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1.
J Agric Food Chem ; 69(36): 10709-10721, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34476938

RESUMO

Thirty-one new 4H-chromene derivatives were designed and synthesized. Their structures were identified with IR, 1H NMR, 13C NMR, and HRMS. The crystal structure of compound 2a was determined by single-crystal X-ray diffraction. Their antifungal activities were evaluated against Pyricularia oryzae, Erysiphe graminis, Coniella diplodiella, Pseudoperonospora cubensis, and Sclerotinia sclerotiorum. These results demonstrated that most compounds exhibited remarkable inhibitory activities at 20 µg/mL. Compounds 4b and 4c displayed excellent antifungal activity against S. sclerotiorum and possessed better efficacy than fluopyram. At the same time, the inhibitory activity of the bioactive compounds was evaluated against succinate dehydrogenase (SDH). The results showed that these compounds possessed outstanding activity. Compounds 4b and 4c displayed better inhibitory activity than fluopyram. The molecular modeling results revealed that compound 4c had stronger affinity to SDH than fluopyram. It is the first time that the inhibitory activity of 4H-chromene analogs against SDH has been reported.


Assuntos
Benzopiranos , Succinato Desidrogenase , Antifúngicos/farmacologia , Ascomicetos , Benzopiranos/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade , Succinato Desidrogenase/metabolismo
2.
Nat Commun ; 12(1): 5321, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493732

RESUMO

CARM1 is often overexpressed in human cancers including in ovarian cancer. However, therapeutic approaches based on CARM1 expression remain to be an unmet need. Cancer cells exploit adaptive responses such as the endoplasmic reticulum (ER) stress response for their survival through activating pathways such as the IRE1α/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1α/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1α/XBP1s pathway was effective against ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model. Our data show that pharmacological inhibition of the IRE1α/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.


Assuntos
Carcinoma Epitelial do Ovário/terapia , Endorribonucleases/genética , Neoplasias Ovarianas/terapia , Receptor de Morte Celular Programada 1/genética , Proteína-Arginina N-Metiltransferases/genética , Proteínas Serina-Treonina Quinases/genética , Proteína 1 de Ligação a X-Box/genética , Animais , Anticorpos Monoclonais/farmacologia , Sequência de Bases , Benzopiranos/farmacologia , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endorribonucleases/antagonistas & inibidores , Endorribonucleases/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Himecromona/análogos & derivados , Himecromona/farmacologia , Inibidores de Checkpoint Imunológico , Camundongos , Terapia de Alvo Molecular , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Ligação Proteica , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/imunologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/imunologia , Transdução de Sinais , Proteína 1 de Ligação a X-Box/antagonistas & inibidores , Proteína 1 de Ligação a X-Box/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Molecules ; 26(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299576

RESUMO

The search for a safe and effective inhibitor of ferroptosis, a recently described cell death pathway, has attracted increasing interest from scientists. Two hydrolyzable tannins, chebulagic acid and chebulinic acid, were selected for the study. Their optimized conformations were calculated using computational chemistry at the B3LYP-D3(BJ)/6-31G and B3LYP-D3(BJ)/6-311 + G(d,p) levels. The results suggested that (1) chebulagic acid presented a chair conformation, while chebulinic acid presented a skew-boat conformation; (2) the formation of chebulagic acid requires 762.1729 kcal/mol more molecular energy than chebulinic acid; and (3) the 3,6-HHDP (hexahydroxydiphenoyl) moiety was shown to be in an (R)- absolute stereoconfiguration. Subsequently, the ferroptosis inhibition of both tannins was determined using a erastin-treated bone marrow-derived mesenchymal stem cells (bmMSCs) model and compared to that of ferrostatin-1 (Fer-1). The relative inhibitory levels decreased in the following order: Fer-1 > chebulagic acid > chebulinic acid, as also revealed by the in vitro antioxidant assays. The UHPLC-ESI-Q-TOF-MS analysis suggested that, when treated with 16-(2-(14-carboxytetradecyl)-2-ethyl-4,4-dimethyl-3-oxazolidinyloxy free radicals, Fer-1 generated dimeric products, whereas the two acids did not. In conclusion, two hydrolyzable tannins, chebulagic acid and chebulinic acid, can act as natural ferroptosis inhibitors. Their ferroptosis inhibition is mediated by regular antioxidant pathways (ROS scavenging and iron chelation), rather than the redox-based catalytic recycling pathway exhibited by Fer-1. Through antioxidant pathways, the HHDP moiety in chebulagic acid enables ferroptosis-inhibitory action of hydrolyzable tannins.


