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1.
J Enzyme Inhib Med Chem ; 35(1): 139-144, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31724435

RESUMO

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


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Chalconas/farmacologia , Naftalenos/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalconas/química , Colchicina/antagonistas & inibidores , Colchicina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Naftalenos/química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
2.
Eur J Med Chem ; 183: 111737, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31581002

RESUMO

A series of novel chalcone-O-alkylamine derivatives were designed, synthesized and evaluated as multifunctional anti-Alzheimer's disease agents. Based on the experimental results, compound 23c exhibited good inhibitory potency on both acetylcholinesterase (IC50 = 1.3 ±â€¯0.01 µM) and butyrylcholinesterase (IC50 = 1.2 ±â€¯0.09 µM). Besides, 23c exhibited selective MAO-B inhibitory activity with IC50 value of 0.57 ±â€¯0.01 µM. Compound 23c was also a potential antioxidant and neuroprotectant. In addition, compound 23c could inhibit self-induced Aß1-42 aggregation. Moreover, compound 23c was a selective metal chelator, and could inhibit and disaggregate Cu2+-induced Aß1-42 aggregation, which was supported by the further transmission electron microscopy images. Furthermore, 23c could cross the blood-brain barrier in vitro, and improved scopolamine-induced memory impairment in vivo assay. Molecular modeling studies showed that 23c could bind to the active site of AChE, BuChE, Aß1-42 and MAO-B. Taken together, these results suggested that compound 23c might be a potential multifunctional agent for the treatment of AD.


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Chalconas/química , Inibidores da Colinesterase/química , Peptídeos beta-Amiloides/efeitos dos fármacos , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Chalconas/farmacologia , Quelantes/química , Inibidores da Colinesterase/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Cobre/química , Desenho de Drogas , Feminino , Humanos , Masculino , Transtornos da Memória/tratamento farmacológico , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Ligação Proteica , Escopolamina/metabolismo , Relação Estrutura-Atividade
3.
Eur J Med Chem ; 182: 111637, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494471

RESUMO

Natural products like coumarins, chalcones, and resveratrol have inherent biological activity in several models of diseases; therefore, their natural dimeric forms are highlighted in this review and their key structural similarities, isolation and pharmacological significance is discussed. These natural products may be dimerized during their biosynthesis, which proceeds through atom- and energy-sufficient methods involving dimeric enzymes, to provide complex structures from simple compounds. Coumarin-derived dimers features the C-C or C-O-C biaryl, terpene sidechain linkages or by cyclobutane ring and acts as inhibitors of α-glucosidase, and cytochrome p450 while some show anti-inflammatory and anti-viral activities, while chalcone-derived dimers have the 1,3-dihydroxy phenyl (resorcinol) substitution on the periphery of cyclobutane or cyclohexane ring and inhibit topoisomerase, protein tyrosine phosphatase 1B (PTP1B), and cathepsins and others possess anti-cancer, anti-inflammatory, and anti-plasmodial activities. Resveratrol-derived dimers have the resorcinol structure and are formed by oxidative coupling showing antioxidant, neuroprotective, anti-HIV, anti-tyrosinase, and cytotoxic activity. Bioavailability evidence of closely related structural monomers could be applicable to their dimeric forms. Application of bioisosteric principles to such dimeric compounds is also discussed. Overall, these dimeric natural products can provide potent templates for the natural product-based drug discovery against several diseases.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , DNA Topoisomerases/metabolismo , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase/farmacologia , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Chalconas/síntese química , Chalconas/química , Chalconas/farmacologia , Cumarínicos/síntese química , Cumarínicos/química , Cumarínicos/farmacologia , Dimerização , Humanos , Estrutura Molecular , Resveratrol/síntese química , Resveratrol/química , Resveratrol/farmacologia , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/química
4.
Anal Chim Acta ; 1082: 146-151, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31472703

RESUMO

Glutathione (GSH) is an important antioxygen and free radical scavenger in the organism. Level of GSH in vivo is associated with many diseases and specific recognition for GSH is very important. Here, a pyrene chalcone derivative 1 1-(2-hydroxyphenyl)-3-(1-pyrenyl)-2-propen-1-one as specific probe for GSH was developed. The probe can give rise to rapid blue fluorescence enhancement for GSH based on Michael addition reaction in pure PBS solution with high sensitivity, fast response rate and high specificity. The compound also can be applied for GSH detection in HeLa cell. Simultaneously, the compound exhibits blue fluorescence emission enhancement in methanol-water (1:1, v/v) solution with fluorescence quantum yield being 0.45 due to the competition of water molecules for hydrogen bonds between hydroxyl and carbonyl and the formation of structurally regular rodlike crystals, which allows regulating fluorescence emission by different solvent condition.


