Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 940
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Eur J Med Chem ; 187: 111954, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31838326

RESUMO

Great strides have been made in triple negative breast cancer (TNBC) treatment, which represents 20% of total predicted annual US breast cancer (BC) cases. Despite the development of several therapeutics, TNBC patients have poor overall survival rate, compared to other BC patients, justifying the urgent need to discover new entities for use to control TNBC. Chalcones are important natural products with diverse bioactivities including anticancer effects. This study aimed to design, synthesize and validate novel chalcone leads as potential therapies for TNBC. Fourteen novel chalcone analogs were designed and synthesized comprising alicyclic amines (pyrrolidine, morpholine and piperidine) or nitrogen mustard (Bis-(2-chloroethyl) amine) substituents. Among them, compound 14((E)-3-(4-(Bis(2-chloroethyl) amino) phenyl)-1-(3-methoxyphenyl) prop-2-en-1-one) was identified as the most effective against TNBC and other BC phenotypes, with anti-proliferative IC50 values ranging between 3.94 and 9.22 µM against the TNBC cell lines MDA-MB-231 and MDA-MB-468, as well as against the estrogen positive MCF-7 cell line. Chalcone 14 effectively suppressed the colony formation capacity of MDA-MB-231, MDA-MB-468, and MCF-7 cell lines at 5 and 10 µM treatment concentrations. Furthermore, compound 14 has significantly inhibited cell invasion and migration of MDA-MB-231 and MCF-7 BC cell lines. Additionally, compound 14 had significantly promoted apoptosis by upregulating BAX and downregulating Bcl-2 proteins. Compound 14 induced significant cell cycle arrest of TNBC cells at the G2/M phase. It also induced a reversal of Epithelial Mesenchymal Transition (EMT) by upregulating the epithelial markers E-cadherin and Pan-cadherin and downregulating FAK. Furthermore, it had dramatically diminished new vessel formation (vasculogenesis) in chick chorioallantoic membrane (CAM) model by 60.20 ± 8.47%. Chalcone 14 inhibited 46.41 ± 0.71% of the TNBC MAD-MB-231 cells growth in a nude mouse orthotopic xenograft model in comparison with vehicle control treated animals. Collectively, this study results propose chalcone 14 as a promising lead molecule for the control of TNBC as well as other breast cancer phenotypes.


Assuntos
Chalcona/farmacologia , Desenho de Fármacos , Nitrogênio/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chalcona/síntese química , Chalcona/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Nitrogênio/química , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas
2.
Parasitol Res ; 119(1): 165-175, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31807868

RESUMO

A novel library of synthetic piperidine derivatives was used to screen against human lymphatic filarial parasite Brugia malayi. Piperidine has earlier been reported to have effect against parasites including rodent filarial nematodes. Compounds with hydroxyl substitutions (4Q and 4H) showed marked antifilarial effect. Molecular docking of 4H derivative showed more favorable thermodynamic parameters against thymidylate synthase of B. malayi than human counterpart. A wide difference between IC50 and LD50 ensured the therapeutic safety of the candidates against the filarial parasites. Addition of thymidine to the treatment regimen led to a significant reversal of antifilarial effect of 4H that confirmed inhibition of thymidylate synthase as pharmacological rationale. Apoptosis induced in the parasite as a consequence of probable inhibition of thymidylate synthase was studied by acridine orange/ethidium bromide fluorescent staining and poly (ADP-ribose) polymerase activity inhibition. Involvement of mitochondria was confirmed by decreased 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) conversion and increased cytosolic cytochrome c level in 4H treated microfilariae, compared with the untreated microfilariae. Moreover, Michael adduct of chalcone targeting dihydrofolate reductase and piperidine targeting thymidylate synthase demonstrated synergistic effect on the parasite, indicating the importance of inhibition of DNA synthesis by combined effect. In conclusion, piperidine derivatives with hydroxyl substitution have a great therapeutic potential with an apoptotic rationale involving mitochondrial pathway, due to possible inhibition of parasitic thymidylate synthase.