Assuntos
Benzopiranos/farmacologia , Ferroptose/efeitos dos fármacos , Glucosídeos/farmacologia , Taninos Hidrolisáveis/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Benzopiranos/química , Células Cultivadas , Glucosídeos/química , Taninos Hidrolisáveis/química , Células-Tronco Mesenquimais/citologia , Modelos Moleculares , Ratos Sprague-Dawley
4.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299247

RESUMO

A series of new heteroleptic copper(II) complexes of the composition [Cu(L)(bpy)]NO3·2MeOH (1), [Cu(L)(dimebpy)]NO3·2H2O (2), [Cu(L)(phen)]NO3·2MeOH (3), [Cu(L)(bphen)]NO3·MeOH (4), [Cu(L)(dppz)]NO3·MeOH (5) was prepared, where HL = 3-(3,4-dihydroxyphenyl)-5-hydroxy-8,8-dimethyl-6-(3-methylbut-2-ene-1-yl)-4H,8H-benzo[1,2-b:3,4-b']dipyran-4-one, (pomiferin) and bpy = 2,2'-bipyridine, dimebpy = 4,4'-dimethyl-2,2'-bipyridine, phen = 1,10-phenanthroline, bphen = 4,7-diphenyl-1,10-phenanthroline, and dppz = dipyrido[3,2-a:2',3'-c]phenazine. The complexes were characterized using elemental analysis, infrared and UV/Vis spectroscopies, mass spectrometry, thermal analysis and conductivity measurements. The in vitro cytotoxicity, screened against eight human cancer cell lines (breast adenocarcinoma (MCF-7), osteosarcoma (HOS), lung adenocarcinoma (A549), prostate adenocarcinoma (PC-3), ovarian carcinoma (A2780), cisplatin-resistant ovarian carcinoma (A2780R), colorectal adenocarcinoma (Caco-2) and monocytic leukemia (THP-1), revealed the complexes as effective antiproliferative agents, with the IC50 values of 2.2-13.0 µM for the best performing complexes 3 and 5. All the complexes 1-5 showed the best activity against the A2780R cells (IC50 = 2.2-6.6 µM), and moreover, the complexes demonstrated relatively low toxicity on healthy human hepatocytes, with IC50 > 100 µM. The complexes were evaluated by the Annexin V/propidium iodide apoptosis assay, induction of cell cycle modifications in A2780 cells, production of reactive oxygen species (ROS), perturbation of mitochondrial membrane potential, inhibition of apoptosis and inflammation-related signaling pathways (NF-κB/AP-1 activity, NF-κB translocation, TNF-α secretion), and tested for nuclease mimicking activity. The obtained results revealed the corresponding complexes to be effective antiproliferative and anti-inflammatory agents.


Assuntos
Benzopiranos/farmacologia , Complexos de Coordenação/farmacologia , Cobre/química , Isoflavonas/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzopiranos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Cobre/metabolismo , Cobre/farmacologia , Flavonoides/metabolismo , Flavonoides/farmacologia , Humanos , Isoflavonas/química , Espécies Reativas de Oxigênio/metabolismo
5.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281274

RESUMO

It has been recognized that serotonin 2A receptor (5-HT2A) agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI) impairs serotonergic homeostasis. However, the mechanism of DOI-induced serotonergic behaviors remains to be explored. Moreover, little is known about therapeutic interventions against serotonin syndrome, although evidence suggests that ginseng might possess modulating effects on the serotonin system. As ginsenoside Re (GRe) is well-known as a novel antioxidant in the nervous system, we investigated whether GRe modulates 5-HT2A receptor agonist DOI-induced serotonin impairments. We proposed that protein kinase Cδ (PKCδ) mediates serotonergic impairments. Treatment with GRe or 5-HT2A receptor antagonist MDL11939 significantly attenuated DOI-induced serotonergic behaviors (i.e., overall serotonergic syndrome behaviors, head twitch response, hyperthermia) by inhibiting mitochondrial translocation of PKCδ, reducing mitochondrial glutathione peroxidase activity, mitochondrial dysfunction, and mitochondrial oxidative stress in wild-type mice. These attenuations were in line with those observed upon PKCδ inhibition (i.e., pharmacologic inhibitor rottlerin or PKCδ knockout mice). Furthermore, GRe was not further implicated in attenuation mediated by PKCδ knockout in mice. Our results suggest that PKCδ is a therapeutic target for GRe against serotonergic behaviors induced by DOI.