Assuntos
Chalconas/química , Corantes Fluorescentes/química , Glutationa/análise , Pirenos/química , Chalconas/efeitos da radiação , Fluorescência , Corantes Fluorescentes/efeitos da radiação , Células HeLa , Humanos , Luz , Limite de Detecção , Modelos Químicos , Pirenos/efeitos da radiação , Espectrometria de Fluorescência/métodos
5.
Eur J Med Chem ; 180: 350-366, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31325783

RESUMO

Overexpression of P-glycoprotein (P-gp) is one of the major causes for multidrug resistance (MDR), which has become a major obstacle in cancer therapy. One hopeful approach to reverse the MDR is to develop inhibitors of P-gp in expression and/or function. Here, we designed and synthesized a series of chalcone derivatives as P-gp inhibitors and evaluated their potential reversal activities against MDR. Among them, the most active compound MY3 had little intrinsic cytotoxicity and showed the highest activity (RF = 50.19) in reversing DOX resistance in MCF-7/DOX cells. Further studies demonstrated that MY3 could increase intracellular accumulation of DOX and inhibit expression of P-gp at mRNA and protein levels. More importantly, MY3 significantly enhanced the efficacy of DOX against the tumor xenografts bearing MCF-7/DOX cells with the precondition of unchanged body weight. Therefore, MY3 might represent a promising lead to develop MDR reversal agents for cancer chemotherapy.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Chalconas/farmacologia , Desenho de Drogas , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Chalconas/síntese química , Chalconas/química , Relação Dose-Resposta a Droga , Doxorrubicina/química , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Células MCF-7 , Estrutura Molecular , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Relação Estrutura-Atividade
6.
Phytomedicine ; 63: 153014, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31323446

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR) gene alterations are associated with sensitization to tyrosine kinase inhibitors such as gefitinib in lung cancer. Some patients suffering from non-small cell lung cancer (NSCLC) have difficulty in treating the cancer due to resistance acquired to gefitinib with MET amplification. Therefore EGFR and MET may be attractive targets for lung cancer therapy. PURPOSE: This study aimed to investigate the anti-cancer activity of Licochalcone (LC)B extracted from Glycyrrhiza inflata, in gefitinib-sensitive or gefitinib-resistant NSCLC cells, and to define its mechanisms. STUDY DESIGN: We investigated the mechanism of action of LCB by targeting EGFR and MET in human NSCLC cells. METHODS: We used the HCC827 and HCC827GR lines as gefitinib-sensitive and -resistant cells respectively, and determined the effects of LCB on both, by performing cell proliferation assay, flow cytometry analysis and Western blotting. Targets of LCB were identified by pull-down/kinase assay and molecular docking simulation. RESULTS: LCB inhibited both EGFR and MET kinase activity by directly binding to their ATP-binding pockets. The ability of this interaction was verified by computational docking and molecular dynamics simulations. LCB suppressed viability and colony formation of both HCC827 and HCC827GR cells while exhibiting no cytotoxicity to normal cells. The induction of G2/M cell-cycle arrest and apoptosis by LCB was confirmed by Annexin V/7-AAD double staining, ER stress and reactive oxygen species induction, mitochondrial membrane potential loss and caspase activation as well as related-proteins regulation. Inhibition of EGFR and MET by LCB decreased ERBB3 and AKT axis activation. CONCLUSION: We provide insights into the LCB-mediated mechanisms involved in reducing cell proliferation and inducing apoptosis in NSCLC cells. This occurs through dual inhibition of EGFR and MET in NSCLC cells regardless of their sensitivity or resistance to gefitinib. LCB may be a promising novel therapeutic medicine for gefitinib-sensitive or resistant NSCLC treatment.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Chalconas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/metabolismo , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalconas/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/química , Receptores ErbB/metabolismo , Gefitinibe/farmacologia , Glycyrrhiza/química , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Espécies Reativas de Oxigênio/metabolismo
7.
Molecules ; 24(13)2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31269698