Assuntos
Brugia Malayi/efeitos dos fármacos , Filariose Linfática/tratamento farmacológico , Filaricidas/farmacologia , Piperidinas/farmacologia , Timidilato Sintase/antagonistas & inibidores , Animais , Chalcona/farmacologia , Replicação do DNA/efeitos dos fármacos , Filariose Linfática/parasitologia , Antagonistas do Ácido Fólico/farmacologia , Humanos , Microfilárias/efeitos dos fármacos , Simulação de Acoplamento Molecular , Tetra-Hidrofolato Desidrogenase/efeitos dos fármacos , Sais de Tetrazólio , Timidina/farmacologia
3.
Eur J Med Chem ; 185: 111777, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31670201

RESUMO

Alzheimer's disease is a common neurodegenerative disease characterized by progressive degeneration and neuronal cell death, resulting in neural network dysfunction. As the underlying mechanisms, oxidative damage and neuroinflammation have been reported to contribute to the onset and deterioration of Alzheimer's disease. The nuclear factor E2-related factor 2-antioxidant responsive element signaling pathway is a pivotal cellular defense mechanism against oxidative stress. Nrf2, a transcription factor, regulates the cellular redox balance and is primarily involved in anti-inflammatory responses. In this study, we synthesized novel chalcone derivatives and found a highly potent Nrf2 activator, compound 20a. Compound 20a confirmed to activate Nrf2 and induce expression of the Nrf2-dependent enzymes HO-1 and GCLC at both mRNA and protein levels. It also suppressed the production of nitric oxide and downregulated inflammatory mediators in BV-2 microglial cells. We found that compound 20a effectively increased the expression level and the activity of superoxide dismutase in both BV-2 microglial cells and brain hippocampus region of the scopolamine-induced mouse model. In addition, compound 20a effectively recovered the learning and memory impairment in a scopolamine-induced mouse model.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Chalcona/farmacologia , Modelos Animais de Doenças , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Chalcona/síntese química , Chalcona/química , Relação Dose-Resposta a Droga , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Masculino , Transtornos da Memória/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Escopolamina , Relação Estrutura-Atividade
4.
Molecules ; 24(22)2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31718009

RESUMO

By means of copper(I)-and ruthenium(II)-catalyzed click reactions of quinine- and quinidine-derived alkynes with azide-substituted chalcones a systematic series of novel cinchona-chalcone hybrid compounds, containing 1,4-disubstituted- and 1,5-disubstituted 1,2,3-triazole linkers, were synthesized and evaluated for their cytotoxic activity on four human malignant cell lines (PANC-1, COLO-205, A2058 and EBC-1). In most cases, the cyclization reactions were accompanied by the transition-metal-catalyzed epimerization of the C9-stereogenic centre in the cinchona fragment. The results of the in vitro assays disclosed that all the prepared hybrids exhibit marked cytotoxicity in concentrations of low micromolar range, while the C9-epimerized model comprising quinidine- and (E)-1-(4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenyl) fragments, connected by 1,5-disubstituted 1,2,3-triazole linker, and can be regarded as the most potent lead of which activity is probably associated with a limited conformational space allowing for the adoption of a relatively rigid well-defined conformation identified by DFT modelling. The mechanism of action of this hybrid along with that of a model with markedly decreased activity were approached by comparative cell-cycle analyses in PANC-1 cells. These studies disclosed that the hybrid of enhanced antiproliferative activity exerts significantly more extensive inhibitory effects in subG1, S and G2/M phases than does the less cytotoxic counterpart.


Assuntos
Chalcona/química , Chalcona/farmacologia , Técnicas de Química Sintética , Cinchona/química , Triazóis/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalcona/síntese química , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 184: 111752, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610374

RESUMO

This study describes the synthesis of a series of chalcones, including pyrazole and α,ß-epoxide derivatives, and evaluation of their cell growth inhibitory activity in three human tumor cell lines, as well as their lipophilicity using liposomes as a biomimetic membrane model. Structure-activity and structure-lipophilicity relationships were established for the synthetized chalcones. From this work, nine chalcones (3, 5, 9, 11, 15-19) showing suitable drug-like lipophilicity with potent growth inhibitory activity were identified, being the growth inhibitory effect of compounds 15-17 associated with a pronounced antimitotic effect. Compounds 15-17 affected spindle assembly and, as a consequence, arrested cells at metaphase in NCI-H460 cells, culminating in cell death. Amongst the compounds tested, compound 15 exhibited the highest antimitotic activity as revealed by mitotic index calculation. Moreover, 15 was able to enhance chemosensitivity of tumor cells to low doses of paclitaxel in NCI-H460 cells. The results indicate that 15 exerts its antiproliferative activity by affecting microtubules and causing cell death subsequently to a mitotic arrest, and thus has the potential for antitumor activity.


