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1.
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
2.
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
3.
Int J Vitam Nutr Res ; 90(5-6): 411-416, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30961461

RESUMO

Chalcones are a type of flavonoids characterized by an α-ß unsaturated structural element which may react with thiol groups to activate pathways such as the Nrf2-Keap-1 system. Naringenin chalcone is abundant in the diet but little is known about its bioavailability. In this work, the bioavailability of naringenin chalcone from tomatoes was investigated in a group of healthy men (n=10). After ingestion of 600 grams of tomatoes providing a single dose of 17.3 mg naringenin chalcone, 0.2 mg of naringenin, and 195 mg naringin plasma levels of free and conjugated naringenin and naringenin chalcone (glucuronide and sulfate) were analyzed by UHPLC-QTOF-MS at 0.5, 1, 3, and 6 h post-consumption. Plasma levels of conjugated naringenin increased to about 12 nmol/L with a maximum at about 3 h. Concentrations of free naringenin hardly elevated above baseline. Plasma levels of free and conjugated naringenin chalcone significantly increased. A maximum of the conjugated chalcone was reached at about 3 h after ingestion with an average concentration of about 0.5 nmol/L. No free chalcone was detectable at baseline but low amounts of the unconjugated compound could be detected with an average maximum of 0.8 nmol/L at about 1 h after ingestion. The data demonstrate that naringenin chalcone is bioavailable in humans from cherry tomatoes as a dietary source. However, availability is poor and intramolecular cyclisation as well as extended metabolism likely contribute to the inactivation of the reactive alpha-beta unsaturated reactive center as well as the excretion of the biologically active molecule, respectively.


Assuntos
Chalconas/metabolismo , Lycopersicon esculentum , Disponibilidade Biológica , Flavonoides/metabolismo , Humanos , Masculino
4.
Food Chem Toxicol ; 136: 111027, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31870919

RESUMO

The incubation system of CYP2E1 and CYP3A4 enzymes in rat liver microsomes was established to investigate the effects of psoralidin, isobavachalcone, neobavaisoflavone and daidzein from Fructus Psoraleae in vitro. The relevant metabolites were measured by the method of high performance liquid chromatography (HPLC), after probe substrates of 4-nitrophenol, testosterone and the drugs at different concentrations were added to the incubation systems. In addition, real-time RT-PCR was performed to determine the effect of psoralidin, neobavaisoflavone and daidzein on the mRNA expression of CYP3A4 in rat liver. The results suggested that psoralidin, isobavachalcone and neobavaisoflavone were Medium-intensity inhibitors of CYP2E1 with Ki values of 2.58, 1.28 and 19.07 µM, respectively, which could inhibit the increase of CYP2E1 and reduce diseases caused by lipid peroxidation. Isobavachalcone (Ki = 37.52 µM) showed a weak competitive inhibition on CYP3A4. Psoralidin and neobavaisoflavone showed obvious induction effects on CYP3A4 in the expression level of mRNA, which could accelerate the effects of drug metabolism and lead to the risk of inducing DDIs and serious adverse reactions. The results could be used for guideline of Fructus Psoraleae in clinic, which aimed to calculate the drug toxicity by studying the drug-drug interactions caused by the induction and inhibition of CYP450.


Assuntos
Benzofuranos/toxicidade , Chalconas/toxicidade , Cumarínicos/toxicidade , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP3A/metabolismo , Isoflavonas/toxicidade , Microssomos Hepáticos/metabolismo , Animais , Benzofuranos/metabolismo , Chalconas/metabolismo , Cumarínicos/metabolismo , Inibidores do Citocromo P-450 CYP2E1/metabolismo , Inibidores do Citocromo P-450 CYP2E1/toxicidade , Inibidores do Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/toxicidade , Interações Medicamentosas , Isoflavonas/metabolismo , Ratos Sprague-Dawley
5.
Med Chem ; 16(2): 212-228, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31146672