RESUMO

Licochalcone A, a flavonoid extracted from licorice root, has been shown to exhibit broad anti-inflammatory, anti-bacterial, anticancer, and antioxidative bioactivity. In this study, we investigated the antitumor activity of Licochalcone A against human osteosarcoma cell lines. The data showed that Licochalcone A significantly suppressed cell viability in MTT assay and colony formation assay in osteosarcoma cell lines. Exposure to Licochalcone A blocked cell cycle progression at the G2/M transition and induced extrinsic apoptotic pathway in osteosarcoma cell lines. Furthermore, we found the Licochalcone A exposure resulted in rapid ATM and Chk2 activation, and high levels of nuclear foci of phosphorylated Chk2 at Thr 68 site in osteosarcoma cell lines. In addition, Licochalcone A exposure significantly induced autophagy in osteosarcoma cell lines. When Licochalcone A-induced autophagy was blocked by the autophagy inhibitor chloroquine, the expression of activated caspase-3 and Annexin V positive cells were reduced, and cell viability was rescued in Licochalcone A-treated osteosarcoma cell lines. These data indicate that the activation of ATM-Chk2 checkpoint pathway and autophagy may contribute to Licochalcone A-induced anti-proliferating effect in osteosarcoma cell lines. Our findings display the possibility that Licochalcone A may serve as a potential therapeutic agent against osteosarcoma.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Autofagia/efeitos dos fármacos , Chalconas/farmacologia , Quinase do Ponto de Checagem 2/metabolismo , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chalconas/química , Humanos
8.
Molecules ; 24(14)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31336786

RESUMO

2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC), a principal natural chalcone of Cleistocalyx operculatus buds, suppresses the growth of many types of cancer cells. However, the effects of this compound on pancreatic cancer cells have not been evaluated. In our experiments, we explored the effects of this chalcone on two human pancreatic cancer cell lines. A cell proliferation assay revealed that DMC exhibited concentration-dependent cytotoxicity against PANC-1 and MIA PACA2 cells, with IC50 values of 10.5 ± 0.8 and 12.2 ± 0.9 µM, respectively. Treatment of DMC led to the apoptosis of PANC-1 by caspase-3 activation as revealed by annexin-V/propidium iodide double-staining. Western blotting indicated that DMC induced proteolytic activation of caspase-3 and -9, degradation of caspase-3 substrate proteins (including poly[ADP-ribose] polymerase [PARP]), augmented bak protein level, while attenuating the expression of bcl-2 in PANC-1 cells. Taken together, our results provide experimental evidence to support that DMC may serve as a useful chemotherapeutic agent for control of human pancreatic cancer cells.


Assuntos
Antineoplásicos/farmacologia , Chalconas/farmacologia , Extratos Vegetais/farmacologia , Syzygium/química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Apoptose/genética , Biomarcadores , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalconas/química , Regulação da Expressão Gênica , Humanos , Estrutura Molecular , Neoplasias Pancreáticas , Extratos Vegetais/química
9.
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
10.
Molecules ; 24(12)2019 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-31208152