Assuntos
Ginsenosídeos/farmacologia , Proteína Quinase C-delta/metabolismo , Antagonistas da Serotonina/farmacologia , Síndrome da Serotonina/prevenção & controle , Acetofenonas/farmacologia , Anfetaminas/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Benzopiranos/farmacologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/farmacologia , Proteína Quinase C-delta/deficiência , Proteína Quinase C-delta/genética , Inibidores de Proteínas Quinases/farmacologia , Serotonina/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Síndrome da Serotonina/induzido quimicamente , Síndrome da Serotonina/fisiopatologia
6.
Int J Mol Sci ; 22(12)2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-34203049

RESUMO

The present study aims to determine the neuroprotective effect of Bergenin against spatial memory deficit associated with neurodegeneration. Preliminarily, the protective effect of Bergenin was observed against H2O2-induced oxidative stress in HT-22 and PC-12 cells. Further studies were performed in 5xFAD Tg mouse model by administering Bergenin (1, 30 and 60 mg/kg; orally), whereas Bergenin (60 mg/kg) significantly attenuated the memory deficit observed in the Y-maze and Morris water maze (MWM) test. Fourier transform-infrared (FT-IR) spectroscopy displayed restoration of lipids, proteins and their derivatives compared to the 5xFAD Tg mice group. The differential scanning calorimeter (DSC) suggested an absence of amyloid beta (Aß) aggregation in Bergenin-treated mice. The immunohistochemistry (IHC) analysis suggested the neuroprotective effect of Bergenin by increasing Reelin signaling (Reelin/Dab-1) and attenuated Aß (1-42) aggregation in hippocampal regions of mouse brains. Furthermore, IHC and western blot results suggested antioxidant (Keap-1/Nrf-2/HO-1), anti-inflammatory (TLR-4/NF-kB) and anti-apoptotic (Bcl-2/Bax/Caspase-3) effect of Bergenin. Moreover, a decrease in Annexin V/PI-stained hippocampal cells suggested its effect against neurodegeneration. The histopathological changes were reversed significantly by Bergenin. In addition, a remarkable increase in antioxidant level with suppression of pro-inflammatory cytokines, oxidative stress and nitric oxide production were observed in specific regions of the mouse brains.


Assuntos
Benzopiranos/farmacologia , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Serina Endopeptidases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Benzopiranos/química , Biomarcadores , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Ligação de Hidrogênio , Mediadores da Inflamação/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/diagnóstico , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Relação Estrutura-Atividade , Resultado do Tratamento
7.
Molecules ; 26(12)2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205355

RESUMO

Rottlerin is a natural product consisting of chalcone and flavonoid scaffolds, both of which have previously shown quorum sensing (QS) inhibition in various bacteria. Therefore, the unique rottlerin scaffold highlights great potential in inhibiting the QS system of Pseudomonas aeruginosa. Rottlerin analogues were synthesised by modifications at its chalcone- and methylene-bridged acetophenone moieties. The synthesis of analogues was achieved using an established five-step synthetic strategy for chalcone derivatives and utilising the Mannich reaction at C6 of the chromene to construct morpholine analogues. Several pyranochromene chalcone derivatives were also generated using aldol conditions. All the synthetic rottlerin derivatives were screened for QS inhibition and growth inhibition against the related LasR QS system. The pyranochromene chalcone structures displayed high QS inhibitory activity with the most potent compounds, 8b and 8d, achieving QS inhibition of 49.4% and 40.6% and no effect on bacterial growth inhibition at 31 µM, respectively. Both compounds also displayed moderate biofilm inhibitory activity and reduced the production of pyocyanin.


Assuntos
Acetofenonas/farmacologia , Benzopiranos/farmacologia , Produtos Biológicos/farmacologia , Percepção de Quorum/efeitos dos fármacos , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Flavonoides/farmacologia , Testes de Sensibilidade Microbiana/métodos , Pseudomonas aeruginosa/efeitos dos fármacos , Piocianina/farmacologia
8.
Molecules ; 26(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203527

