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1.
J Am Soc Mass Spectrom ; 33(1): 181-188, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34939787

RESUMO

Affinity selection-mass spectrometry, which includes magnetic microbead affinity selection-screening (MagMASS), is ideal for the discovery of ligands in complex mixtures that bind to pharmacological targets. Therapeutic agents are needed to prevent or treat COVID-19, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Infection of human cells by SARS-CoV-2 involves binding of the virus spike protein subunit 1 (S1) to the human cell receptor angiotensin converting enzyme-2 (ACE2). Like antibodies, small molecules have the potential to block the interaction of the viral S1 protein with human ACE2 and prevent SARS-CoV-2 infection. Therefore, a MagMASS assay was developed for the discovery of ligands to the S1 protein. Unlike previous MagMASS approaches, this new assay used robotics for 5-fold enhancement of throughput and sensitivity. The assay was validated using the SBP-1 peptide, which is identical to the ACE2 amino acid sequence recognized by the S1 protein, and then applied to the discovery of natural ligands from botanical extracts. Small molecule ligands to the S1 protein were discovered in extracts of the licorice species, Glycyrrhiza inflata. In particular, the licorice ligand licochalcone A was identified through dereplication and comparison with standards using HPLC with high-resolution tandem mass spectrometry.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Descoberta de Drogas/métodos , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/química , Sítios de Ligação/efeitos dos fármacos , COVID-19/metabolismo , Chalconas/química , Chalconas/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Fabaceae/química , Humanos , Ligantes , Espectrometria de Massas/métodos , Simulação de Acoplamento Molecular , Ligação Proteica/efeitos dos fármacos , SARS-CoV-2/metabolismo
2.
Arch Microbiol ; 204(1): 63, 2021 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-34940944

RESUMO

The Staphylococcus aureus bacteria is a Gram-positive, immobile, non-spore bacterium, with catalase and positive coagulase, among other characteristics. It is responsible for important infections caused in the population and for hospital infections. Because of that many strategies are being developed to combat the resistance of microorganisms to drugs, in recent times, chalcones have been studied for this purpose. Chalcones are found in parts of plants and can be found, for example, in the roots, leaves, bark, among others, but are mainly found as petal pigments, they are a class of compounds considered an exceptional model due to chemical simplicity and a wide variety of biological activities. This study aimed to evaluate the ability of chalcone (E)-3-(2,4-dichlorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one to reverse the efflux pump resistance, present in the bacteria S. aureus 1199B and S. aureus K2068. The synthetic chalcone (E)-3-(2,4-dichlorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one was able to synergistically modulate the antibiotic Ciprofloxacino and Ethidium Bromide against the bacterial strain S. aureus K2068, and with the antibiotic Norfloxacino against the strain 1199B. Thus, it is suggested that this chalcone may be acting by inhibiting the efflux pump mechanism of these bactéria. The theoretical physicochemical and pharmacokinetic properties of chalcone showed that the chalocne did not present a severe risk of toxicity, such as genetic mutation or cardiotoxicity. Molecular docking showed that the chalcone could act as a competitive inhibitor of the MepA efflux pump, as at hinders the binding of other substrates, such as EtBr.


Assuntos
Chalcona , Chalconas , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Chalcona/farmacologia , Chalconas/farmacologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Staphylococcus aureus/metabolismo
3.
Chem Biol Interact ; 350: 109699, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34648814

RESUMO

Despite extensive efforts, cancer is still often considered as an incurable disease and initiation of novel drug development programs is crucial to improve the prognosis and clinical outcome of patients. One of the major approaches in designing the novel cancer drugs has historically comprised studies of natural agents with diverse anticancer properties. As only a marginal part of natural compounds has been investigated, this approach still represents an attractive source of new potential antitumor molecules. In this review article, different anticancer effects of plant-derived chalcone, butein, are discussed, including its growth inhibitory action, proapoptotic, antiangiogenic and antimetastatic activities in a variety of cancer cells. The molecular mechanisms underlying these effects are presented in detail, revealing interactions of butein with multiple cellular targets (Bcl-2/Bax, caspases, STAT3, cyclins, NF-κB, COX-2, MMP-9, VEGF/R etc.) and regulation of a wide range of intracellular signal transduction pathways. These data altogether allow a good basis for initiating further in vivo studies as well as clinical trials. Along with the efforts to overcome low bioavailability issues generally characteristic to plant metabolites, butein can be considered as a potential lead compound for safe and more efficient cancer drugs in the future.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Chalconas/farmacologia , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Anticarcinógenos/química , Anticarcinógenos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Chalconas/química , Chalconas/farmacocinética , Quimioprevenção , Sistemas de Liberação de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Nanotecnologia , Oxirredução
4.
Int J Mol Sci ; 22(19)2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34639190