RESUMO

BACKGROUND: Novel 4-[3-(6/7/8-Substituted 4-Oxo-4H-chromen-3-yl)acryloyl]phenylboronic acid derivatives (5a-h) as well as other 6/7/8-substituted-3-(3-oxo-3-(4-substitutedphenyl) prop-1-enyl)-4H-chromen-4-one derivatives (3a-u) have been designed as p53-MDM2 pathway inhibitors and reported to possess significant cytotoxic properties against several cancer cell lines. OBJECTIVES: The current project aims to frame the structure-anticancer activity relationship of chromen-4-on-3-yl chalcones (3a-u/5a-h). In addition, docking studies were performed on these chromeno-chalcones in order to have an insight into their interaction possibilities with MDM2 protein. METHODS: Twenty-nine chromen-4-on-3-yl chalcone derivatives (3a-u/5a-h) were prepared by utilizing silica supported-HClO4 (green route with magnificent yield) and tested against four cancer cell lines (HCT116, MCF-7, THP-1, NCIH322). RESULTS: Among the series 3a-u, compound 3b exhibited the highest anticancer activity (with IC50 values ranging from 8.6 to 28.4 µM) overall against tested cancer cell lines. Interestingly, para- Boronic acid derivative (5b) showed selective inhibition against colon cancer cell line, HCT-116 with an IC50 value of 2.35 µM. Besides the emblematic hydrophobic interactions of MDM2 inhibitors, derivative 5b was found to exhibit extra hydrogen bonding with GLN59 and GLN72 residues of MDM2 in molecular dynamics (MD) simulation. All the compounds were virtually nontoxic against normal fibroblast cells. CONCLUSION: Novel compounds were obtained with good anticancer activity especially 6- Chlorochromen-4-one substituted boronic acid derivative 5b. The molecular docking study proposed good activity as a MDM-2 inhibitor suggesting hydrophobic as well as hydrogen bonding interactions with MDM2.


Assuntos
Benzopiranos/química , Ácidos Borônicos/química , Chalconas/síntese química , Chalconas/farmacologia , Desenho de Fármacos , Simulação de Acoplamento Molecular , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Chalconas/química , Chalconas/metabolismo , Técnicas de Química Sintética , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Dinâmica Molecular , Conformação Proteica , Proteínas Proto-Oncogênicas c-mdm2/química , Relação Estrutura-Atividade
6.
Oxid Med Cell Longev ; 2019: 1670759, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885773

RESUMO

Neuroblastoma is an embryonal malignancy that arises from cells of sympathoadrenal lineage during the development of the nervous system. It is the most common pediatric extracranial solid tumor and is responsible for 15% of childhood deaths from cancer. Fifty percent of cases are diagnosed as high-risk metastatic disease with a low overall 5-year survival rate. More than half of patients experience disease recurrence that can be refractory to treatment. Amplification of the MYCN gene is an important prognostic indicator that is associated with rapid disease progression and a poor prognosis, highlighting the need for new therapeutic approaches. In recent years, there has been an increasing focus on identifying anticancer properties of naturally occurring chalcones, which are secondary metabolites with variable phenolic structures. Here, we report that 4-hydroxychalcone is a potent cytotoxin for MYCN-amplified IMR-32 and SK-N-BE (2) neuroblastoma cells, when compared to non-MYCN-amplified SH-SY5Y neuroblastoma cells and to the non-neuroblastoma human embryonic kidney cell line, HEK293t. Moreover, 4-hydroxychalcone treatment significantly decreased cellular levels of the antioxidant glutathione and increased cellular reactive oxygen species. In addition, 4-hydroxychalcone treatment led to impairments in mitochondrial respiratory function, compared to controls. In support of this, the cytotoxic effect of 4-hydroxychalcone was prevented by co-treatment with either the antioxidant N-acetyl-L-cysteine, a pharmacological inhibitor of oxidative stress-induced cell death (IM-54) or the mitochondrial reactive oxygen species scavenger, Mito-TEMPO. When combined with the anticancer drugs cisplatin or doxorubicin, 4-hydroxychalcone led to greater reductions in cell viability than was induced by either anti-cancer agent alone. In summary, this study identifies a cytotoxic effect of 4-hydroxychalcone in MYCN-amplified human neuroblastoma cells, which rationalizes its further study in the development of new therapies for pediatric neuroblastoma.