RESUMO

The natural products pulchrol and pulchral, isolated from the roots of the Mexican plant Bourreria pulchra, have previously been shown to possess antiparasitic activity towards Trypanosoma cruzi, Leishmania braziliensis and L. amazonensis, which are protozoa responsible for Chagas disease and leishmaniasis. These infections have been classified as neglected diseases, and still require the development of safer and more efficient alternatives to their current treatments. Recent SARs studies, based on the pulchrol scaffold, showed which effects exchanges of its substituents have on the antileishmanial and antitrypanosomal activity. Many of the analogues prepared were shown to be more potent than pulchrol and the current drugs used to treat leishmaniasis and Chagas disease (miltefosine and benznidazole, respectively), in vitro. Moreover, indications of some of the possible interactions that may take place in the binding sites were also identified. In this study, 12 analogues with modifications at two or three different positions in two of the three rings were prepared by synthetic and semi-synthetic procedures. The molecules were assayed in vitro towards T. cruzi epimastigotes, L. braziliensis promastigotes, and L. amazonensis promastigotes. Some compounds had higher antiparasitic activity than the parental compound pulchrol, and in some cases even benznidazole and miltefosine. The best combinations in this subset are with carbonyl functionalities in the A-ring and isopropyl groups in the C-ring, as well as with alkyl substituents in both the A- and C-rings combined with a hydroxyl group in position 1 (C-ring). The latter corresponds to cannabinol, which indeed was shown to be potent towards all the parasites.


Assuntos
Benzopiranos , Leishmania braziliensis/crescimento & desenvolvimento , Tripanossomicidas , Trypanosoma cruzi/crescimento & desenvolvimento , Benzopiranos/química , Benzopiranos/farmacologia , Doença de Chagas/tratamento farmacológico , Humanos , Leishmaniose Cutânea/tratamento farmacológico , Tripanossomicidas/química , Tripanossomicidas/farmacologia
9.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299073

RESUMO

Theasinensin A (TSA) is a major group of catechin dimers mainly found in oolong tea and black tea. This compound is also manufactured with epigallocatechin gallate (EGCG) as a substrate and is refined after the enzyme reaction. In previous studies, TSA has been reported to be effective against inflammation. However, the effect of these substances on skin melanin formation remains unknown. In this study, we unraveled the role of TSA in melanogenesis using mouse melanoma B16F10 cells and normal human epidermal melanocytes (NHEMs) through reverse transcription polymerase chain reaction (RT-PCR), Western blotting analysis, luciferase reporter assay, and enzyme-linked immunosorbent assay analysis. TSA inhibited melanin formation and secretion in α-melanocyte stimulating hormone (α-MSH)-induced B16F10 cells and NHEMs. TSA down-regulated the mRNA expression of tyrosinase (Tyr), tyrosinase-related protein 1 (Tyrp1), and Tyrp2, which are all related to melanin formation in these cells. TSA was able to suppress the activities of certain proteins in the melanocortin 1 receptor (MC1R) signaling pathway associated with melanin synthesis in B16F10 cells: cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), protein kinase A (PKA), tyrosinase, and microphthalmia-associated transcription factor (MITF). We also confirmed α-MSH-mediated CREB activities through a luciferase reporter assay, and that the quantities of cAMP were reduced by TSA in the enzyme linked immunosorbent assay (ELISA) results. Based on these findings, TSA should be considered an effective inhibitor of hyperpigmentation.


Assuntos
Benzopiranos/farmacologia , AMP Cíclico/metabolismo , Melaninas/metabolismo , Melanócitos/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Fenóis/farmacologia , Animais , Humanos , Melanócitos/citologia , Melanócitos/metabolismo , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Fosforilação , Transdução de Sinais
10.
Chem Biodivers ; 18(8): e2100186, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34159725

RESUMO

A series of pyrimidine-containing 4H-chromen-4-one derivatives were designed and synthesized by combining bioactive substructures. Preliminary biological activity results showed that most of the compounds displayed significant inhibitory activities in vitro against Xanthomonas axonopodis pv. Citri (X. axonopodis), Xanthomonas oryzae pv. oryzae (X. oryzae) and Ralstonia solanacearum (R. solanacearum). In particular, compound 2-[(3-{[5,7-dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-1-benzopyran-3-yl]oxy}propyl)sulfanyl]-4-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4c) demonstrated a good inhibitory effect against X. axonopodis and X. oryzae, with the half-maximal effective concentration (EC50 ) values of 15.5 and 14.9 µg/mL, respectively, and compound 2-[(3-{[5,7-Dimethoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)-4H-1-benzopyran-3-yl]oxy}propyl)sulfanyl]-4-(3-fluorophenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (4h) showed the best antibacterial activity against R. solanacearum with an EC50 value of 14.7 µg/mL. These results were better than commercial reagents bismerthiazol (BT, 51.7, 70.1 and 52.7 µg/mL, respectively) and thiodiazole copper (TC, 77.9, 95.8 and 72.1 µg/mL, respectively). In vivo antibacterial activity results indicated that compound 4c displayed better curative (42.4 %) and protective (49.2 %) activities for rice bacterial leaf blight than BT (35.2, 39.1 %) and TC (30.8, 27.3 %). The mechanism of compound 4c against X. oryzae was analyzed through scanning electron microscopy (SEM). These results indicated that pyrimidine-containing 4H-chromen-4-one derivatives have important value in the research of new agrochemicals.