Assuntos
Antineoplásicos/farmacologia , Chalcona/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chalcona/síntese química , Chalcona/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
6.
Inorg Chem ; 58(19): 12954-12963, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31550148

RESUMO

The luminescent chalcone gold(I) conjugates [Au(PPh3)(AN3E)]PF6(1) and [Au(SIMes)(AN3E)]PF6 (2) (AN3E = (E)-3-(9-anthracenyl)-1-(4-pyridyl)propenone; SIMes = N,N'-dimesitylimidazolidin-2-ylidene; Mes = 2,4,6-trimethylphenyl)) were prepared and characterized; complex 1 was also characterized by X-ray crystallography. In MTT assays against a panel of three human colon, a melanoma and a breast cancer cell lines both complexes were antiproliferative with low micromolar IC50 values. It is noteworthy that HCT116p53-/- colon carcinoma cells lacking functional p53 (a vital tumor suppressor) were more susceptible to them than the wildtype parent cell line. In flow cytometry analyses, the gold conjugates induced a significant arrest in G2/M phase primarily. Complexes 1 and 2 quickly increased the production of reactive oxygen species (ROS) and induced mitochondrial membrane potential depolarization, higher ROS values being obtained after coadministration with enzymatic inhibitors. The free chalcone AN3E and its gold(I) complex conjugates located in the cell mitochondria according to confocal microscopy. In addition, complexes 1 and 2 showed in vivo antivascular effects on the chorioallantoic membrane (CAM) of fertilized specific-pathogen-free (SPF) chicken eggs.


Assuntos
Inibidores da Angiogênese/farmacologia , Antracenos/farmacologia , Antineoplásicos/farmacologia , Chalcona/farmacologia , Neoplasias do Colo/tratamento farmacológico , Compostos Organoáuricos/farmacologia , Inibidores da Angiogênese/química , Animais , Antracenos/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalcona/análogos & derivados , Galinhas , Cristalografia por Raios X , Células HCT116 , Humanos , Modelos Moleculares , Compostos Organoáuricos/química
7.
Inflammation ; 42(6): 2048-2055, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31473901

RESUMO

High-fat diet (HFD) increases the risk of non-communicable inflammatory diseases including pulmonary disorders. Trans-chalcone is a chalcone with antioxidant and anti-inflammatory effects. This study aimed to explore the effect of this natural compound and molecular mechanism of its effect on HFD-induced pulmonary inflammation. Twenty-eight male Wistar rats were randomly divided into four main groups (n = 7 per each group): control, receiving 10% tween 80; Chal, receiving trans-chalcone, HFD, receiving a high-fat emulsion and 10% tween 80; HFD + Chal, receiving a high-fat emulsion and trans-chalcone. After 6 weeks, the lungs were dissected, and the expression levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and miR-146a were determined using real-time PCR. Moreover, histological analysis was done by hematoxylin and eosin staining. Significant elevations in TNF-α, IL-1ß, IL-6, and miR-146a expression levels (P < 0.001) were observed within the lungs of HFD-fed rats compared with the control. However, oral administration of trans-chalcone reduced TNF-α, IL-1ß, IL-6 (P < 0.001), and miR-146a (P < 0.05) expression levels and also improved HFD-induced histological abnormalities. These findings indicate that trans-chalcone ameliorates lung inflammatory response and structural alterations. It seems that this beneficial effect is associated with the down-regulation of pro-inflammatory cytokines and miR-146a.