RESUMO

Methylglyoxal (MG) acts as a reactive precursor of advanced glycation end products (AGEs). This compound is often connected with pathologies such as diabetes, neurodegenerative processes and diseases of aging. 2-iodo-4'-methoxychalcone (CHA79), a synthetic halogen-containing chalcone derivative, has been reported its anti-diabetic activity. This study aims to investigate the potential protective capability of CHA79 against MG-mediated neurotoxicity in SH-SY5Y cells. Results indicated CHA79 increased viability of cells and attenuated the rate of apoptosis in MG-exposed SH-SY5Y. CHA79 up-regulated expression of anti-apoptotic protein (Bcl-2) and down-regulated apoptotic proteins (Bax, cytochrome c, caspase-3, caspase-9). Moreover, CHA79 significantly up-regulated expression of neurotrophic factors, including glucagon-like peptide-1 receptor (GLP-1R), brain derived neurotrophic factor (BDNF), p75NTR, p-TrkB, p-Akt, p-GK-3ß and p-CREB. CHA79 attenuated MG-induced ROS production and enhanced the antioxidant defense including nuclear factor erythroid 2-related factor 2 (Nrf2), HO-1, SOD and GSH. Furthermore, CHA79 attenuated MG-induced reduction of glyoxalase-1 (GLO-1), a vital enzyme on removing AGE precursors. In conclusion, CHA79 is the first novel synthetic chalcone possessing the GLP-1R and GLO-1 activating properties. CHA 79 also exhibits neuroprotective effects against MG toxicity by enhancing neurotrophic signal, antioxidant defense and anti-apoptosis pathway.


Assuntos
Antioxidantes/farmacologia , Chalconas/farmacologia , Síndromes Neurotóxicas/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Chalconas/química , Humanos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia , Aldeído Pirúvico/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
11.
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
12.
Spectrochim Acta A Mol Biomol Spectrosc ; 222: 117190, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31177006

RESUMO

Chalcone derivative of (2E)­1­(3­bromo­2­thienyl)­3­(2,5­dimethoxyphenyl) prop­2­en­1­one (BTD) molecule has been deliberated for spectroscopic properties experimentally and theoretically. The title compound was characterized by FT-IR, FT-Raman and UV-Vis analyses. The structural activity and vibrational wavenumbers were calculated by a DFT method. The Natural Bond Orbital (NBO) analysis which reveals the hyper conjugative interactions of the present molecule has been performed. Meanwhile, the Chemical reactivity of Condensed Fukui function, MEP and HOMO-LUMO energies of the molecule were also analyzed. Furthermore, Multiwfn 3.3.9 program has been utilized to study MEP and the electron excitation analysis. Docking studies which play a significant role in determining the endothelial nitric oxide synthase inhibition activity of the present compound have also been carried out to predict the binding energy and inhibition constant of the title compound. In addition, drug resemblance parameters have also considered by QSAR study in which the comparison of chemical parameters of chalcone drugs of title molecule has been done.


Assuntos
Chalconas/química , Chalconas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Animais , Bovinos , Halogenação , Simulação de Acoplamento Molecular , Óxido Nítrico Sintase Tipo III/metabolismo , Relação Quantitativa Estrutura-Atividade , Teoria Quântica , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Termodinâmica
13.
Eur J Med Chem ; 178: 726-739, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31229875

RESUMO

To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a series of chalcone-O-carbamate derivatives was designed and synthesized based on the multitarget-directed ligands strategy. The in vitro biological activities were evaluated including AChE/BChE inhibition, MAO-A/MAO-B inhibition, antioxidant activities, Aß1-42 aggregation inhibition, metal-chelating properties and neuroprotective effects against H2O2-induced PC12 cell injury. The results showed compounds 5b and 5h indicated highly selective BChE inhibitory activity with IC50 values of 3.1 µM and 1.2 µM, respectively and showed highly selective MAO-B inhibitory potency with IC50 values of 1.3 µM and 3.7 µM, respectively. In addition, compounds 5b and 5h could inhibit self-induced Aß1-42 aggregation with 63.9% and 53.1% inhibition percent rate, respectively. Particularly, compound 5b was a potent antioxidant agent and neuroprotectant, as well as a selective metal chelator by chelating Cu2+ and Al3+. Moreover, compound 5b could inhibit and disaggregate Cu2+-induced Aß1-42 aggregation, which was further supported by the TEM images. Furthermore, compounds 5b and 5h could cross the blood-brain barrier (BBB) in vitro and conformed to the Lipinski's rule of five. Finally, the in vivo assay exhibited that compound 5b could improve scopolamine-induced cognitive impairment. Taken together, these results revealed that compound 5b might be a potential multifunctional agent for the treatment of AD, and deserved to do further structure optimization.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Chalconas/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Drogas , Inibidores da Monoaminoxidase/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Chalconas/síntese química , Chalconas/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Enguias , Feminino , Cavalos , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fragmentos de Peptídeos/antagonistas & inibidores , Agregados Proteicos/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
14.
J Nat Med ; 73(4): 847-854, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31218551

RESUMO

Two new flavonoid glycosides, 2',4'-dihydroxydihydrochalcone-4-O-ß-D-glucopyranoside (1) and medicarpin-3-O-ß-D-apiofuranosyl (1 → 2)-ß-D-glucopyranoside (2), together with 34 known flavonoids were isolated from the 75% EtOH extract of the dried roots of Glycyrrhiza uralensis Fisch. Their structures were elucidated on the basis of spectroscopic analyses. The flavonoids were classified into ten sub-types, namely, dihydrochalcone (1), pterocarpans (2-4), flavones (5-6), flavanones (7-11), chalcones (12-15), retro-chalcones (16-18), isoflavans (19-21), isoflavones (22-28), 3-arylcoumarins (29-30), and coumestans (31-36). The isolated flavonoids were evaluated for in vitro hepatoprotective activity against D-galactosamine-induced toxicity in human hepatoma HepG2 cells.


Assuntos
Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Glycyrrhiza uralensis/química , Linhagem Celular Tumoral , Chalconas/química , Chalconas/isolamento & purificação , Cumarínicos/química , Cumarínicos/isolamento & purificação , Flavanonas/química , Flavanonas/isolamento & purificação , Flavonas/química , Flavonas/isolamento & purificação , Flavonoides/química , Glicosídeos/química , Glycyrrhiza/química , Células Hep G2 , Humanos , Isoflavonas/química , Isoflavonas/isolamento & purificação , Raízes de Plantas/química , Pterocarpanos/química , Pterocarpanos/isolamento & purificação
15.
Food Funct ; 10(5): 2881-2887, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31070208

RESUMO

Three dihydrochalcone-derived polyphenols, huperolides A-C (1-3), along with thirteen known compounds (4-16) were isolated from the leaves of Malus hupehensis, the well-known tea crab apple in China. Their chemical structures were elucidated by extensive spectroscopic analysis including NMR (HSQC, HMBC, 1H-1H COSY and ROESY), HRMS and CD spectra. Huperolide A is a polyphenol with a new type of carbon skeleton, while huperolides B and C are a couple of atropisomers, which were isolated from natural sources for the first time. The antihyperglycemic effects of the isolated compounds were evaluated based on assaying their inhibitory activities against α-glucosidase. As a result, phlorizin (4), 3-hydroxyphloridzin (5), 3-O-coumaroylquinic acid (12) and ß-hydroxypropiovanillone (15) showed significant concentration-dependent inhibitory effects on α-glucosidase. Therefore, those compounds might be responsible for the antihyperglycemic effect of this herb, and are the most promising compounds to lead discovery of drugs against diabetes.


Assuntos
Chalconas/química , Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/química , Malus/química , Extratos Vegetais/química , Folhas de Planta/química , Polifenóis/química , China , Humanos , Análise Espectral , alfa-Glucosidases/química
16.
Molecules ; 24(10)2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31117192

RESUMO

Butein (3,4,2',4'-tetrahydroxychalcone) belongs to the chalcone family of flavonoids and possesses various biological activities. In this study, butein was synthesized through aldol condensation catalyzed by thionyl chloride (SOCl2)/ethyl alcohol (EtOH) for the first time. The optimal reaction conditions including the molar ratio of reactants, the dosage of catalyst, and the reaction time on the yield of product were investigated, and the straightforward strategy assembles the yield of butein up to 88%. Butein has been found to inhibit xanthine oxidase (XO) activity. Herein, the inhibitory mechanism of butein against XO was discussed in aspects of inhibition kinetic, fluorescence titration, synchronous fluorescence spectroscopy, and molecular docking. The inhibition kinetic analysis showed that butein possessed a stronger inhibition on XO in an irreversible competitive manner with IC50 value of 2.93 × 10-6 mol L-1. The results of fluorescence titrations and synchronous fluorescence spectroscopy indicated that butein was able to interact with XO at one binding site, and the fluorophores of XO were placed in a more hydrophobic environment with the addition of butein. Subsequently, the result of molecular docking between butein and XO protein revealed that butein formed hydrogen bonding with the amino acid residues located in the hydrophobic cavity of XO. All the results suggested that the inhibitory mechanism of butein on XO may be the insertion of butein into the active site occupying the catalytic center of XO to avoid the entrance of xanthine and inducing conformational changes in XO.


Assuntos
Catálise , Chalconas/síntese química , Óxidos de Enxofre/química , Xantina Oxidase/química , Sítios de Ligação , Domínio Catalítico , Chalconas/química , Etanol/química , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Cinética , Oxirredução , Conformação Proteica , Relação Estrutura-Atividade , Xantina Oxidase/antagonistas & inibidores
17.
J Enzyme Inhib Med Chem ; 34(1): 1093-1099, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31117836

RESUMO

Chalcones are valuable structures for drug discovery due to their broad bioactivity spectrum. In this study, we evaluated 20 synthetic chalcones against estrogen-receptor-positive breast cancer cells (MCF-7 line) and triple-negative breast cancer (TNBC) cells (MDA-MB-231 line). Antiproliferative screening by MTT assay resulted in two most active compounds: 2-fluoro-4'-aminochalcone (11) and 3-pyridyl-4'-aminochalcone (17). Their IC50 values ranged from 13.2 to 34.7 µM against both cell lines. Selected chalcones are weak basic compounds and maintained their antiproliferative activity under acidosis conditions (pH 6.7), indicating their resistance to ion-trapping effect. The mode of breast cancer cells death was investigated and chalcones 11 and 17 were able to induce apoptosis rather than necrosis in both lines. Antiproliferative target investigations with MCF-7 cells suggested 11 and 17 upregulated p53 protein expression and did not affect Sp1 protein expression. Future studies on chalcones 11 and 17 can define their in vivo therapeutic potential.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Chalconas/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Chalconas/síntese química , Chalconas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
18.
PLoS Negl Trop Dis ; 13(5): e0007030, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31125333

RESUMO

BACKGROUND: Chemotherapy is a principle tool for the control and prevention of piroplasmosis. The search for a new chemotherapy against Babesia and Theileria parasites has become increasingly urgent due to the toxic side effects of and developed resistance to the current drugs. Chalcones have attracted much attention due to their diverse biological activities. With the aim to discover new drugs and drug targets, in vitro and in vivo antibabesial activity of trans-chalcone (TC) and chalcone 4 hydrate (CH) alone and combined with diminazene aceturate (DA), clofazimine (CF) and atovaquone (AQ) were investigated. METHODOLOGY/PRINCIPAL FINDINGS: The fluorescence-based assay was used for evaluating the inhibitory effect of TC and CH on four Babesia species, including B. bovis, B. bigemina, B. divergens, B. caballi, and T. equi, the combination with DA, CF, and AQ on in vitro cultures, and on the multiplication of a B. microti-infected mouse model. The cytotoxicity of compounds was tested on Madin-Darby bovine kidney (MDBK), mouse embryonic fibroblast (NIH/3T3), and human foreskin fibroblast (HFF) cell lines. The half maximal inhibitory concentration (IC50) values of TC and CH against B. bovis, B. bigemina, B. divergens, B. caballi, and T. equi were 69.6 ± 2.3, 33.3 ± 1.2, 64.8 ± 2.5, 18.9 ± 1.7, and 14.3 ± 1.6 µM and 138.4 ± 4.4, 60.9 ± 1.1, 82.3 ± 2.3, 27.9 ± 1.2, and 19.2 ± 1.5 µM, respectively. In toxicity assays, TC and CH affected the viability of MDBK, NIH/3T3, and HFF cell lines the with half maximum effective concentration (EC50) values of 293.9 ± 2.9, 434.4 ± 2.7, and 498 ± 3.1 µM and 252.7 ± 1.7, 406.3 ± 9.7, and 466 ± 5.7 µM, respectively. In the mouse experiment, TC reduced the peak parasitemia of B. microti by 71.8% when administered intraperitoneally at 25 mg/kg. Combination therapies of TC-DA and TC-CF were more potent against B. microti infection in mice than their monotherapies. CONCLUSIONS/SIGNIFICANCE: In conclusion, both TC and CH inhibited the growth of Babesia and Theileria in vitro, and TC inhibited the growth of B. microti in vivo. Therefore, TC and CH could be candidates for the treatment of piroplasmosis after further studies.


Assuntos
Antiprotozoários/administração & dosagem , Babesia/efeitos dos fármacos , Babesia/crescimento & desenvolvimento , Babesiose/tratamento farmacológico , Chalconas/administração & dosagem , Theileria/efeitos dos fármacos , Theileria/crescimento & desenvolvimento , Theileriose/tratamento farmacológico , Animais , Antiprotozoários/química , Babesia/genética , Babesiose/parasitologia , Linhagem Celular , Chalconas/química , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Concentração Inibidora 50 , Camundongos Endogâmicos BALB C , Theileria/genética , Theileriose/parasitologia
19.
Eur J Med Chem ; 176: 135-148, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31102934

RESUMO

Angiogenesis plays an essential role in tumourigenesis and tumour progression, and anti-angiogenesis therapies have shown promising antitumour effects in solid tumours. 2-Methoxyestradiol (2ME2), an endogenous metabolite of estradiol, has been regarded as a potential antitumour agent mainly targeting angiogenesis. Here we synthesized a novel series of chalcones based on 2-methoxyestradiol and evaluated their potential activities against tumours. Compound 11e was demonstrated to have potent antiangiogenic activity. Further studies showed that 11e suppressed tumour growth in human breast cancer (MCF-7) xenograft models without obvious side effects. Evaluation of the mechanism revealed that 11e targeted the epithelial to mesenchymal transition (EMT) process in MCF-7 cells and inhibited HUVEC migration and then contributed to hindrance of angiogenesis. Thus, 11e may be a promising antitumour agent with excellent efficacy and low toxicity.


Assuntos
2-Metoxiestradiol/análogos & derivados , 2-Metoxiestradiol/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Chalconas/uso terapêutico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , 2-Metoxiestradiol/síntese química , 2-Metoxiestradiol/toxicidade , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/toxicidade , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalconas/síntese química , Chalconas/química , Chalconas/toxicidade , Galinhas , Membrana Corioalantoide/efeitos dos fármacos , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos Nus , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Estereoisomerismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Eur J Med Chem ; 176: 50-60, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096118

RESUMO

New sulfonamides 5/6 derived from 4-methoxyacetophenone 1 were synthesized by N-sulfonation reaction of ammonia (3) and aminopyrimidinone (4) with its sulfonyl chloride derivative 2. Sulfonamides 5 and 6 were used as precursors of two new series of chalcones 8a-f and 9a-f, which were obtained through Claisen-Schmidt condensation with aromatic aldehydes 7a-f. Compounds 5/6, 8a-d, 8f, 9a-d, and 9f were screened by the US National Cancer Institute (NCI) at 10 µM against sixty different human cancer cell lines (one-dose trial). Chalcones 8b and 9b satisfied the pre-determined threshold inhibition criteria and were selected for screening at five different concentrations (100, 10, 1.0, 0.1, and 0.01 µM). Compound 8b exhibited remarkable GI50 values ranging from 0.57 to 12.4 µM, with cytotoxic effects being observed in almost all cases, especially against the cell lines K-562 of Leukemia and LOX IMVI of Melanoma with GI50 = 0.57 and 1.28 µM, respectively. Moreover, all compounds were screened against Mycobacterium tuberculosis H37Rv, chalcones 8a-c and 9a-c were the most active showing MIC values between 14 and 42 µM, and interestingly they were devoid of antibacterial activity against Mycobacterium smegmatis and Staphylococcus aureus. These antituberculosis hits showed however low selectivity, being equally inhibitory to M. tuberculosis and mammalian T3T cells. The chalcone-sulfonamide hybrids 8a-f and 9a-f resulted to be appealing cytotoxic agents with significant antituberculosis activity.


Assuntos
Antineoplásicos/farmacologia , Antituberculosos/farmacologia , Chalconas/farmacologia , Sulfonamidas/farmacologia , Células 3T3 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/toxicidade , Linhagem Celular Tumoral , Chalconas/síntese química , Chalconas/química , Chalconas/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/toxicidade
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