RESUMO

Calcium signaling plays a vital role in the regulation of various cellular processes, including activation, proliferation, and differentiation of T-lymphocytes, which is mediated by ORAI1 and potassium (K+) channels. These channels have also been identified as highly attractive therapeutic targets for immune-related diseases. Licochalcone A is a licorice-derived chalconoid known for its multifaceted beneficial effects in pharmacological treatments, including its anti-inflammatory, anti-asthmatic, antioxidant, antimicrobial, and antitumorigenic properties. However, its anti-inflammatory effects involving ion channels in lymphocytes remain unclear. Thus, the present study aimed to investigate whether licochalcone A inhibits ORAI1 and K+ channels in T-lymphocytes. Our results indicated that licochalcone A suppressed all three channels (ORAI1, Kv1.3, and KCa3.1) in a concentration-dependent matter, with IC50 values of 2.97 ± 1.217 µM, 0.83 ± 1.222 µM, and 11.21 ± 1.07 µM, respectively. Of note, licochalcone A exerted its suppressive effects on the IL-2 secretion and proliferation in CD3 and CD28 antibody-induced T-cells. These results indicate that the use of licochalcone A may provide an effective treatment strategy for inflammation-related immune diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Chalconas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/antagonistas & inibidores , Canal de Potássio Kv1.3/antagonistas & inibidores , Proteína ORAI1/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Cálcio/metabolismo , Sinalização do Cálcio , Células HEK293 , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Células Jurkat , Canal de Potássio Kv1.3/genética , Canal de Potássio Kv1.3/metabolismo , Proteína ORAI1/genética , Proteína ORAI1/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
5.
Molecules ; 26(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34641467

RESUMO

Sulfonamidochalcones continue to assert themselves as versatile synthetic intermedi-ates and several articles continue to appear in literature describing their synthesis, chemical transformation and biological properties. These compounds are not only of interest from the medicinal chemistry context, their conformations and crystalline structures also continue to attract attention to explore non-covalent (intramolecular and intermolecular) interactions, control molecular conformations, and improve their physicochemical and optical properties. Despite an exhaustive list of examples of the ring-A sulfonamide-appended chalcones described in the literature, there is no com-prehensive review dedicated to their synthesis, structural and biological properties. This review focuses attention on the synthesis, structure and biological properties of the ring-A sulfonamide-appended chalcones (o/m/p-sulfonamidochalcones) as well as their potential as non-linear optical materials.


Assuntos
Chalconas/química , Chalconas/farmacologia , Desenho de Fármacos , Sulfonamidas/química , Animais , Antimaláricos/farmacologia , Antineoplásicos/farmacologia , Química Farmacêutica , Humanos , Inibidores de Fosfodiesterase/farmacologia , Relação Estrutura-Atividade
6.
Phytomedicine ; 93: 153785, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34638032

RESUMO

BACKGROUND: Acute lung injury (ALI) is a systemic inflammatory process, which has no pharmacological therapy in clinic. Accumulating evidence has demonstrated that natural compounds from herbs have potent anti-inflammatory efficacy in several disease models, which could be the potential candidates for the treatment of ALI. HYPOTHESIS/PURPOSE: Anti-inflammatory screening from natural product bank may provide new anti-inflammatory compounds for therapeutic target discovery and ALI treatment. METHODS: 165 natural compounds were screened for their anti-inflammatory activity in LPS-stimulated macrophages. PCR array, SPR and ELISA were used to determine the potential target of the most active compound, Cardamonin (CAR). The pharmacological effect of CAR was further evaluated in both LPS-stimulated macrophages and ALI mice model. RESULTS: Out of the screened 165 compounds, CAR significantly inhibited LPS-induced inflammatory cytokine secretion in macrophages. We further showed that CAR significantly inhibited NF-κB and JNK signaling activation, and thereby inflammatory cytokine production via directly interacting with MD2 in vitro. In vivo, our data show that CAR treatment inhibited LPS-induced lung damage, systemic inflammatory cytokine production, and reduced macrophage infiltration in the lungs, accompanied with reduced TLR4/MD2 complex in lung tissues, Treatment with CAR also dose-dependently increased survival in the septic mice induced by DH5α bacterial infection. CONCLUSION: We demonstrate that a natural product, CAR, attenuates LPS-induced lung injury and sepsis by inhibiting inflammation via interacting with MD2, leading to the inactivation of the TLR4/MD2-MyD88-MAPK/NF-κB pathway.