Assuntos
Antibacterianos/síntese química , Benzopiranos/química , Desenho de Fármacos , Pirimidinas/química , Antibacterianos/química , Antibacterianos/farmacologia , Benzopiranos/síntese química , Benzopiranos/farmacologia , Cristalografia por Raios X , Testes de Sensibilidade Microbiana , Conformação Molecular , Oryza/crescimento & desenvolvimento , Oryza/microbiologia , Doenças das Plantas/microbiologia , Doenças das Plantas/terapia , Ralstonia solanacearum/efeitos dos fármacos , Relação Estrutura-Atividade , Compostos de Sulfidrila/farmacologia , Tiadiazóis/farmacologia , Xanthomonas/efeitos dos fármacos
11.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073595

RESUMO

Urolithins (hydroxylated 6H-benzo[c]chromen-6-ones) are the main bioavailable metabolites of ellagic acid (EA), which was shown to be a cognitive enhancer in the treatment of neurodegenerative diseases. As part of this research, a series of alkoxylated 6H-benzo[c]chromen-6-one derivatives were designed and synthesized. Furthermore, their biological activities were evaluated as potential PDE2 inhibitors, and the alkoxylated 6H-benzo[c]chromen-6-one derivative 1f was found to have the optimal inhibitory potential (IC50: 3.67 ± 0.47 µM). It also exhibited comparable activity in comparison to that of BAY 60-7550 in vitro cell level studies.


Assuntos
Benzopiranos , Desenho de Fármacos , Inibidores Enzimáticos , Exonucleases/antagonistas & inibidores , Benzopiranos/síntese química , Benzopiranos/química , Benzopiranos/farmacologia , Linhagem Celular , Avaliação de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Exonucleases/metabolismo , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
12.
PLoS One ; 16(6): e0253489, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34138966

RESUMO

In the pursuit of suitable and effective solutions to SARS-CoV-2 infection, we investigated the efficacy of several phenolic compounds in controlling key cellular mechanisms involved in its infectivity. The way the SARS-CoV-2 virus infects the cell is a complex process and comprises four main stages: attachment to the cognate receptor, cellular entry, replication and cellular egress. Since, this is a multi-part process, it creates many opportunities to develop effective interventions. Targeting binding of the virus to the host receptor in order to prevent its entry has been of particular interest. Here, we provide experimental evidence that, among 56 tested polyphenols, including plant extracts, brazilin, theaflavin-3,3'-digallate, and curcumin displayed the highest binding with the receptor-binding domain of spike protein, inhibiting viral attachment to the human angiotensin-converting enzyme 2 receptor, and thus cellular entry of pseudo-typed SARS-CoV-2 virions. Both, theaflavin-3,3'-digallate at 25 µg/ml and curcumin above 10 µg/ml concentration, showed binding with the angiotensin-converting enzyme 2 receptor reducing at the same time its activity in both cell-free and cell-based assays. Our study also demonstrates that brazilin and theaflavin-3,3'-digallate, and to a still greater extent, curcumin, decrease the activity of transmembrane serine protease 2 both in cell-free and cell-based assays. Similar pattern was observed with cathepsin L, although only theaflavin-3,3'-digallate showed a modest diminution of cathepsin L expression at protein level. Finally, each of these three compounds moderately increased endosomal/lysosomal pH. In conclusion, this study demonstrates pleiotropic anti-SARS-CoV-2 efficacy of specific polyphenols and their prospects for further scientific and clinical investigations.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/prevenção & controle , Polifenóis/farmacologia , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus/efeitos dos fármacos , Células A549 , Benzopiranos/farmacologia , Biflavonoides/farmacologia , COVID-19/virologia , Catequina/análogos & derivados , Catequina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Curcumina/farmacologia , Humanos , Ligação Proteica/efeitos dos fármacos , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Vírion/efeitos dos fármacos , Vírion/metabolismo , Vírion/fisiologia , Ligação Viral/efeitos dos fármacos
13.
Mol Cell Biochem ; 476(10): 3701-3709, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34081254