Assuntos
Morte Celular/genética , Chalconas/metabolismo , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/genética , Linhagem Celular Tumoral , Humanos , Neuroblastoma/patologia , Estresse Oxidativo
7.
Malar J ; 18(1): 388, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791339

RESUMO

BACKGROUND: Malaria kills over 400,000 people each year and nearly half the world's population live in at-risk areas. Progress against malaria has recently stalled, highlighting the need for developing novel therapeutics. The parasite haemoglobin degradation pathway, active in the blood stage of the disease where malaria symptoms and lethality manifest, is a well-established drug target. A key enzyme in this pathway is the papain-type protease falcipain-2. METHODS: The crystallographic structure of falcipain-2 at 3.45 Å resolution was resolved in complex with an (E)-chalcone small-molecule inhibitor. The falcipain-2-(E)-chalcone complex was analysed with reference to previous falcipain complexes and their similarity to human cathepsin proteases. RESULTS: The (E)-chalcone inhibitor binds falcipain-2 to the rear of the substrate-binding cleft. This is the first structure of a falcipain protease where the rear of the substrate cleft is bound by a small molecule. In this manner, the (E)-chalcone inhibitor mimics interactions observed in protein-based falcipain inhibitors, which can achieve high interaction specificity. CONCLUSIONS: This work informs the search for novel anti-malaria therapeutics that target falcipain-2 by showing the binding site and interactions of the medically privileged (E)-chalcone molecule. Furthermore, this study highlights the possibility of chemically combining the (E)-chalcone molecule with an existing active-site inhibitor of falcipain, which may yield a potent and selective compound for blocking haemoglobin degradation by the malaria parasite.


Assuntos
Chalconas/metabolismo , Cisteína Endopeptidases/metabolismo , Plasmodium falciparum/metabolismo , Cisteína Endopeptidases/genética
8.
Molecules ; 24(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614687

RESUMO

The demand for licorice and its natural product derivatives in domestic and foreign market is considerably huge. The core production areas of licorice are covered with salinity and drought land in northwestern China. Studies have shown that suitable environmental stress can promote the accumulation of glycyrrhizin and liquiritin to improve its quality as medicinal materials. However, there are few reports on other bioactive constituents of licorice, not to mention their dynamic accumulation under stressed conditions. To explore the quality formation of licorice from the perspective of salt influence, a reliable method based on ultra-fast liquid chromatography tandem triple quadrupole mass spectrometry (UFLC-MS/MS) was established for simultaneous determination of sixteen bioactive constituents, including triterpenoids, flavonoids, chalcones and their glycosides. Physiological experiments were performed to investigate salt tolerance of licorice under different salinity treatments. The expressions of crucial genes (bAS and CHS), key enzymes of triterpenoid and flavonoid synthesis, were also tested by qRT-PCR. Our study found that 50 mM NaCl treatment (low stress) was the most favorable to promote the accumulation of bioactive constituents in the long term, without harming the plants. Flavonoid accumulation of non-stressed and low-stressed groups became different in the initial synthesis stage, and glycosyltransferases may have great influence on their downstream synthesis. Furthermore, bAS and CHS also showed higher levels in low-stressed licorice at harvest time. This work provides valuable information on dynamic variations in multiple bioactive constituents in licorice treated by salt and insight into its quality formation under stressed conditions.


Assuntos
Medicamentos de Ervas Chinesas/química , Flavonoides/química , Glycyrrhiza/química , Extratos Vegetais/química , Chalconas/química , Chalconas/metabolismo , Cromatografia Líquida , Medicamentos de Ervas Chinesas/metabolismo , Flavanonas/química , Flavanonas/metabolismo , Flavonoides/metabolismo , Glucosídeos/química , Glucosídeos/metabolismo , Ácido Glicirrízico/química , Ácido Glicirrízico/metabolismo , Humanos , Extratos Vegetais/metabolismo , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Folhas de Planta/metabolismo , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Estresse Salino , Espectrometria de Massas em Tandem , Triterpenos/química , Triterpenos/metabolismo
9.
Eur J Pharmacol ; 865: 172722, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31614142