Assuntos
Lesão Pulmonar Aguda , Chalconas , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Chalconas/farmacologia , Citocinas/metabolismo , Lipopolissacarídeos , Pulmão/metabolismo , Antígeno 96 de Linfócito , Camundongos , NF-kappa B/metabolismo
7.
Nutrients ; 13(10)2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34684383

RESUMO

Rapid postprandial blood glucose elevation can cause lifestyle-related diseases, such as type II diabetes. The absorption of food-derived glucose is primarily mediated by sodium/glucose cotransporter 1 (SGLT1). Moderate SGLT1 inhibition can help attenuate postprandial blood glucose elevation and prevent lifestyle-related diseases. In this study, we established a CHO cell line stably expressing human SGLT1 and examined the effects of phytochemicals on SGLT1 activity. Among the 50 phytochemicals assessed, tangeretin and cardamonin inhibited SGLT1 activity. Tangeretin and cardamonin did not affect the uptake of L-leucine, L-glutamate, and glycyl-sarcosine. Tangeretin, but not cardamonin, inhibited fructose uptake, suggesting that the inhibitory effect of tangeretin was specific to the monosaccharide transporter, whereas that of cardamonin was specific to SGLT1. Kinetic analysis suggested that the suppression of SGLT1 activity by tangeretin was associated with a reduction in Vmax and an increase in Km, whereas suppression by cardamonin was associated with a reduction in Vmax and no change in Km. Oral glucose tolerance tests in mice showed that tangeretin and cardamonin significantly suppressed the rapid increase in blood glucose levels. In conclusion, tangeretin and cardamonin were shown to inhibit SGLT1 activity in vitro and lower blood glucose level in vivo.


Assuntos
Glicemia/metabolismo , Chalconas/farmacologia , Flavonas/farmacologia , Intestinos/fisiologia , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Administração Oral , Aminoácidos/metabolismo , Animais , Células CHO , Células CACO-2 , Chalconas/química , Cricetulus , Flavonas/química , Frutose/metabolismo , Humanos , Cinética , Camundongos Endogâmicos ICR , Compostos Fitoquímicos/farmacologia , Sarcosina/metabolismo , Sódio/metabolismo , Transportador 1 de Glucose-Sódio/metabolismo
8.
Int J Mol Sci ; 22(17)2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34502529

RESUMO

Natural chalcones possess antitumor properties and play a role as inducers of apoptosis, antioxidants and cytotoxic compounds. We recently reported that novel nitrogen chalcone-based compounds, which were generated in our lab, have specific effects on triple-negative breast cancer cells. However, the outcome of these two new compounds on human epidermal growth factor receptor 2 (HER2)-positive breast cancer remains nascent. Thus, we herein investigated the effects of these compounds (DK-13 and DK-14) on two HER2-positive breast cancer cell lines, SKBR3 and ZR75. Our data revealed that these compounds inhibit cell proliferation, deregulate cell-cycle progression and significantly induce cell apoptosis in both cell lines. Furthermore, the two chalcone compounds cause a significant reduction in the cell invasion ability of SKBR3 and ZR75 cancer cells. In parallel, we found that DK-13 and DK-14 inhibit colony formation of both cell lines in comparison to their matched controls. On the other hand, we noticed that these two compounds can inhibit angiogenesis in the chorioallantoic membrane model. The molecular pathway analysis of chalcone compounds exposed cells revealed that these compounds inhibit the expression of both JNK1/2/3 and ERK1/2, the major plausible molecular pathways behind these events. Our findings implicate that DK-13 and DK-14 possess effective chemotherapeutic outcomes against HER2-positive breast cancer via the ERK1/2 and JNK1/2/3 signaling pathways.