RESUMO

Hyaluronic acid (HA)-CD44 pathway showed association with several malignancies. The natural polyphenols Plumbagin, Pongapin and Karanjin showed anti-cancer activities in different tumors including cervical carcinoma. To understand their mechanism of anti-cancer activity, the effect of the compounds on HA-CD44 pathway was analyzed in cervical cancer cell line HeLa. The mRNA expression of three different isoforms of CD44 i.e., CD44s, CD44v3, and CD44v6, was differentially downregulated by the compounds. This was validated by Western blot and immunocytochemical analysis of CD44s.The low molecular weight HA (LMW-HA) showed growth promoting activity in HeLa at low concentration, whereas high molecular weight HA (HMW-HA) had no such effect. The compounds could preferentially downregulate the LMW-HA level in HeLa, as evident in the cell as well as in the cell-free conditioned medium. Concentration-dependent upregulation of HA synthase-2 (HAS2) was seen in the cell by the compounds, whereas differential downregulation of hyalurinidases 1-4 (HYAL 1-4), predominantly HYAL1, were seen. The compounds could also downregulate the downstream target of the pathway p-AKT (T-308) in concentration-dependent manner. Thus, the compounds could attenuate the HA-CD44 pathway in HeLa cell to restrict the tumor growth.


Assuntos
Benzopiranos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Flavonas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Receptores de Hialuronatos/biossíntese , Ácido Hialurônico/metabolismo , Naftoquinonas/farmacologia , Proteínas de Neoplasias/biossíntese , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/metabolismo , Feminino , Células HeLa , Humanos , Receptores de Hialuronatos/genética , Ácido Hialurônico/genética , Proteínas de Neoplasias/genética , Transdução de Sinais/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
14.
Eur J Med Chem ; 222: 113603, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34126456

RESUMO

We reported three distinct series of novel benzothiopyranones, derived from an active metabolite (M-1) of anti-TB agent 6b. These small molecules were evaluated for their biological activities against a range of Mycobacterium tuberculosis (M. tuberculosis) strains. Preliminary druggability evaluation demonstrated that M-1 showed good aqueous solubility and hepatocyte stability. Benzothiopyranones with acyl, sulfonyl and phosphoryl groups exhibited potent in vitro inhibitory activity against M. tuberculosis H37Rv and low cytotoxicity. In particular, compound 3d, containing a benzoate fragment, displayed marked metabolic stability and potent in vitro activity against drug-resistant tuberculosis clinical strains. Further druggability evaluation based on the identified compounds 3d, 4e and 5b is ongoing for the discovery of promising anti-TB agents.


Assuntos
Amidas/farmacologia , Antituberculosos/farmacologia , Benzopiranos/farmacologia , Ésteres/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Amidas/química , Amidas/metabolismo , Antituberculosos/química , Antituberculosos/metabolismo , Benzopiranos/química , Benzopiranos/metabolismo , Relação Dose-Resposta a Droga , Ésteres/química , Ésteres/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
15.
Biomed Pharmacother ; 140: 111765, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34058438

RESUMO

Xenocoumacin (Xcn) 1 and 2 are the major antibiotics produced by the insect-pathogenic bacterium Xenorhabdus nematophila. Although the antimicrobial activity of Xcns has been explored, research regarding their action on mammalian cells is lacking. We aimed to investigate the action of Xcns in the context of inflammation and angiogenesis. We found that Xcns do not impair the viability of primary endothelial cells (ECs). Particularly Xcn2, but not Xcn1, inhibited the pro-inflammatory activation of ECs: Xcn2 diminished the interaction between ECs and leukocytes by downregulating cell adhesion molecule expression and blocked critical steps of the NF-κB activation pathway including the nuclear translocation of NF-κB p65 as well as the activation of inhibitor of κBα (IκBα) and IκB kinase ß (IKKß). Furthermore, the synthesis of pro-inflammatory mediators and enzymes, nitric oxide (NO) production and prostaglandin E2 (PGE2), inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2), was evaluated in leukocytes. The results showed that Xcns reduced viability, NO release, and iNOS expression in activated macrophages. Beyond these anti-inflammatory properties, Xcn2 effectively hindered pro-angiogenic processes in HUVECs, such as proliferation, undirected and chemotactic migration, sprouting, and network formation. Most importantly, we revealed that Xcn2 inhibits de novo protein synthesis in ECs. Consequently, protein levels of receptors that mediate the inflammatory and angiogenic signaling processes and that have a short half-live are reduced by Xcn2 treatment, thus explaining the observed pharmacological activities. Overall, our research highlights that Xcn2 exhibits significant pharmacological in vitro activity regarding inflammation and angiogenesis, which is worth to be further investigated preclinically.


Assuntos
Inibidores da Angiogênese/farmacologia , Anti-Inflamatórios/farmacologia , Benzopiranos/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Selectina E/genética , Selectina E/metabolismo , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/fisiologia , Camundongos , NF-kappa B/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Receptores de Fatores de Crescimento/biossíntese , Receptores de Fatores de Crescimento/genética , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
16.
Nat Commun ; 12(1): 2507, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947863

RESUMO

Notch1 is a crucial oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL), making it an attractive therapeutic target. However, the success of targeted therapy using γ-secretase inhibitors (GSIs), small molecules blocking Notch cleavage and subsequent activation, has been limited due to development of resistance, thus restricting its clinical efficacy. Here, we systematically compare GSI resistant and sensitive cell states by quantitative mass spectrometry-based phosphoproteomics, using complementary models of resistance, including T-ALL patient-derived xenografts (PDX) models. Our datasets reveal common mechanisms of GSI resistance, including a distinct kinase signature that involves protein kinase C delta. We demonstrate that the PKC inhibitor sotrastaurin enhances the anti-leukemic activity of GSI in PDX models and completely abrogates the development of acquired GSI resistance in vitro. Overall, we highlight the potential of proteomics to dissect alterations in cellular signaling and identify druggable pathways in cancer.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Oligopeptídeos/farmacologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Proteína Quinase C/metabolismo , Receptor Notch1/antagonistas & inibidores , Acetofenonas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Antineoplásicos/uso terapêutico , Benzopiranos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Imunoprecipitação da Cromatina , Cromatografia Líquida de Alta Pressão , Resistencia a Medicamentos Antineoplásicos/genética , Ontologia Genética , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos NOD , Fosforilação , Análise Serial de Proteínas , Biossíntese de Proteínas/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/genética , Proteínas Quinases/metabolismo , Proteômica , Receptor Notch1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas em Tandem , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Bioorg Med Chem Lett ; 41: 128008, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33831560

RESUMO

Various 6-alkynyl analogues of a known 3-nitro-2-(trifluoromethyl)-2H-chromene antagonist 3 of the Gq-coupled P2Y6 receptor (P2Y6R) were synthesized using a Sonogashira reaction to replace a 6-iodo group. The analogues were tested in a functional assay consisting of inhibition of calcium mobilization in P2Y6R-expressing astrocytoma cells elicited by native P2Y6R agonist UDP. 6-Ethynyl and 6-cyano groups were installed, and the alkynes were extended through both alkyl and aryl spacers. The most potent antagonists, with IC50 of ~1 µM, were found to be trialkylsilyl-ethynyl 7 and 8 (3-5 fold greater affinity than reference 3), t-butyl prop-2-yn-1-ylcarbamate 14 and p-carboxyphenyl-ethynyl 16 derivatives, and 3 and 8 displayed surmountable antagonism of UDP-induced production of inositol phosphates. Other chain-extended terminal carboxylate derivatives were less potent than the corresponding methyl ester derivatives. Thus, the 6 position in this chromene series is suitable for derivatization with flexibility of substitution, even with sterically extended chains, without losing P2Y6R affinity. However, a 3-carboxylic acid or 3-ester substitution did not serve as a nitro bioisostere, as the affinity was eliminated. These compounds provide additional ligand tools for the underexplored P2Y6R, which is a target for inflammatory, neurodegenerative and metabolic diseases.


Assuntos
Benzopiranos/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2/metabolismo , Benzopiranos/síntese química , Benzopiranos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Antagonistas do Receptor Purinérgico P2Y/síntese química , Antagonistas do Receptor Purinérgico P2Y/química , Relação Estrutura-Atividade
18.
Int J Mol Sci ; 22(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33920793