Assuntos
Chalcona/uso terapêutico , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , MicroRNAs/metabolismo , Pneumonia/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Chalcona/farmacologia , Citocinas/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Pneumonia/induzido quimicamente , Ratos
8.
Biol Pharm Bull ; 42(11): 1942-1946, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31462605

RESUMO

Amyloid ß protein (Aß) causes neurotoxicity and cognitive impairment in Alzheimer's disease (AD). Oxidative stress is closely related to the pathogenesis of AD. We have previously reported that 2',3'-dihydroxy-4',6'-dimethoxychalcone (DDC), a component of green perilla, enhances cellular resistance to oxidative damage through the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway. Here, we investigated the effects of DDC on cortical neuronal death induced by Aß. When Aß and DDC had been preincubated for 3 h, the aggregation of Aß was significantly suppressed. In this condition, we found that DDC provided a neuroprotective action on Aß-induced cytotoxicity. Treatment with DDC for 24 h increased the expression of heme oxygenase-1 (HO-1), and this was controlled by the activation of the Nrf2-ARE pathway. However, DDC did not affect Aß-induced neuronal death under any of these conditions. These results suggest that DDC prevents the aggregation of Aß and inhibits neuronal death induced by Aß, and although it activates the Nrf2-ARE pathway, this mechanism is less involved its neuroprotective effect.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Chalcona/análogos & derivados , Chalcona/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/metabolismo , Heme Oxigenase-1/metabolismo , Síndromes Neurotóxicas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Perilla , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
9.
Food Funct ; 10(8): 4661-4673, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31292579

RESUMO

Hydroxysafflor yellow A (HSYA) is the main active ingredient of edible plant safflower. HSYA has demonstrated anti-inflammatory effects. The inflammatory response is the key mechanism responsible for asthma, and the pro-inflammatory platelet-activating factor (PAF) is known to play a role in the pathology of bronchial asthma. In this study, we stimulated human bronchial smooth muscle cells (HBSMCs) with PAF and examined the effects of HSYA on the resulting asthma-related process. PAF stimulation induced HBSMC activation, induced proliferation, increased expression of the pro-inflammatory cytokines interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α, and activated asthma-related signaling pathways. All these effects were significantly inhibited by treatment with HSYA (9, 27, 81 µmol L-1). The effects of HSYA were prevented by the addition of a PAF receptor (PAFR) antagonist or by PAFR gene silencing with small interfering RNA. These results suggest that HSYA may inhibit PAF-induced activation of HBSMCs by targeting the PAFR. Overall, these findings provide evidence that HSYA can be applied as a potential therapeutic agent in the treatment of bronchial asthma.


Assuntos
Brônquios/efeitos dos fármacos , Chalcona/análogos & derivados , Músculo Liso/metabolismo , Fator de Ativação de Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo , Quinonas/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Brônquios/metabolismo , Chalcona/farmacologia , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Músculo Liso/efeitos dos fármacos , NF-kappa B/genética , NF-kappa B/metabolismo , Fator de Ativação de Plaquetas/genética , Glicoproteínas da Membrana de Plaquetas/genética , Receptores Acoplados a Proteínas-G/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
10.
Microbiol Immunol ; 63(10): 438-443, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31329291

RESUMO

The effects of chalcone and butein on the induction of the superoxide anion (O2 - )-generating system were studied in U937 cells by all-trans retinoic acid (RA). The chalcone skeleton, a common structural motif in them, significantly enhanced the transcription of gp91-phox in an epigenetic manner. In contrast, chalcone and butein showed opposite effects on the induction of the O2 - -generating activity by RA and the expression of gp91-phox protein. Chalcone inhibited, whereas butein promoted, the induction of O2 - -generating activity by RA and the expression of gp91-phox protein. These data raise the possibility that modification of the chalcone skeleton could produce more effective differentiation-promoting agents.


Assuntos
Chalcona/farmacologia , Chalconas/farmacologia , NADPH Oxidase 2/genética , NADPH Oxidase 2/metabolismo , Superóxidos/metabolismo , Humanos , Tretinoína/química , Células U937
11.
Zhongguo Zhong Yao Za Zhi ; 44(12): 2566-2571, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31359725

