophytes revealed that most of compounds had potent activity against the dermatophyte strains. In particular, the 4-ethoxy derivative 4d with MIC values of 0.25-2 µg/ml was the most potent compound against Trichophyton interdigitale, Trichophyton veruccosum and Microsporum fulvum. Moreover, the 4-butoxy analog 4i displaying MIC values in the range of 1-16 µg/ml had the highest inhibitory activity against Trichophyton mentagrophytes, Microsporum canis, and Arthroderma benhamiae. To predict whether the synthesized compounds interact with tubulin binding site of dermatophytes, the 3D-structure of target protein was modeled by homology modeling and then used for molecular docking and molecular dynamics (MD) simulation studies. Docking simulation revealed that the promising compound 4d can properly bind with tubulin. The molecular dynamics analysis showed that interactions of compound 4d with the active site of target protein have binding stability throughout MD simulation. The results of this study could utilize in the design of more effective antifungal drugs with tubulin inhibition mechanism against keratinophilic fungi.


Assuntos
Antifúngicos/farmacologia , Chalconas/farmacologia , Indóis/farmacologia , Sequência de Aminoácidos , Antifúngicos/química , Antifúngicos/metabolismo , Arthrodermataceae/efeitos dos fármacos , Sítios de Ligação , Chalconas/química , Chalconas/metabolismo , Humanos , Indóis/química , Indóis/metabolismo , Testes de Sensibilidade Microbiana , Fungos Mitospóricos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Alinhamento de Sequência , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo
14.
Eur J Med Chem ; 189: 112062, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31986406

RESUMO

A new series of 1,2,3-triazole-chalcone hybrids has been synthesized and screened in vitro against a panel of 60 human cancer cell lines according to NCI (USA) protocol. Compound 4d having 3, 4-dimethoxyphenyl chalcone moiety, the most potent derivative, inhibited the growth of RPMI-8226 and SR leukemia cell lines by 99.73% and 94.95% at 10 µM, respectively. Also, it inhibited the growth of M14 melanoma, K-562 leukemia, and MCF7 breast cancer cell lines by more than 80% at the same test concentration. 4d showed IC50 values less than 1 µM on six types of tumor cells and high selectivity index reached to 104 fold on MCF7. Compound 4d showed superior activity than methotrexate and gefitinib against the most sensitive leukemia cell lines in addition to higher or comparable activity against the rest sensitive cell lines. Flow cytometry analysis in RPMI-8226 cells revealed that compound 4d caused cell cycle arrest at G2/M phase and induced apoptosis in a dose dependant manner. Mechanistic evaluation referred this apoptosis induction to triggering mitochondrial apoptotic pathway through inducing ROS accumulation, increasing Bax/Bcl-2 ratio and activation of caspases 3, 7 and 9.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose , Chalconas/química , Mieloma Múltiplo/patologia , Triazóis/química , Caspase 3/metabolismo , Ciclo Celular , Proliferação de Células , Humanos , Estrutura Molecular , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
15.
J Enzyme Inhib Med Chem ; 35(1): 139-144, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31724435

RESUMO

A series of naphthalene-chalcone derivatives (3a-3t) were prepared and evaluated as tubulin polymerisation inhibitor for the treatment of breast cancer. All compounds were evaluated for their antiproliferative activity against MCF-7 cell line. The most of compounds displayed potent antiproliferative activity. Among them, compound 3a displayed the most potent antiproliferative activity with an IC50 value of 1.42 ± 0.15 µM, as compared to cisplatin (IC50 = 15.24 ± 1.27 µM). Additionally, the promising compound 3a demonstrated relatively lower cytotoxicity on normal cell line (HEK293) compared to tumour cell line. Furthermore, compound 3a was found to induce significant cell cycle arrest at the G2/M phase and cell apoptosis. Compound 3a displayed potent tubulin polymerisation inhibitory activity with an IC50 value of 8.4 µM, which was slightly more active than the reference compound colchicine (IC50 = 10.6 µM). Molecular docking analysis suggested that 3a interact and bind at the colchicine binding site of the tubulin.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Chalconas/farmacologia , Naftalenos/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalconas/química , Colchicina/antagonistas & inibidores , Colchicina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Naftalenos/química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
16.
DNA Repair (Amst) ; 86: 102765, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31846836

RESUMO

Cancer, also called malignancy, is a disease which is closely related with the oxidative stress instigated by the overproduction of vulnerable oxygen and nitrogen species. Available drugs are relatively painful and toxic and so are trailing their captivation. Keeping this in mind, we have attempted to reach a novel anti-cancer drug by taking a set of nineteen ligands which are hybrids of Indole-chalcone and triazole. These ligands were allowed to interact with the DNA dodecamer 5'(CGCGAATTCGCG)3' one by one using various docking protocols of Glide. Better docked complexes screened through docking scores and reported activity data were selected and exposed to molecular dynamics run of 20 ns. The dynamical pathways were investigated for each complex comparing the pre- and post- dynamics run. The outcome of the work is discussed in this paper. Among the better hybrids of this series, one of the molecules has shown interesting features, confirming its non-toxic nature and working as intercalator as well minor groove binder, perhaps making it suitable as a potent drug for further pharmacological use.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Chalconas/química , Compostos Heterocíclicos/farmacologia , Indóis/química , Triazóis/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Ligação de Hidrogênio , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular
17.
Eur J Med Chem ; 187: 111980, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31877539

RESUMO

Chalcones, containing an α,ß-unsaturated ketone fragment, are an important pharmacologically active agents because of their diverse mechanisms. This review provides an update on the recent developments (2009-2019.3) in the antibacterial activity of natural and synthetic chalcones. Moreover, the structure-activity relationships and mechanisms are also carefully summarized which will provide some important guidance for design and synthesis in future. This comprehensive and critical review will be helpful for medicinal chemists to develop more candidate antibacterial agents.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Chalconas/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Chalconas/síntese química , Chalconas/química , Química Farmacêutica , Humanos , Testes de Sensibilidade Microbiana
18.
Cell Biochem Biophys ; 78(1): 65-76, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31707583

RESUMO

Esophageal cancer is one of the malignant cancers with a low 5-year survival rate. Licochalcone (LC) H, a chemically synthesized substance, is a regioisomer of LCC extracted from licorice. The purpose of this study was to determine whether LCH might have anticancer effect on human esophageal squamous cell carcinoma (ESCC) cell lines via apoptosis signaling pathway. After 48 h of treatment, IC50 of LCH in KYSE 30, KYSE 70, KYSE 410, KYSE 450, and KYSE 510 cells were 15, 14, 18, 15, and 16 µM, respectively. This study demonstrated that LCH potently suppressed proliferation of ESCC cells in a concentration- and time-dependent manner. LCH triggered G2/M-phase arrest by modulating expression levels of cdc2, cyclin B1, p21, and p27. LCH also induced apoptosis of ESCC cells through reactive oxygen species-mediated endoplasmic reticulum (ER) stress via JNK/p38 activation pathways. The anticancer effect of LCH was associated with ER stress and mitochondrial dysfunction. It also affected protein levels of Mcl-1, tBid, Bax, Bcl-2, cytochrome c, Apaf-1, PARP, cleaved-PARP, and ER stress-related proteins (GRP78 and CHOP). Our findings provide the first demonstration that LCH has anticancer effect on ESCC. Thus, LCH might have potential for preventing and/or treating human ESCC.


Assuntos
Apoptose , Chalconas/química , Glycyrrhiza/química , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Chalconas/síntese química , Chalconas/isolamento & purificação , Chalconas/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Glycyrrhiza/metabolismo , Humanos , Janus Quinases/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/química , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Drug Dev Res ; 81(1): 85-92, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31693211

RESUMO

Acute lung injury (ALI) is a clinical syndrome characterized by respiratory failure and acute inflammatory response. Myeloid differentiation protein 2 (MD2) has been reported to play a pivotal role in the recognition of LPS and LPS-mediates inflammatory response. There have been no clinically effective therapeutic drugs for ALI. L6H9, an inhibitor of MD2, showed anti-inflammatory effects and cardiac protective activity. However, its effect on ALI has not been elucidated. In this study, intratracheal instillation of LPS was employed to induce ALI in rats. L6H9 pretreatment attenuates LPS-induced pathological variations in lung tissue and pulmonary edema. LPS instillation enhanced lung microvascular permeability, thereby causing inflammatory cells flow into bronchoalveolar lavage fluid (BALF). However, L6H9 inhibited the LPS-induced upregulation of total protein concentration and the number of inflammatory cells in BALF. In the meantime, macrophages infiltration in lung tissue induced by LPS was also mitigated by L6H9 treatment. Furthermore, L6H9 suppressed LPS-induced inflammatory cytokines expression in BALF, serum, and lung tissue. It is noteworthy that LPS-induced MD2/TLR4 complex formation was inhibited by L6H9 in lung tissue. On the whole, these results show that L6H9 can attenuate LPS-induced ALI in vivo by targeting MD2. Our study provide new candidate for the treatment of ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Chalconas/administração & dosagem , Lipopolissacarídeos/efeitos adversos , Antígeno 96 de Linfócito/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Chalconas/química , Chalconas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Instilação de Medicamentos , Masculino , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
20.
Nat Prod Res ; 34(7): 930-934, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30584772

RESUMO

A new dihydrochalcone, namely 2',5'-dimethyl-3'-methoxy-4',6'-dihydroxyl-dihydrochalcone (1) together with five known compounds were isolated from the CHCl3 extract from Empetrum nigrum L. var. japonicum K. Koch (E. nigrum). The structures of 1 was elucidated by spectroscopic methods, including UV, IR, HR-ESI-MS and extensive 1D and 2D NMR techniques.


Assuntos
Chalconas/isolamento & purificação , Ericaceae/química , Chalconas/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Extratos Vegetais/química , Análise Espectral
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