RESUMO

To investigate a possible methodology of exploiting herbal medicine and design polytherapy for the treatment of skin depigmentation disorder, we have made use of Vernonia anthelmintica (L.) Willd., a traditional Chinese herbal medicine that has been proven to be effective in treating vitiligo. Here, we report that the extract of Vernonia anthelmintica (L.) Willd. effectively enhances melanogenesis responses in B16F10. In its compound library, we found three ingredients (butin, caffeic acid and luteolin) also have the activity of promoting melanogenesis in vivo and in vitro. They can reduce the accumulation of ROS induced by hydrogen peroxide and inflammatory response induced by sublethal concentrations of copper sulfate in wild type and green fluorescent protein (GFP)-labeled leukocytes zebrafish larvae. The overall objective of the present study aims to identify which compatibility proportions of the medicines may be more effective in promoting pigmentation. We utilized the D-optimal response surface methodology to optimize the ratio among three molecules. Combining three indicators of promoting melanogenesis, anti-inflammatory and antioxidant capacities, we get the best effect of butin, caffeic acid and luteolin at the ratio (butin:caffeic acid:luteolin = 7.38:28.30:64.32) on zebrafish. Moreover, the effect of melanin content recovery in the best combination is stronger than that of the monomer, which suggests that the three compounds have a synergistic effect on inducing melanogenesis. After simply verifying the result, we performed in situ hybridization on whole-mount zebrafish embryos to further explore the effects of multi-drugs combination on the proliferation and differentiation of melanocytes and the expression of genes (tyr, mitfa, dct, kit) related to melanin synthesis. In conclusion, the above three compatible compounds can significantly enhance melanogenesis and improve depigmentation in vivo.


Assuntos
Melaninas/biossíntese , Vernonia/química , Animais , Anti-Inflamatórios/farmacologia , Benzopiranos/farmacologia , Ácidos Cafeicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Quimioterapia Combinada , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/patologia , Luteolina/farmacologia , Melaninas/genética , Melanoma Experimental/patologia , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Reprodutibilidade dos Testes , Peixe-Zebra/genética
19.
J Med Chem ; 64(9): 6397-6409, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33901399

RESUMO

Herein, relationships between the structures of 1-aminoethyl-substituted chromenes and their antimalarial activities were thoroughly investigated. At first, the methyl moiety in the side chain was removed to eliminate chirality. The hydrogenation state of the benzopyran system, the position of the phenolic OH moiety, and the distance of the basic amino moiety toward both aromatic rings were varied systematically. 1-Benzopyran-5-ol 8b (IC50 = 10 nM), 1-benzopyran-7-ol 9c (IC50 = 38 nM), and the aminoalcohol 19c (IC50 = 17 nM) displayed antiplasmodial activity with IC50 values below 50 nM. To identify the mechanism of action, inhibition of three key enzymes by 9c was investigated. 9c was not able to reduce the number of Plasmodia in erythrocytes of mice. This low in vivo activity was explained by fast clearance from blood plasma combined with rapid biotransformation of 9c. Three main metabolites of 9c were identified by liquid chromatography-mass spectrometry (LC-MS) methods.


Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Benzopiranos/química , Benzopiranos/farmacologia , Produtos Biológicos/química , Plasmodium/efeitos dos fármacos , Alquilação , Animais , Antimaláricos/síntese química , Benzopiranos/síntese química , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Técnicas de Química Sintética , Eritrócitos/efeitos dos fármacos , Eritrócitos/parasitologia , Cinética , Camundongos , Relação Estrutura-Atividade
20.
Antiviral Res ; 190: 105075, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33872675

RESUMO

The emerging SARS-CoV-2 infection is the cause of the global COVID-19 pandemic. To date, there are limited therapeutic options available to fight this disease. Here we examined the inhibitory abilities of two broad-spectrum antiviral natural products chebulagic acid (CHLA) and punicalagin (PUG) against SARS-CoV-2 viral replication. Both CHLA and PUG reduced virus-induced plaque formation in Vero-E6 monolayer at noncytotoxic concentrations, by targeting the enzymatic activity of viral 3-chymotrypsin-like cysteine protease (3CLpro) as allosteric regulators. Our study demonstrates the potential use of CHLA and PUG as novel COVID-19 therapies.


Assuntos
Antivirais/farmacologia , Benzopiranos/farmacologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Glucosídeos/farmacologia , Taninos Hidrolisáveis/farmacologia , SARS-CoV-2/efeitos dos fármacos , Sítio Alostérico , Animais , Antivirais/química , Benzopiranos/química , COVID-19/tratamento farmacológico , COVID-19/virologia , Chlorocebus aethiops , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/metabolismo , Descoberta de Drogas , Glucosídeos/química , Simulação de Acoplamento Molecular , Inibidores de Proteases/farmacologia , SARS-CoV-2/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos
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