Assuntos
Apoptose/efeitos dos fármacos , Chalconas/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Chalconas/química , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Nitrogênio/química
9.
Medicina (Kaunas) ; 57(9)2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34577821

RESUMO

Background and Objectives: Gouty arthritis is an acute inflammatory response caused by the precipitation of monosodium urate (MSU) crystals in joints. The triggering of MSU leads to increased production of inflammatory cytokines, such as interleukin-1ß, which in turn lead to the formation of macromolecular complexes, referred to as inflammasomes. Thorough characterization of the NLRP3 inflammasome can be used as an indicator of an immune response against harmful stimuli. Cardamonin is a chalcone, mainly found in the seeds of Alpinia katsumadai, and exhibits anti-inflammatory activity by inhibiting the release of pro-inflammatory cytokines in vitro. However, the mechanism by which cardamonin treatment alleviates gouty arthritis has yet to be fully elucidated. Materials and Methods: In vitro or in vivo models were used to study whether cardamonimn inhibited NLRP3 inflammasome activation or suppressed gouty inflammation. Results: In the current study, we determined that most NLRP3 was released passively after MSU stimulation, and this release of NLRP3 promoted caspase-1 activation and IL-1ß secretion. Cardamonin was shown to decrease both the activity of caspase-1 and secretion of IL-1ß in J774A.1 macrophage cells subjected to MSU stimulation. Cardamonin was also shown to attenuate the production of COX-2 in MSU-stimulated J774A.1 macrophage cells. Finally, cardamonin reduced the thickness of the synovial lining and the infiltration of gouty arthritis in a rat model. Conclusions: Overall, cardamonin significantly attenuated IL-1ß secretion, caspase-1 activity, and COX-2 production stimulated by MSU. These findings provide new insights into the molecular mechanisms underlying the effects of cardamonin treatment for gouty arthritis.


Assuntos
Artrite Gotosa , Chalconas , Animais , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Chalconas/farmacologia , Chalconas/uso terapêutico , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos , Ácido Úrico
10.
Fitoterapia ; 154: 105029, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34506872

RESUMO

Four new chalchonoid trimers, named cochinchinenins N-Q (1-4), along with a pair of known enantiomers (5-6), were isolated from the total phenolic extract of Chinese dragon's blood (the red resin of Dracaena cochinchinensis). The planar structures of 1-4 were elucidated by extensive spectroscopic analysis including HRESIMS and 1D/2D NMR. The absolute configurations of new compounds were established by ECD data. Compound 1 exhibited significant inhibition of nitric oxide production in lipopolysaccharide-stimulated BV-2 microglial cells with IC50 value of 11.5 ± 1.7 µM.


Assuntos
Chalconas/farmacologia , Dracaena/química , Microglia/efeitos dos fármacos , Extratos Vegetais/química , Animais , Linhagem Celular , Chalconas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Camundongos , Óxido Nítrico , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Resinas Vegetais/química
11.
Molecules ; 26(17)2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34500755

RESUMO

Bacterial infections are regarded as one of the leading causes of fatal morbidity and death in patients infected with diseases. The ability of microorganisms, particularly methicillin-resistant Staphylococcus aureus (MRSA), to develop resistance to current drugs has evoked the need for a continuous search for new drugs with better efficacies. Hence, a series of non-PAINS associated pyrrolylated-chalcones (1-15) were synthesized and evaluated for their potency against MRSA. The hydroxyl-containing compounds (8, 9, and 10) showed the most significant anti-MRSA efficiency, with the MIC and MBC values ranging from 0.08 to 0.70 mg/mL and 0.16 to 1.88 mg/mL, respectively. The time-kill curve and SEM analyses exhibited bacterial cell death within four hours after exposure to 9, suggesting its bactericidal properties. Furthermore, the docking simulation between 9 and penicillin-binding protein 2a (PBP2a, PDB ID: 6Q9N) suggests a relatively similar bonding interaction to the standard drug with a binding affinity score of -7.0 kcal/mol. Moreover, the zebrafish model showed no toxic effects in the normal embryonic development, blood vessel formation, and apoptosis when exposed to up to 40 µM of compound 9. The overall results suggest that the pyrrolylated-chalcones may be considered as a potential inhibitor in the design of new anti-MRSA agents.


Assuntos
Antibacterianos/farmacologia , Chalconas/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Pirróis/farmacologia , Antibacterianos/química , Chalconas/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirróis/química , Relação Estrutura-Atividade
12.
Phytother Res ; 35(11): 6270-6280, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34486187

RESUMO

Licochalcone A (Lico A) is a natural flavonoid belonging to the class of substituted chalcone that has various biological effects. Mast cells (MCs) are innate immune cells that mediate hypersensitivity and pseudo-allergic reactions. MAS-related GPR family member X2 (MRGPRX2) on MCs has been recognized as the main receptor for pseudo-allergic reactions. In this study, we investigated the anti-pseudo-allergy effect of Lico A and its underlying mechanism. Substance P (SP), as an MC activator, was used to establish an in vitro and in vivo model of pseudo-allergy. The in vivo effect of Lico A was investigated using passive cutaneous anaphylaxis (PCA) and active systemic allergy, along with degranulation, Ca2+ influx in vitro. SP-induced laboratory of allergic disease 2 (LAD2) cell mRNA expression was explored using RNA-seq, and Lico A inhibited LAD2 cell activation by reverse transcription polymerase chain reaction (RT-PCR), western blotting, and immunofluorescence staining. Lico A showed an inhibitory effect on SP-induced MC activation and pseudo-allergy both in vitro and in vivo. The nuclear factor (NF)-κB pathway is involved in MRGPRX2 induced MC activation, which is inhibited by Lico A. In conclusion, Lico A inhibited the pseudo-allergic reaction mediated by MRGPRX2 by blocking NF-κB nuclear migration.


Assuntos
Chalconas , Hipersensibilidade , Degranulação Celular , Chalconas/farmacologia , Família , Humanos , Hipersensibilidade/tratamento farmacológico , Mastócitos , NF-kappa B , Proteínas do Tecido Nervoso , Receptores Acoplados a Proteínas G/genética , Receptores de Neuropeptídeos
13.
Comput Biol Chem ; 94: 107565, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34474201

RESUMO

A series of novel urea, sulfamide and N,N-dipropargyl substituted benzylamines were synthesized from dihydrochalcones. The synthesized compounds were evaluated for their cholinesterases and carbonic anhydrase inhibitory actions. The known dihydrochalcones were converted into four new benzylamines via reductive amination. N,N-Dipropargylamines, ureas and sulfamides were synthesized following the reactions of benzylamines with propargyl bromide, N,N-dimethyl sulfamoyl chloride and N,N-dimethyl carbamoyl chloride. The novel substituted benzylamines derived from dihydrochalcones were evaluated against some enzymes such as human erythrocyte carbonic anhydrase I and II isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The novel substituted benzylamines derived from dihydrochalcones exhibited Ki values in the range of 0.121-1.007 nM on hCA I, and 0.077-0.487 nM on hCA II closely related to several pathological processes. On the other hand, Ki values were found in the range of 0.112-0.558 nM on AChE, 0.061-0.388 nM on BChE. As a result, novel substituted benzylamines derived from dihydrochalcones showed potent inhibitory profiles against indicated metabolic enzymes. In addition, Induced-Fit Docking (IFD) simulations and ADME prediction studies have also been carried out to elucidate the inhibition mechanisms and drug-likeness of the synthesized compounds. Therefore, these results can make significant contributions to the treatment of some global diseases, especially Alzheimer's diseases and glaucoma, and the development of new drugs.


Assuntos
Benzilaminas/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Chalconas/farmacologia , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/metabolismo , Animais , Benzilaminas/síntese química , Benzilaminas/química , Butirilcolinesterase/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Chalconas/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
14.
Pharmacol Res ; 172: 105820, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34403732

RESUMO

Coronavirus Disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which enter the host cells through the interaction between its receptor binding domain (RBD) of spike glycoprotein with angiotensin-converting enzyme 2 (ACE2) receptor on the plasma membrane of host cell. Neutralizing antibodies and peptide binders of RBD can block viral infection, however, the concern of accessibility and affordability of viral infection inhibitors has been raised. Here, we report the identification of natural compounds as potential SARS-CoV-2 entry inhibitors using the molecular docking-based virtual screening coupled with bilayer interferometry (BLI). From a library of 1871 natural compounds, epigallocatechin gallate (EGCG), 20(R)-ginsenoside Rg3 (RRg3), 20(S)-ginsenoside Rg3 (SRg3), isobavachalcone (Ibvc), isochlorogenic A (IscA) and bakuchiol (Bkc) effectively inhibited pseudovirus entry at concentrations up to 100 µM. Among these compounds, four compounds, EGCG, Ibvc, salvianolic acid A (SalA), and isoliensinine (Isl), were effective in inhibiting SARS-CoV-2-induced cytopathic effect and plaque formation in Vero E6 cells. The EGCG was further validated with no observable animal toxicity and certain antiviral effect against SARS-CoV-2 pseudovirus mutants (D614G, N501Y, N439K & Y453F). Interestingly, EGCG, Bkc and Ibvc bind to ACE2 receptor in BLI assay, suggesting a dual binding to RBD and ACE2. Current findings shed some insight into identifications and validations of SARS-CoV-2 entry inhibitors from natural compounds.


Assuntos
Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Antivirais/química , Produtos Biológicos/química , COVID-19/tratamento farmacológico , Inibidores Enzimáticos/química , SARS-CoV-2/enzimologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Animais , Antivirais/farmacologia , Ligação Competitiva , Produtos Biológicos/farmacologia , Catequina/análogos & derivados , Catequina/farmacologia , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Chalconas/farmacologia , Ácido Clorogênico/análogos & derivados , Ácido Clorogênico/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacologia , Ginsenosídeos/farmacologia , Humanos , Interferometria , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Fenóis/farmacologia , Ligação Proteica
15.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361789

RESUMO

Isobavachalcone (IBC) is an active substance from the medicinal plant Psoralea corylifolia. This prenylated chalcone was reported to possess antioxidative, anti-inflammatory, antibacterial, and anticancer activities. Multidrug resistance (MDR) associated with the over-expression of the transporters of vast substrate specificity such as ABCB1 (P-glycoprotein) belongs to the main causes of cancer chemotherapy failure. The cytotoxic, MDR reversing, and ABCB1-inhibiting potency of isobavachalcone was studied in two cellular models: human colorectal adenocarcinoma HT29 cell line and its resistant counterpart HT29/Dx in which doxorubicin resistance was induced by prolonged drug treatment, and the variant of MDCK cells transfected with the human gene encoding ABCB1. Because MDR modulators are frequently membrane-active substances, the interaction of isobavachalcone with model phosphatidylcholine bilayers was studied by means of differential scanning calorimetry. Molecular modeling was employed to characterize the process of membrane permeation by isobavachalcone. IBC interacted with ABCB1 transporter, being a substrate and/or competitive inhibitor of ABCB1. Moreover, IBC intercalated into model membranes, significantly affecting the parameters of their main phospholipid phase transition. It was concluded that isobavachalcone interfered both with the lipid phase of cellular membrane and with ABCB1 transporter, and for this reason, its activity in MDR cancer cells was presumptively beneficial.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Chalconas/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Psoralea/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Ligação Competitiva , Linhagem Celular Tumoral , Chalconas/química , Chalconas/isolamento & purificação , Cães , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/genética , Expressão Gênica , Células HT29 , Humanos , Concentração Inibidora 50 , Bicamadas Lipídicas/química , Bicamadas Lipídicas/metabolismo , Células Madin Darby de Rim Canino , Membranas Artificiais , Modelos Moleculares , Fosfatidilcolinas/química , Fosfatidilcolinas/metabolismo , Extratos Vegetais/química , Plantas Medicinais , Ligação Proteica , Transgenes , Verapamil/farmacologia
16.
Phytother Res ; 35(10): 5861-5870, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34435401

RESUMO

The incidence of ulcerative colitis (UC), one of the two types of inflammatory bowel disease, is increasing in many countries. Various natural products have been demonstrated with therapeutic potentials for UC. Herein, the therapeutic effects and mechanisms of isobavachalcone (IBC), a natural chalcone, were evaluated in dextran sulfate sodium (DSS)-induced colitis mice and lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The results demonstrated that IBC treatment significantly improved the clinical symptoms, assessed by the disease activity index (DAI) scores and the histological changes of the colon. The levels of myeloperoxidase (MPO), TNF-α, IL-6, IL-1ß, and prostaglandin E2 (PGE2) in colon tissues were suppressed by IBC. The upregulation of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and NF-κB p65 in colon tissues were reversed by IBC as well. Furthermore, IBC significantly inhibited LPS-triggered secretion of TNF-α, IL-6, and nitrite, and nuclear translocation of NF-κB p65, in RAW264.7 cells. The luciferase reporter assay indicated that IBC significantly inhibited LPS-triggered transcription of toll-like receptor 4 (TLR4). Molecular docking results showed that the binding pocket of IBC was adjacent to Ser276 of p65-p50 heterodimer and IBC could form H-bond with Thr191. Collectively, these results demonstrated that IBC ameliorated colitis in mice possibly through inhibition of NF-κB p65.


Assuntos
Chalconas , Colite Ulcerativa , Colite , Animais , Chalconas/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Citocinas , Sulfato de Dextrana , Flavonoides/farmacologia , Camundongos , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Transdução de Sinais
17.
Molecules ; 26(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34443487

RESUMO

The chalcone and quinoline scaffolds are frequently utilized to design novel anticancer agents. As the continuation of our work on effective anticancer agents, we assumed that linking chalcone fragment to the quinoline scaffold through the principle of molecular hybridization strategy could produce novel compounds with potential anticancer activity. Therefore, quinoline-chalcone derivatives were designed and synthesized, and we explored their antiproliferative activity against MGC-803, HCT-116, and MCF-7 cells. Among these compounds, compound 12e exhibited a most excellent inhibitory potency against MGC-803, HCT-116, and MCF-7 cells with IC50 values of 1.38, 5.34, and 5.21 µM, respectively. The structure-activity relationship of quinoline-chalcone derivatives was preliminarily explored in this report. Further mechanism studies suggested that compound 12e inhibited MGC-803 cells in a dose-dependent manner and the cell colony formation activity of MGC-803 cells, arrested MGC-803 cells at the G2/M phase and significantly upregulated the levels of apoptosis-related proteins (Caspase3/9 and cleaved-PARP) in MGC-803 cells. In addition, compound 12e could significantly induce ROS generation, and was dependent on ROS production to exert inhibitory effects on gastric cancer cells. Taken together, all the results suggested that directly linking chalcone fragment to the quinoline scaffold could produce novel anticancer molecules, and compound 12e might be a valuable lead compound for the development of anticancer agents.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Chalconas/síntese química , Chalconas/farmacologia , Desenho de Fármacos , Quinolinas/síntese química , Quinolinas/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalconas/química , Humanos , Quinolinas/química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
18.
Biomolecules ; 11(8)2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34439870

RESUMO

Chalcones belong to the flavonoid class of phenolic compounds. They form one of the largest groups of bioactive natural products. The potential anticancer, anti-inflammatory, antimicrobial, antioxidant, and antiparasitic properties of naturally occurring chalcones, and their unique chemical structural features inspired the synthesis of numerous chalcone derivatives. In fact, structural features of chalcones are easy to construct from simple aromatic compounds, and it is convenient to perform structural modifications to generate functionalized chalcone derivatives. Many of these synthetic analogs were shown to possess similar bioactivities as their natural counterparts, but often with an enhanced potency and reduced toxicity. This review article aims to demonstrate how bioinspired synthesis of chalcone derivatives can potentially introduce a new chemical space for exploitation for new drug discovery, justifying the title of this article. However, the focus remains on critical appraisal of synthesized chalcones and their derivatives for their bioactivities, linking to their interactions at the biomolecular level where appropriate, and revealing their possible mechanisms of action.


Assuntos
Antibacterianos , Anti-Inflamatórios , Antineoplásicos , Antioxidantes , Produtos Biológicos , Chalconas , Antibacterianos/química , Antibacterianos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Linhagem Celular , Chalconas/química , Chalconas/farmacologia , Descoberta de Drogas , Humanos , Relação Estrutura-Atividade
19.
J Ethnopharmacol ; 280: 114488, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34358653

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine (TCM) has a long history in the prevention and treatment of pandemics. The TCM formula Lung Cleansing and Detoxifying Decoction (LCDD), also known as Qing Fei Pai Du Decoction, has been demonstrated effective against Coronavirus Disease 2019 (COVID-19). AIM OF THE STUDY: This work aimed to elucidate the active ingredients, targets and pathway mechanism of LCDD related to suppression of inflammatory, immunity regulation and relaxation of airway smooth muscle for the treatment of COVID-19. MATERIALS AND METHODS: Mining chemical ingredients reported in LCDD, 144 compounds covering all herbs were selected and screened against inflammatory-, immunity- and respiratory-related GPCRs including GPR35, H1, CB2, B2, M3 and ß2-adrenoceptor receptor using a label-free integrative pharmacology method. Further, all active compounds were detected using liquid chromatography-tandem mass spectrometry, and an herb-compound-target network based on potency and content of compounds was constructed to elucidate the multi-target and synergistic effect. RESULTS: Thirteen compounds were identified as GPR35 agonists, including licochalcone B, isoliquiritigenin, etc. Licochalcone B, isoliquiritigenin and alisol A exhibited bradykinin receptor B2 antagonism activities. Atractyline and shogaol showed as a cannabinoid receptor CB2 agonist and a histamine receptor H1 antagonist, respectively. Tectorigenin and aristofone acted as muscarinic receptor M3 antagonists, while synephrine, ephedrine and pseudoephedrine were ß2-adrenoceptor agonists. Pathway deconvolution assays suggested activation of GPR35 triggered PI3K, MEK, JNK pathways and EGFR transactivation, and the activation of ß2-adrenoceptor mediated MEK and Ca2+. The herb-compound-target network analysis found that some compounds such as licochalcone B acted on multiple targets, and multiple components interacted with the same target such as GPR35, reflecting the synergistic mechanism of Chinese medicine. At the same time, some low-abundance compounds displayed high target activity, meaning its important role in LCDD for anti-COVID-19. CONCLUSIONS: This study elucidates the active ingredients, targets and pathways of LCDD. This is useful for elucidating multitarget synergistic action for its clinical therapeutic efficacy.


Assuntos
Técnicas Biossensoriais/métodos , COVID-19/tratamento farmacológico , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Animais , Linhagem Celular Tumoral , Chalconas/farmacologia , Cricetulus , Medicamentos de Ervas Chinesas/análise , Efedrina/farmacologia , Células HEK293 , Humanos , Imunidade/efeitos dos fármacos , Inflamação/metabolismo , Pneumopatias/metabolismo , Músculo Liso/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Respiração/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
20.
Biomolecules ; 11(6)2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208562

RESUMO

Chalcones (1,3-diaryl-2-propen-1-ones) are precursors for flavonoids and isoflavonoids, which are common simple chemical scaffolds found in many naturally occurring compounds. Many chalcone derivatives were also prepared due to their convenient synthesis. Chalcones as weandhetic analogues have attracted much interest due to their broad biological activities with clinical potentials against various diseases, particularly for antitumor activity. The chalcone family has demonstrated potential in vitro and in vivo activity against cancers via multiple mechanisms, including cell cycle disruption, autophagy regulation, apoptosis induction, and immunomodulatory and inflammatory mediators. It represents a promising strategy to develop chalcones as novel anticancer agents. In addition, the combination of chalcones and other therapies is expected to be an effective way to improve anticancer therapeutic efficacy. However, despite the encouraging results for their response to cancers observed in clinical studies, a full description of toxicity is required for their clinical use as safe drugs for the treatment of cancer. In this review, we will summarize the recent advances of the chalcone family as potential anticancer agents and the mechanisms of action. Besides, future applications and scope of the chalcone family toward the treatment and prevention of cancer are brought out.


Assuntos
Chalcona/análogos & derivados , Chalconas/farmacologia , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Chalcona/química , Chalcona/farmacologia , Chalconas/química , Chalconas/metabolismo , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
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