RESUMO

This study was to investigate the mechanism of safflower yellow injection for regulating inflammatory response against myocardial ischemia-reperfusion injury( MIRI) in rats. Male Wistar rats were randomly divided into sham operation group,model group,Hebeishuang group,safflower yellow injection high,medium and low dose groups. MIRI model was established by ligating left anterior descending coronary artery. Myocardial histopathological changes were observed by HE staining; myocardial infarct size was detected by TTC staining; content and changes of tumor necrosis factor-α( TNF-α) and interleukin-6( IL-6),serum creatine kinase( CK),aspartate aminotransferase( AST),and lactate dehydrogenase( LDH) were detected by biochemical method or enzyme-linked immunosorbent assay( ELISA). Western blot assay was used to detect the protein expression of Toll-like receptor 4( TLR4) and nuclear factor-κB( NF-κB p65) in myocardial tissues. The results showed that as compared with the sham operation group,the myocardial arrangement of the model group was disordered,with severe edemain the interstitial,significantly increased area of myocardial infarction,increased activities of AST,CK and LDH in serum,and significantly increased contents of TNF-α and IL-6; the expression levels of TLR4 and NF-κB( p65) protein in myocardial tissues were also increased. As compared with the model group,the myocardial tissues were arranged neatlyin the Hebeishuang group and safflower yellow injection high,medium and low dose groups; the edema was significantly reduced; the myocardial infarct size was significantly reduced; the serum AST,CK,LDH activity and TNF-α,IL-6 levels were significantly decreased,and the expression levels of TLR4 and NF-κB( p65) protein in myocardial tissues were decreased. As compared with the Hebeishuang group,the myocardial infarct size was larger in the safflower yellow injection high,medium and low dose groups; the activities of AST,CK and LDH in serum and the contents of TNF-α and IL-6 in serum were higher,but there was no statistically significant difference in the expression levels of TLR4 and NF-κB( p65) protein in tissues. It is suggested that safflower yellow injection has a significant anti-MIRI effect,and its mechanism may be related to the regulation of TLR-NF-κB pathway to inhibit inflammatory response.


Assuntos
Anti-Inflamatórios/farmacologia , Chalcona/análogos & derivados , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Animais , Aspartato Aminotransferases/sangue , Chalcona/farmacologia , Creatina Quinase/sangue , Interleucina-6/metabolismo , L-Lactato Desidrogenase/sangue , Masculino , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
12.
Eur J Med Chem ; 180: 238-252, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31310916

RESUMO

A series of novel chalcone derivatives was designed, synthesized and evaluated as multifunctional agents for the treatment of AD. Among of these synthesized compounds, compound TM-2 was a selective BuChE inhibitor (IC50 = 2.6 µM) and selective MAO-B inhibitor (IC50 = 5.3 µM), which were supported by docking study. Compound TM-2 also showed good antioxidant activity, and was a selective metal chelator, as well as a neuroprotectant. Moreover, compound TM-2 could significantly inhibit self-induced and Cu2+-induced Aß1-42 aggregation with 70.2% and 80.7% inhibition rate, respectively, and could disaggregate Cu2+-induced Aß1-42 aggregation (73.5%), the further TEM images observed provided rational explanation. Besides, compound TM-2 displayed good PAMPA-BBB permeability and conformed to the Lipinski's rule of five. Further, compound TM-2 presented precognitive effect on scopolamine-induced memory impairment in vivo assay. Therefore, compound TM-2 might be a promising multifunctional hit compound for the treatment of AD, and the further structure optimization are in progress.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Chalcona/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Chalcona/síntese química , Chalcona/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Enguias , Cavalos , Humanos , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos
13.
Chem Biol Interact ; 310: 108741, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31299238

RESUMO

Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in redox homeostasis. Activation of Nrf2 pathway by natural molecules effectively inhibits oxidants and toxicants-induced redox imbalance, and thus is able to intervene the onset and progression of many human diseases. In our previous study, a chalcone named as artocarmitin B (ACB), formed by artocarmitin A (ACA) and a trans-feruloyl substituent, was found to be a potential Nrf2 activator. In the present research, we found that ACB up-regulated the expressions of Nrf2, NAD(P)H: quinone oxidoreductase 1 (NQO1) and glutamate-cysteine ligase, modifier subunit (GCLM), inhibited Nrf2 degradation and promoted Nrf2 translocation to the nucleus under non-toxic doses. Moreover, ACB enhanced intracellular antioxidant capability in human lung epithelial cells through up-regulating reduced glutathione (GSH) level. Furthermore, ACB-induced activation of Nrf2 was related to the kinase pathways, including mitogen-activated protein kinase (MAPK), protein kinase C (PKC), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and protein kinase R-like endoplasmic reticulum kinase (PERK). In terms of activation of Nrf2 pathway, ACB was more potent than ACA and ferulic acid (FA) individually or in combination. Collectively, our results indicate that ACB is an novel Nrf2 activator and enhances intracellular antioxidant capacity in human lung epithelial cells.