RESUMO

Sofalcone is a synthetic chalcone being used as a gastric mucosa protective agent in Japan. Sofalcone contains a 1,3-diaryl-2-propen-1-one moiety, which is a common chemical scaffold in naturally occurring chalcones. The α,ß-unsaturated carbonyl group (Michael reaction acceptor) has electrophilic properties. We investigated the biochemical mechanisms by which sofalcone activated the cytoprotective and anti-inflammatory nuclear factor-erythroid 2 (NF-E2) p45-related factor 2 (Nrf2)-heme oxygenase (HO)-1 pathway. Furthermore, we investigated whether the activation of this pathway was involved in sofalcone -mediated protective effects in an experimental colitis model. Sofalcone induced HO-1 protein expression, which was dependent on increased nuclear accumulation of Nrf2 in human colon carcinoma cells. In addition, Sofalcone reacted with nucleophilic thiol compounds to form Michael adducts. A reduced form of sofalcone (SFCR) in which the Michael reaction acceptor was deactivated, did not exert biological or chemical activity. Biotin-tagged sofalcone bound to Kelch-like ECH-associated protein 1 (KEAP1), a cytosolic repressor of Nrf2. This binding was prevented by pretreatment with sofalcone and a thiol compound but not with SFCR. Furthermore, sofalcone treatment induced dissociation of the Nrf2-KEAP1 complex. Rectal administration of sofalcone alleviated colon damage and inflammation and increased colon nuclear accumulation of Nrf2 and HO-1 levels in a dinitrobenzene sulfonic acid-induced rat colitis model. The protective effects of sofalcone against colon damage and inflammation were significantly inhibited by co-administration of an HO-1 inhibitor. In conclusion, sofalcone activated the Nrf2-HO-1 pathway by covalently binding to KEAP1 via Michael addition, and may confer anti-colitic effects by inducing Nrf2 activation.


Assuntos
Chalconas/metabolismo , Chalconas/farmacologia , Colite/tratamento farmacológico , Trato Gastrointestinal/efeitos dos fármacos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Chalconas/uso terapêutico , Colite/metabolismo , Colite/patologia , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/patologia , Masculino , Ligação Proteica , Ratos , Ratos Sprague-Dawley
10.
EMBO Mol Med ; 11(11): e10469, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31609086

RESUMO

Caloric restriction mimetics (CRMs) are natural or synthetic compounds that mimic the health-promoting and longevity-extending effects of caloric restriction. CRMs provoke the deacetylation of cellular proteins coupled to an increase in autophagic flux in the absence of toxicity. Here, we report the identification of a novel candidate CRM, namely 3,4-dimethoxychalcone (3,4-DC), among a library of polyphenols. When added to several different human cell lines, 3,4-DC induced the deacetylation of cytoplasmic proteins and stimulated autophagic flux. At difference with other well-characterized CRMs, 3,4-DC, however, required transcription factor EB (TFEB)- and E3 (TFE3)-dependent gene transcription and mRNA translation to trigger autophagy. 3,4-DC stimulated the translocation of TFEB and TFE3 into nuclei both in vitro and in vivo, in hepatocytes and cardiomyocytes. 3,4-DC induced autophagy in vitro and in mouse organs, mediated autophagy-dependent cardioprotective effects, and improved the efficacy of anticancer chemotherapy in vivo. Altogether, our results suggest that 3,4-DC is a novel CRM with a previously unrecognized mode of action.