Assuntos
Antioxidantes/farmacologia , Chalcona/farmacologia , Células Epiteliais/metabolismo , Pulmão/citologia , Fator 2 Relacionado a NF-E2/metabolismo , Chalcona/uso terapêutico , Glutationa/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Transdução de Sinais
14.
Phytochemistry ; 164: 228-235, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31181354

RESUMO

Terminthia paniculata (Sanyeqi) is widely used for treating inflammation and rheumatic arthritis in the folk areas of Yunnan province, China. Its total extract was first revealed with xanthine oxidase (XO) inhibitory activity in vitro and anti-hyperuricemic effect in vivo. Bioassay-guided separation on Fr. A5 yielded six chalcone-flavonone heterodimers, termipaniculatones A-F. Their structures were elucidated based on extensive spectroscopic analyses involving HRESIMS, 1D and 2D NMR, UV, IR and [α]D, and the absolute configuration of termipaniculatone F was verified by ECD calculation. Termipaniculatones A and E showed obvious XO inhibitory activity with IC50 values of 55.6 and 89.5 µM, respectively, which took effects via a mix-type mode. A molecular modeling study revealed that termipaniculatone A was well located into the active site of XO by interacting with Glu802, Arg880, Thr1010 and Val1011 residues. Termipaniculatone A showed anti-hyperuricemic effects by decreasing serum uric acid levels and inhibiting XO activity in both serum and liver on potassium oxonate (PO)-induced hyperuricemia mice, and anti-inflammatory activity through alleviating paw swelling on monosodium urate (MSU)-induced mice, at the concentration of 20 mg/kg. This is the first time to reveal the anti-hyperuricemic and anti-acute gouty arthritis potency of T. paniculata and the characteristic biflavonoids as active constituents, which provides valuable information for searching new XO inhibitors from natural sources.


Assuntos
Anacardiaceae/química , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Gotosa/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Hiperuricemia/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/metabolismo , Chalcona/química , Chalcona/isolamento & purificação , Chalcona/farmacologia , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Flavanonas/química , Flavanonas/isolamento & purificação , Flavanonas/farmacologia , Hiperuricemia/induzido quimicamente , Hiperuricemia/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Ácido Oxônico/antagonistas & inibidores , Relação Estrutura-Atividade , Ácido Úrico/antagonistas & inibidores , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismo
15.
BMC Genomics ; 20(1): 411, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31117938

RESUMO

BACKGROUND: Trichophyton rubrum is the main etiological agent of skin and nail infections worldwide. Because of its keratinolytic activity and anthropophilic nature, infection models based on the addition of protein substrates have been employed to assess transcriptional profiles and to elucidate aspects related to host-pathogen interactions. Chalcones are widespread compounds with pronounced activity against dermatophytes. The toxicity of trans-chalcone towards T. rubrum is not fully understood but seems to rely on diverse cellular targets. Within this context, a better understanding of the mode of action of trans-chalcone may help identify new strategies of antifungal therapy and reveal new chemotherapeutic targets. This work aimed to assess the transcriptional profile of T. rubrum grown on different protein sources (keratin or elastin) to mimic natural infection sites and exposed to trans-chalcone in order to elucidate the mechanisms underlying the antifungal activity of trans-chalcone. RESULTS: Overall, the use of different protein sources caused only slight differences in the transcriptional profile of T. rubrum. The main differences were the modulation of proteases and lipases in gene categories when T. rubrum was grown on keratin and elastin, respectively. In addition, some genes encoding heat shock proteins were up-regulated during the growth of T. rubrum on keratin. The transcriptional profile of T. rubrum exposed to trans-chalcone included four main categories: fatty acid and lipid metabolism, overall stress response, cell wall integrity pathway, and alternative energy metabolism. Consistently, T. rubrum Mapk was strongly activated during the first hours of trans-chalcone exposure. Noteworthy, trans-chalcone inhibited genes involved in keratin degradation. The results also showed effects of trans-chalcone on fatty acid synthesis and metabolic pathways involved in acetyl-CoA supply. CONCLUSION: Our results suggest that the mode of action of trans-chalcone is related to pronounced changes in fungal metabolism, including an imbalance between fatty acid synthesis and degradation that interferes with cell membrane and cell wall integrity. In addition, this compound exerts activity against important virulence factors. Taken together, trans-chalcone acts on targets related to dermatophyte physiology and the infection process.


Assuntos
Parede Celular/química , Chalcona/farmacologia , Ácidos Graxos/metabolismo , Proteínas Fúngicas/metabolismo , Tinha/metabolismo , Trichophyton/metabolismo , Fatores de Virulência/antagonistas & inibidores , Antifúngicos/farmacologia , Parede Celular/genética , Elastina/metabolismo , Proteínas Fúngicas/genética , Perfilação da Expressão Gênica , Regulação Fúngica da Expressão Gênica , Humanos , Queratinas/metabolismo , Transdução de Sinais , Tinha/tratamento farmacológico , Tinha/microbiologia , Trichophyton/efeitos dos fármacos , Trichophyton/genética
16.
Recent Pat Anticancer Drug Discov ; 14(2): 187-197, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31096897

RESUMO

BACKGROUND: A recent patent has been issued for hydroxysafflor yellow A (HSYA) as a drug to prevent blood circulation disorders. Hydroxysafflor yellow B (HSYB), an isomer of HSYA with antioxidative effects, has been isolated from the florets of Carthamus tinctorius. The effects of HSYB on the proliferation of cancer cells and its mechanism of action have not been investigated. OBJECTIVE: The aims of this study were to investigate the anti-cancer effects and the molecular mechanism of HSYB for breast cancer MCF-7 cells. METHODS: MTT assays and colony formation assays were used to assess the survival and proliferation of MCF-7 cells, respectively. Hoechst 33258 and flow cytometry were used to measure cell apoptosis and flow cytometry to determine effects on the cell cycle. Western blots were used to measure protein levels. RESULTS: Treatment with HSYB reduced survival and proliferation of human breast cancer MCF-7 cells in a dose-dependent manner. Furthermore, HSYB arrested the MCF-7 cell cycle at the S phase and downregulated cyclin D1, cyclin E, and CDK2. Compared with a control group, HSYB suppressed the protein levels of p-PI3K, PI3K, AKT, and p-AKT in MCF-7 cells. In addition, HSYB decreased the levels of Bcl- 2, increased the levels of Bax, cleaved caspase-3 and caspase-9, and subsequently induced MCF-7 cell apoptosis. CONCLUSION: These data demonstrate that HSYB arrests the MCF-7 cell cycle at the S phase and induces cell apoptosis. Patent US20170246228 indicates that HSYB can be potentially used for the prevention and treatment of human breast cancer.


Assuntos
Adenocarcinoma/patologia , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Pigmentos Biológicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Chalcona/análogos & derivados , Chalcona/química , Chalcona/farmacologia , Feminino , Humanos , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pigmentos Biológicos/química , Quinonas/química , Quinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos
17.
Eur J Med Chem ; 173: 1-14, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30981112

RESUMO

Further optimization of the trimethoxyphenyl scaffold of parent chalcone compound (2a) by introducing a pyridine ring afforded a series of novel pyridine-chalcone derivatives as potential anti-tubulin agents. All the target compounds were evaluated for their antiproliferative activities. Among them, representative compound 16f exhibited the most potent activity with the IC50 values ranging from 0.023 to 0.045 µM against a panel of cancer cell lines. Further mechanism study results demonstrated that compound 16f effectively inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Moreover, cellular mechanism studies disclosed that 16f caused G2/M phase arrest, induced cell apoptosis and disrupted the intracellular microtubule network. Also, 16f reduced the cell migration and disrupted the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs). Importantly, 16f significantly inhibited tumor growth in H22 xenograft models without apparent toxicity, which was stronger than the reference compound CA-4, indicating that it is worthy to investigate 16f as a potent microtubule-destabilizing agent for cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Chalcona/farmacologia , Desenho de Fármacos , Microtúbulos/efeitos dos fármacos , Piridinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalcona/síntese química , Chalcona/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células K562 , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microtúbulos/metabolismo , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Cicatrização/efeitos dos fármacos
18.
Biomed Pharmacother ; 114: 108815, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30954890