Assuntos
Autofagia/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Cardiotônicos/metabolismo , Chalconas/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética/efeitos dos fármacos , Acetilação , Estruturas Animais/patologia , Animais , Cardiotônicos/administração & dosagem , Linhagem Celular , Chalconas/administração & dosagem , Hepatócitos/efeitos dos fármacos , Humanos , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Processamento de Proteína Pós-Traducional , Transporte Proteico
11.
Molecules ; 24(17)2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31480751

RESUMO

Biotransformations were performed on eight selected yeast strains, all of which were able to selectively hydrogenate the chalcone derivatives 3-(2"-furyl)- (1) and 3-(2"-thienyl)-1-(2'-hydroxyphenyl)-prop-2-en-1-one (3) into 3-(2"-furyl)- (2) and 3-(2"-thienyl)-1-(2'-hydroxyphenyl)-propan-1-one (4) respectively. The highest efficiency of hydrogenation of the double bond in the substrate 1 was observed in the cultures of Saccharomyces cerevisiae KCh 464 and Yarrowia lipolytica KCh 71 strains. The substrate was converted into the product with > 99% conversion just in six hours after biotransformation started. The compound containing the sulfur atom in its structure was most effectively transformed by the Yarrowia lipolytica KCh 71 culture strain (conversion > 99%, obtained after three hours of substrate incubation). Also, we observed that, different strains of tested yeasts are able to carry out the bioreduction of the used substrate with different yields, depending on the presence of induced and constitutive ene reductases in their cells. The biggest advantage of this process is the efficient production of one product, practically without the formation of side products.


Assuntos
Tiofenos/metabolismo , Leveduras/metabolismo , Biotransformação , Células Cultivadas , Chalconas/metabolismo , Hidrogenação , Especificidade por Substrato , Tiofenos/síntese química , Tiofenos/química
12.
Appl Environ Microbiol ; 85(19)2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31375488

RESUMO

The human intestinal anaerobe Eubacterium ramulus is known for its ability to degrade various dietary flavonoids. In the present study, we demonstrate the cleavage of the heterocyclic C-ring of flavanones and flavanonols by an oxygen-sensitive NADH-dependent reductase, previously described as enoate reductase, from E. ramulus This flavanone- and flavanonol-cleaving reductase (Fcr) was purified following its heterologous expression in Escherichia coli and further characterized. Fcr cleaved the flavanones naringenin, eriodictyol, liquiritigenin, and homoeriodictyol. Moreover, the flavanonols taxifolin and dihydrokaempferol served as substrates. The catalyzed reactions were stereospecific for the (2R)-enantiomers of the flavanone substrates and for the (2S,3S)-configured flavanonols. The enantioenrichment of the nonconverted stereoisomers allowed for the determination of hitherto unknown flavanone racemization rates. Fcr formed the corresponding dihydrochalcones and hydroxydihydrochalcones in the course of an unusual reductive cleavage of cyclic ether bonds. Fcr did not convert members of other flavonoid subclasses, including flavones, flavonols, and chalcones, the latter indicating that the reaction does not involve a chalcone intermediate. This view is strongly supported by the observed enantiospecificity of Fcr. Cinnamic acids, which are typical substrates of bacterial enoate reductases, were also not reduced by Fcr. Based on the presence of binding motifs for dinucleotide cofactors and a 4Fe-4S cluster in the amino acid sequence of Fcr, a cofactor-mediated hydride transfer from NADH onto C-2 of the respective substrate is proposed.IMPORTANCE Gut bacteria play a crucial role in the metabolism of dietary flavonoids, thereby contributing to their activation or inactivation after ingestion by the human host. Thus, bacterial activities in the intestine may influence the beneficial health effects of these polyphenolic plant compounds. While an increasing number of flavonoid-converting gut bacterial species have been identified, knowledge of the responsible enzymes is still limited. Here, we characterized Fcr as a key enzyme involved in the conversion of flavonoids of several subclasses by Eubacterium ramulus, a prevalent human gut bacterium. Sequence similarity of this enzyme to hypothetical proteins from other flavonoid-degrading intestinal bacteria in databases suggests a more widespread occurrence of this enzyme. Functional characterization of gene products of human intestinal microbiota enables the assignment of metagenomic sequences to specific bacteria and, more importantly, to certain activities, which is a prerequisite for targeted modulation of gut microbial functionality.


Assuntos
Proteínas de Bactérias/metabolismo , Eubacterium/enzimologia , Flavanonas/metabolismo , NADH NADPH Oxirredutases/metabolismo , Catálise , Chalconas/metabolismo , Cinamatos/metabolismo , Intestinos/microbiologia , Estereoisomerismo
13.
Bioorg Chem ; 90: 103034, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31280015

RESUMO

The chalcone and bis-chalcone derivatives have been synthesized under sonication conditions via Claisen-Schmidt condensation with KOH in ethanol at room temperature (20-89%). The structures were established on the basis of NMR, IR, Single-crystal XRD, and MS. The best compound 3u had inhibitory activity (IC50 = 7.50 µM). The synthesis, the antioxidative properties, chemical reactivity descriptors supported in Density Functional Theory (DFT), acetylcholinesterase (AChE) inhibition and their potential binding modes, and affinity were predicted by molecular docking of a number of morpholine-chalcones and quinoline-chalcone. A series of bis-chalcones are also reported. Molecular docking and an enzyme kinetic study on compound 3u suggested that it simultaneously binds to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. Moreover, the pharmacokinetic profile of these compounds was investigated using a computational method.


Assuntos
Acetilcolinesterase/metabolismo , Antioxidantes/química , Chalconas/química , Inibidores da Colinesterase/química , Acetilcolinesterase/química , Antioxidantes/síntese química , Antioxidantes/metabolismo , Antioxidantes/farmacocinética , Domínio Catalítico , Chalconas/síntese química , Chalconas/metabolismo , Chalconas/farmacocinética , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacocinética , Ensaios Enzimáticos , Humanos , Cinética , Simulação de Acoplamento Molecular , Ligação Proteica , Ondas Ultrassônicas
14.
Int J Biol Macromol ; 137: 426-432, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31271801

RESUMO

Six synthetic (1-6) and six natural (7-12) chalcones were tested for human monoamine oxidases (hMAOs) and acetylcholinesterase (AChE) inhibitory activities. Compounds 4-dimethylaminochalcone (2), 4'-chloro-4-dimethylaminochalcone (5), and 2,4'-dichloro-4-dimethylaminochalcone (1) potently inhibited hMAO-B with IC50 values of 0.029, 0.061, and 0.075 µM, respectively. 4-Nitrochalcone (4) and 4-chlorochalcone (3) also potently inhibited hMAO-B with IC50 values of 0.066 and 0.082 µM, respectively (2.3- and 2.6-fold less than compound 2). Compound 2 had a high selectivity index (113.1) for hMAO-B over hMAO-A (IC50 = 3.28 µM). Compounds 1 and 2,2'-dihydroxy-4',6'-dimethoxychalcone (12) potently inhibited hMAO-A with IC50 values of 0.18 and 0.39 µM, respectively. In addition, compounds 4 and 2 also effectively inhibited AChE with IC50 values of 1.25 and 6.07 µM, respectively, and thus, exhibited dual-targeting. Compound 2 reversibly and competitively inhibited hMAO-B with a Ki value of 0.0066 µM. Docking simulations showed binding affinities of compounds 1 to 5 for hMAO-B were higher than those for hMAO-A or AChE and suggested these five chalcones form hydrogen bonds with MAO-B at Cys172 but that they do not form hydrogen bonds with hMAO-A or AChE. These findings suggest compound 2 be considered a promising and dual-targeting lead compound for the treatment of Alzheimer's disease.


Assuntos
Chalconas/química , Chalconas/farmacologia , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Chalconas/metabolismo , Humanos , Simulação de Acoplamento Molecular , Monoaminoxidase/química , Inibidores da Monoaminoxidase/metabolismo , Conformação Proteica
15.
ACS Synth Biol ; 8(8): 1858-1866, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31284719

RESUMO

Licorice (Glycyrrhiza uralensis) is a popular medicinal plant containing more than 70 flavonoid and triterpenoid glycosides. Thus far, only a few reports are available on the glycosylation enzymes involved in their biosynthesis. In this work, we mined the transcriptome data of G. uralensis and discovered 43 candidate genes for O-glycosyltransferase (O-GT). Among them, 17 genes could be expressed in E. coli, and functions of the enzymes were analyzed by catalyzing eight native substrates. As a result, we characterized 11 O-GTs, including isoflavone 7-O-GTs, flavonol 3-O-GTs, and promiscuous O-GTs catalyzing flavones, chalcones, and triterpenoids. They could efficiently synthesize key licorice compounds such as liquiritin, isoliquiritin, ononin, and 3-O-ß-d-glucuronosyl glycyrrhetinic acid. The diversity of O-GTs contributes to the biosynthesis of various glycosides in licorice. These enzymes could also be used as biocatalytic tools to synthesize other bioactive O-glycosides.


Assuntos
Flavonoides/metabolismo , Glicosídeos/metabolismo , Glicosiltransferases/metabolismo , Glycyrrhiza uralensis/metabolismo , Triterpenos/metabolismo , Chalconas/metabolismo , Cromatografia Líquida de Alta Pressão , Glicosilação , Ácido Glicirretínico/metabolismo , Glycyrrhiza/metabolismo , Isoflavonas/metabolismo , Filogenia
16.
J Agric Food Chem ; 67(26): 7258-7265, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31188589

RESUMO

This study investigated the environmental fate of myrigalone A, a light absorbing natural herbicide found on leaves and fruits of Myrica gale. Myrigalone A was irradiated in water and as a dry solid deposit to simulate reactions on leaves, alone and in the presence of the terpenes generated by Myrica gale. The phototransformation was fast ( t1/2 = 35 min in water). Analyses by liquid chromatography coupled to high resolution orbitrap electrospray mass spectrometry (MS) and gas chromatography-MS revealed the formation of 11 photoproducts in water and solid and 9 in gaseous phase. Some were detected in the leaf glands and oil covering the fruits of Myrica gale, which suggested that photodegradation occurred in the field. Moreover, myrigalone A photoinduced the oxidation of terpenes that in turn protected it against photolysis. This highlights the need for additional research on the effect of terpenes on the photodegradation of pesticides on vegetation.


Assuntos
Chalconas/química , Myrica/efeitos da radiação , Feromônios/química , Chalconas/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Cinética , Estrutura Molecular , Myrica/química , Myrica/metabolismo , Oxirredução/efeitos da radiação , Feromônios/metabolismo , Fotólise/efeitos da radiação , Terpenos/química , Terpenos/metabolismo
17.
PLoS One ; 14(5): e0216172, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31048842

RESUMO

Aspalathin is a rooibos flavonoid with established blood glucose lowering properties, however, its efficacy to moderate complications associated with hepatic insulin resistance is unknown. To study such effects, C3A liver cells exposed to palmitate were used as a model of hepatic insulin resistance. These hepatocytes displayed impaired substrate metabolism, including reduced glucose transport and free fatty acid uptake. These defects included impaired insulin signaling, evident through reduced phosphatidylinositol-4,5-bisphosphate 3-kinase/ protein kinase B (PI3K/AKT) protein expression, and mitochondrial dysfunction, depicted by a lower mitochondrial respiration rate. Aspalathin was able to ameliorate these defects by correcting altered substrate metabolism, improving insulin signaling and mitochondrial bioenergetics. Activation of 5'-adenosine monophosphate-activated protein kinase (AMPK) may be a plausible mechanism by which aspalathin increases hepatic energy expenditure. Overall, these results encourage further studies assessing the potential use of aspalathin as a nutraceutical to improve hepatocellular energy expenditure, and reverse metabolic disease-associated complications.


Assuntos
Chalconas/farmacologia , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Glicemia/metabolismo , Linhagem Celular , Chalconas/metabolismo , Glucose/metabolismo , Hepatócitos/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Resistência à Insulina/fisiologia , Fígado/metabolismo , Mitocôndrias/metabolismo , Modelos Biológicos , Palmitatos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
18.
Chem Pharm Bull (Tokyo) ; 67(7): 725-728, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30982797

RESUMO

Eighteen novel chalcone derivatives containing indole and naphthalene moieties (2-19) were synthesized and characterized by 1H-NMR, 13C-NMR and high resolution (HR)-MS spectra. All compounds were evaluated for their in vitro cytotoxic potential against human hepatocellular carcinoma (HepG2), human colon carcinoma (HCT116) and human breast adenocarcinoma (MCF-7) cell lines. Among them, compound 2, 3, 4 and 7 showed potent activities against tested cancer cell lines. More significantly, compound 7 exhibited the most potent cytotoxic activity against HepG2, HCT116 and MCF-7 with IC50 values of 0.65, 1.13 and 0.82 µM, respectively. Furthermore, flow cytometry analysis indicated that compound 7 arrested cancer cells in G2/M phase. The compound 7 also displayed significant inhibition of tubulin polymerization (IC50 = 3.9 µM). Finally, molecular docking studies were performed to explore the possible interactions between compound 7 and tubulin binding pockets.


Assuntos
Antineoplásicos/síntese química , Chalconas/química , Indóis/química , Naftalenos/química , Moduladores de Tubulina/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chalconas/metabolismo , Chalconas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/farmacologia
19.
Mar Biotechnol (NY) ; 21(3): 430-439, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30895403

RESUMO

This study describes the chemoselective hydrogenation reaction of halogenated 2'-hydroxychalcones by the marine-derived fungus Penicillium raistrickii CBMAI 931. Initially, 2'-hydroxychalcone was utilized as a model for the selection of the appropriate conditions to perform the biotransformation reactions. The best results were obtained using mycelia and filtered culture broth, and this condition was chosen for the biotransformation reaction of 2'-hydroxychalcones substituted with methoxy and halogen groups. Experiments performed with 2'-hydroxychalcones dissolved in 600 µL-DMSO were more effective than those performed using 300 µL-DMSO, once solubility of the compounds influenced conversion rate in the liquid medium. The halogenated 2'-hydroxy-dihydrochalcones were obtained in good conversions (78-99%) and moderate isolated yields (31-65%). All biotransformation reactions using the marine-derived fungus P. raistrickii CBMAI 931 showed regioselective and chemoselective control for the formation of 2'-hydroxy-dihydrochalcones.


Assuntos
Biotransformação , Chalconas/metabolismo , Micélio/metabolismo , Penicillium/metabolismo , Halogenação , Hidrogenação
20.
J Biotechnol ; 293: 36-46, 2019 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-30690100

RESUMO

Halophilic and freshwater strains of cyanobacteria representing the Oscillatoriales, Nostocales, Chroococcales, and Synechococcales orders of Cyanophyta were examined to determine (i) the resistance of their cultures when suppressed by the presence of exogenous methoxylated and methylated derivatives of 2'-hydroxychalcone, (ii) morphological changes in cells treated with the tested chalcones and, most importantly, (iii) whether these photoautotrophic microorganisms transform chalcone derivatives in a structure- or strain-dependent manner. The growth of cyanobacterial cultures depended on chalcone derivatives and the strain; nevertheless, trends for correlations between these parameters are difficult to determine. The exposure of cyanobacteria to the tested chalcones revealed severe membrane damage that was consistent with the disruption of membrane integrity. All examined blue-green algae transformed methoxy derivatives of 2'-hydroxychalcone via hydrogenative bio-reduction and formed the corresponding hydroxydihydro derivatives with various efficiencies (≤1 - 70%), depending more on the structure than on the strain. We observed dependency of the routes and efficiency of biohydrogenation of tested chalcones on the location of the methoxyl substituent and, to a lesser extent, on cyanobacterial strains. 2'-hydroxy-4″-methylchalcone was also converted by cyanobacteria to various products, amongst which the most interesting were 2'-ethoxy derivatives. The final products of biocatalytic transformation were extracted from the cyanobacterial media, separated by high performance thin-layer chromatography (HPTLC) and identified by a combination of liquid chromatography-tandem mass spectrometry (LC-MS/MS technique) and one-dimensional (1D 1H and 13C) and two-dimensional (2D HSQC and COSY) nuclear magnetic resonance (NMR) spectroscopy.


Assuntos
Chalconas/metabolismo , Cianobactérias/metabolismo , Biotransformação , Metilação
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