RESUMO

This study aimed to explore mechanisms of the effects of hydroxysafflor yellow A (HSYA) on neural stem cells (NSCs) after heat stress (HS). Rat NSCs cells were cultured at 42 °C to impose heat stress. Cell counting kit-8 and Edu assay were used to analyze NSC proliferation. Annexin V/PI apoptosis kit was used to detect NSC apoptosis. Expression and phosphorylation of autophagy and apoptosis-associated proteins were determined by western blotting. We showed that HSYA significantly promoted proliferation and attenuated apoptosis of NSCs after heat stress. HSYA also increased Bcl-2 expression but decreased the expression of Bax and cleaved caspase-3 in NSCs induced by heat stress. In addition, HSYA decreased p38 and Hsp27-78 phosphorylation and MK-2 expression after heat stress, which was consistent with NSCs treated with SB203850 treatment or p38 knockdown. Furthermore, we demonstrated that heat stress increased LC3-II expression and mTOR phosphorylation, and decreased the expression of p62 in NSCs, while HSYA, SB203850 treatment or p38 knockdown reversed these alterations. In conclusion, HSYA significantly reversed the apoptosis and autophagy of NSCs induced by heat stress (P < 0.05), via downregulating MK2 expression and p38 and Hsp27-78 phosphorylation.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Chalcona/análogos & derivados , Resposta ao Choque Térmico/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Quinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Chalcona/farmacologia , Proteínas de Choque Térmico/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Ratos
19.
J Enzyme Inhib Med Chem ; 34(1): 863-876, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30915862

RESUMO

The present study describes the synthesis of a series of 22 chalcone analogs. These compounds were evaluated as potential human MAO-A and MAO-B inhibitors. The compounds showed varied selectivity against the two isoforms. The IC50 values were found to be in the micromolar to submicromolar range. The Ki values of compound 16 were determined to be 0.047 and 0.020 µM for the inhibition of MAO-A and MAO-B, respectively. Dialysis of enzyme-inhibitor mixtures indicated a reversible competitive mode of inhibition. Most of the synthesized chalcone analogs showed a better selectivity toward MAO-B. However, introducing of 2,4,6-trimethoxy substituents on ring B shifted the selectivity toward MAO-A. In addition, we investigated the molecular mechanism of MAO-B inhibition by selected chalcone analogs. Our results revealed that these selected chalcone analogs increased dopamine levels in the rat hepatoma (H4IIE) cells and decreased the relative mRNA expression of the MAO-B enzyme.


Assuntos
Chalcona/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Chalcona/síntese química , Chalcona/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Relação Estrutura-Atividade
20.
Hum Exp Toxicol ; 38(6): 685-693, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30873871

RESUMO

High glucose (HG) induces vascular injury in diabetes. Hydroxysafflor yellow A (HSYA) has been used to ameliorate ischemic cardiovascular diseases in China for many years. In the present study, we assessed whether HSYA has a potential protective role in HG-induced human umbilical vein endothelial cell (HUVEC) injury. Cell viability was determined with an 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Cell apoptosis was detected by fluorescein isothiocyanate/propidium iodide staining assay. The endothelial cell permeability was measured with a permeability assay. Cell adhesion molecule (CAM) expression, vascular endothelial growth factor, and basic fibroblast growth factor levels were detected with an enzyme-linked immunosorbent assay. Reactive oxygen species (ROS) formation was measured with a DCF-DA assay. Protein expression of NADPH oxidase 4 (NOX4) was measured by Western blotting. Our data indicated that HG increases HUVEC apoptosis, vascular permeability, monocyte adhesion, the level of CAMs, the formation of ROS, and NOX4 expression. Our data revealed that HG increases vascular injury, which is attenuated by HSYA. Because vascular inflammation has a key role in the development of diabetes mellitus, our results implied that HSYA is considered as a potential agent for diabetic vascular injury treatment.


Assuntos
Chalcona/análogos & derivados , Glucose/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Pigmentos Biológicos/farmacologia , Quinonas/farmacologia , Adesão Celular/efeitos dos fármacos , Chalcona/farmacologia , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , NADPH Oxidase 4/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células THP-1 , Molécula 1 de Adesão de Célula Vascular/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA