RESUMO
Aim: A series of isocoumarin-chalcone hybrids were prepared and assays for the inhibition of four isoforms of human carbonic anhydrase (hCA; EC 4.2.1.1), hCA I, II, IX and XII. Materials & methods: Isocoumarin-chalcone hybrids were synthesized by condensing acetyl-isocoumarin with aromatic aldehydes. They did not significantly inhibit off-target cytosolic isoforms hCA I and II (KI >100 µM) but acted as low micromolar or submicromolar inhibitors for the tumor-associated isoforms hCA IX and XII. Results & conclusion: Our work provides insights into a new and scarcely investigated chemotype which provides interesting tumor-associated CA inhibitors, considering that some such derivatives like sulfonamide SLC-0111 are in advanced clinical trials for the management of metastatic advanced solid tumors.
A series of isocoumarinchalcone hybrids was prepared and assays for the inhibition of four isoforms of the metalloenzyme carbonic anhydrase (CA; EC 4.2.1.1), i.e., human (h) isoforms hCA I, II, IX and XII. Isocoumarins were less investigated as inhibitors of this enzyme. Here we show that the isocoumarinchalcone hybrids do not significantly inhibit the off-target cytosolic isoforms hCA I and II (KIs >100 µM) but act as low micromolar inhibitors for the tumor-associated isoforms hCA IX and XII. Our work thus provides insights into a new and scarcely investigated chemotype which may provide interesting tumor-associated CA inhibitors, because some such compounds, e.g., the sulfonamide SLC-0111, are presently in advanced clinical trials for the management of metastatic advanced solid tumors.
Assuntos
Inibidores da Anidrase Carbônica , Anidrases Carbônicas , Isocumarinas , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Humanos , Anidrases Carbônicas/metabolismo , Isocumarinas/química , Isocumarinas/farmacologia , Isocumarinas/síntese química , Chalcona/química , Chalcona/farmacologia , Relação Estrutura-Atividade , Isoenzimas/metabolismo , Isoenzimas/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Estrutura Molecular , Chalconas/química , Chalconas/farmacologia , Chalconas/síntese químicaRESUMO
Aim: The purpose of this study is to design and synthesize a series of novel chalcone amide α-glucosidase (AG) inhibitors (L1-L10) based on virtual screening and molecular dynamics (MD) simulation. Materials & methods: Target compounds (L1-L10) were synthesized from 2-hydroxyacetophenone and methyl 4-formylbenzoate. Results: In vitro activity test shows that most compounds have good AG inhibition. Specially, compound L4 (IC50 = 8.28 ± 0.04 µM) had the best inhibitory activity, superior to positive control acarbose (IC50 = 8.36 ± 0.02 µM). Molecular docking results show that the good potency of L4 maybe attributed to strong interactions between chalcone skeleton and active site, and the torsion of carbon nitrogen bond in amide group. Conclusion: Compound L4 maybe regard as a good anti-Type II diabetes candidate to preform further study.
[Box: see text].
Assuntos
Amidas , Desenho de Fármacos , Inibidores de Glicosídeo Hidrolases , Simulação de Acoplamento Molecular , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , alfa-Glucosidases/metabolismo , Amidas/química , Amidas/farmacologia , Amidas/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Humanos , Simulação de Dinâmica Molecular , Chalcona/química , Chalcona/farmacologia , Chalcona/síntese químicaRESUMO
Multidrug resistance (MDR) mechanisms in cancer cells are greatly influenced by glutathione transferase P1-1 (hGSTP1-1). The use of synthetic or natural compounds as hGSTP1-1 inhibitors is considered an effective approach to overcome MDR. Nine compounds consisting of coumarin-6-sulfonamide linked to chalcone derivatives were synthesized and evaluated for their ability to inhibit hGSTP1-1. Among the synthetic derivatives, compounds 5g, 5f, and 5a displayed the most potent inhibitory effect, with IC50 values of 12.2 ± 0.5 µΜ, 12.7 ± 0.7 and 16.3 ± 0.6, respectively. Kinetic inhibition analysis of the most potent molecule, 5g, showed that it behaves as a mixed-type inhibitor of the target enzyme. An in vitro cytotoxicity assessment of 5a, 5f, and 5g against the human prostate cancer cell lines DU-145 and PC3, as well as the breast cancer cell line MCF-7, demonstrated that compound 5g exhibited the most pronounced cytotoxic effect on all tested cell lines. Molecular docking studies were performed to predict the structural and molecular determinants of 5g, 5f, and 5a binding to hGSTP1-1. In agreement with the experimental data, the results revealed that 5g exhibited the lowest docking score among the three studied inhibitors as a consequence of shape complementarity, governed by van der Waals, hydrogen bonds and a π-π stacking interaction. These findings suggest that coumarin-chalcone hybrids offer new perspectives for the development of safe and efficient natural product-based sensitizers that can target hGSTP1-1 for anticancer purposes.
Assuntos
Cumarínicos , Glutationa S-Transferase pi , Simulação de Acoplamento Molecular , Sulfonamidas , Humanos , Cumarínicos/química , Cumarínicos/farmacologia , Glutationa S-Transferase pi/antagonistas & inibidores , Glutationa S-Transferase pi/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Linhagem Celular Tumoral , Chalcona/química , Chalcona/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Chalconas/química , Chalconas/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Células MCF-7RESUMO
A novel series of antitumor hybrids was synthesized using 1,4-benzohydroquinone and chalcone, furane, or pyrazoline scaffolds. This were achieved through isosteric substitution of the aryl group of the chalcone ß-carbon with the furanyl moiety and structural modification of the α,ß-unsaturated carbonyl system. The potential antitumor activity of these hybrids was evaluated in vivo on MCF-7 breast adenocarcinoma and HT-29 colorectal carcinoma cells, demonstrating cytotoxic activity with IC50 values ranging from 28.8 to 124.6 µM. The incorporation of furan and pyrazoline groups significantly enhanced antiproliferative properties compared to their analogues and precursors (VII-X), which were inactive against both neoplastic cell lines. Compounds 4, 5, and 6 exhibited enhanced cytotoxicity against both cell lines, whereas compound 8 showed higher cytotoxic activity against HT-29 cells. Molecular docking studies revealed superior free-energy values (ΔGbin) for carcinogenic pathway-involved kinase proteins, with our in silico data suggesting that these derivatives could be promising chemotherapeutic agents targeting kinase pathways. Among all the synthesized PIBHQ compounds, derivatives 7 and 8 exhibited the best drug-likeness properties, with values of 0.53 and 0.83, respectively. ADME results collectively suggest that most of these compounds hold promise as potential candidates for preclinical assays.
Assuntos
Antineoplásicos , Hidroquinonas , Simulação de Acoplamento Molecular , Pirazóis , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Hidroquinonas/química , Hidroquinonas/farmacologia , Hidroquinonas/síntese química , Células MCF-7 , Proliferação de Células/efeitos dos fármacos , Chalcona/química , Chalcona/farmacologia , Células HT29 , Chalconas/química , Chalconas/farmacologia , Chalconas/síntese química , Relação Estrutura-Atividade , Linhagem Celular Tumoral , AnimaisRESUMO
Carthamus tinctorius L. (Safflower) is extensively used as a functional food and herbal medicine, with its application closely associated with hydroxysafflor yellow A (HSYA). However, the low oral bioavailability of HSYA in safflower extract (SFE) limits its health benefits and application. Our study found that co-administration of 250, 330, and 400 mg/kg peach kernel oil (PKO) increased the oral bioavailability of HSYA in SFE by 1.99-, 2.11-, and 2.49-fold, respectively. The enhanced bioavailability is attributed to improved lipid solubility and intestinal permeability of HSYA in SFE due to PKO. PKO is believed to modify membrane fluidity and tight junctions, increase paracellular penetration, and inhibit the expression and function of P-glycoprotein, enhancing the transcellular transport of substrates. These mechanisms suggest that PKO is an effective absorption enhancer. Our findings provide valuable insights for developing functional foods with improved bioavailability.
Assuntos
Disponibilidade Biológica , Carthamus tinctorius , Chalcona , Extratos Vegetais , Prunus persica , Quinonas , Chalcona/química , Chalcona/análogos & derivados , Chalcona/farmacologia , Extratos Vegetais/química , Extratos Vegetais/administração & dosagem , Extratos Vegetais/metabolismo , Quinonas/química , Quinonas/metabolismo , Carthamus tinctorius/química , Animais , Prunus persica/química , Prunus persica/metabolismo , Humanos , Óleos de Plantas/química , Masculino , Ratos Sprague-Dawley , Ratos , Absorção Intestinal/efeitos dos fármacosRESUMO
Four new compounds, racemic chalcone-monoterpene hybrids (1-3) and a chalcone (9), along with nine known compounds (4-8, 10-13), have been isolated from the buds of Cleistocalyx operculatus. The chemical structures of the isolated compounds were identified through NMR data analysis and confirmed by computational methods, including electronic circular dichroism (ECD) calculations, and further synthetic approaches. Compounds 1-5 were synthesized via a Diels-Alder reaction, a process informed by biomimetic condensation studies that combined chalcones and monoterpenes. These synthetic approaches also yielded various unnatural chalcone-monoterpene derivatives (14-23). The inhibitory effects on protein tyrosine phosphatase 1B (PTP1B) of both naturally isolated and synthetically obtained compounds were evaluated. Compounds 4, 9, 13, and 16b exhibited potent PTP1B inhibitory activity, with IC50 values ranging from 0.9 ± 0.2 to 3.9 ± 0.7 µM. The enantiomers (+)-4 and (-)-16b showed enhanced activity compared to their respective enantiomers. Kinetic studies indicate that all active compounds inhibit PTP1B through mixed mechanisms, and molecular docking simulations agree with the experimental assays on PTP1B. Our results suggest that chalcone-meroterpene adducts from the buds of C. operculatus exhibit potential as antidiabetic agents, partly due to their PTP1B enzyme inhibition.
Assuntos
Monoterpenos , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Estrutura Molecular , Monoterpenos/farmacologia , Monoterpenos/química , Monoterpenos/isolamento & purificação , Chalconas/farmacologia , Chalconas/química , Chalconas/isolamento & purificação , Chalcona/farmacologia , Chalcona/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Humanos , Syzygium/químicaRESUMO
Imidazole-chalcone compounds are recognised for their broad-spectrum antimicrobial properties. Probiotic-friendly, selective new-generation antimicrobials prove to be more efficient in combating gastrointestinal system pathogens. The aim of this study is to identify imidazole-chalcone derivatives that probiotics tolerate and evaluate their in vitro synergistic antimicrobial effects on pathogens. In this study, fifteen previously identified imidazole-chalcone derivatives were analyzed for their in vitro antimicrobial properties against gastrointestinal microorganisms. Initially, the antimicrobial activity of pathogens was measured using the agar well diffusion method, while the susceptibility of probiotics was determined by microdilution. The chosen imidazole-chalcone derivatives were assessed for synergistic effects using the checkerboard method. Four imidazole-chalcone derivatives to which probiotic bacteria were tolerant exhibited antibacterial and antifungal activity against the human pathogens tested. To our knowledge, this study is the first to reveal the fractional inhibitory concentration (FIC) of combinations of imidazole-chalcone derivatives. Indeed, the minimum inhibitory concentrations (MIC) for morpholinyl- (ZDO-3f) and 4-ethylpiperazinyl- (ZDO-3 m) imidazole-chalcones were notably low when tested against E. coli and B. subtilis, with values of 31.25 µg/mL and 125 µg/mL, respectively. The combination of morpholinyl- and 4-ethylpiperazinyl derivatives demonstrated an indifferent effect against E. coli, but an additive effect was observed for B. subtilis. Additionally, it was observed that imidazole-chalcone derivatives did not exhibit any inhibitory effects on probiotic organisms like Lactobacillus fermentum (CECT-5716), Lactobacillus rhamnosus (GG), and Lactobacillus casei (RSSK-591). This study demonstrates that imidazole-chalcone derivatives that are well tolerated by probiotics can potentially exert a synergistic effect against gastrointestinal system pathogens.
Assuntos
Sinergismo Farmacológico , Imidazóis , Testes de Sensibilidade Microbiana , Probióticos , Probióticos/farmacologia , Imidazóis/farmacologia , Imidazóis/química , Chalcona/farmacologia , Chalcona/química , Chalcona/análogos & derivados , Antibacterianos/farmacologia , Antibacterianos/química , Chalconas/farmacologia , Chalconas/química , Trato Gastrointestinal/microbiologia , Humanos , Bactérias/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/químicaRESUMO
A highly selective bis thiophene-based chalcone as a chemosensor for detecting Fe3+ metal ions in DMF: H2O (9:1). This sensor was selective toward ferric ions over other metal ions with a detection limit in micromolar range.
Assuntos
Espectrometria de Fluorescência , Tiofenos , Tiofenos/química , Ferro/análise , Ferro/química , Estrutura Molecular , Compostos Férricos/química , Compostos Férricos/análise , Chalconas/química , Chalconas/análise , Chalcona/química , Corantes Fluorescentes/químicaRESUMO
Five undescribed monoterpene-chalcone conjugates (1-5), one undescribed hypothetical precursor of diarylheptanoid (6), two undescribed diarylheptanoids (7-8), and fourteen known compounds (9-22) were isolated from the seeds of Alpinia katsumadai. Their structures were elucidated through the interpretation of HRESIMS, NMR, ECD, and X-ray diffraction data. MTT assays on human cancer cell lines (HepG2, A549, SGC7901, and SW480) revealed that compounds 3-8, 11, and 13 exhibited broad-spectrum antiproliferative activities with IC50 values ranging from 3.59 to 21.78 µM. B cell lymphoma 2 was predicted as the target of sumadain C (11) by network pharmacology and verified by homogeneous time-resolved fluorescence assay and molecular docking.
Assuntos
Alpinia , Antineoplásicos Fitogênicos , Proliferação de Células , Diarileptanoides , Ensaios de Seleção de Medicamentos Antitumorais , Monoterpenos , Sementes , Alpinia/química , Humanos , Diarileptanoides/química , Diarileptanoides/farmacologia , Diarileptanoides/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Sementes/química , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Monoterpenos/química , Monoterpenos/isolamento & purificação , Monoterpenos/farmacologia , Relação Estrutura-Atividade , Chalconas/química , Chalconas/farmacologia , Chalconas/isolamento & purificação , Chalcona/química , Chalcona/farmacologia , Chalcona/isolamento & purificação , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Simulação de Acoplamento MolecularRESUMO
Chalcone is a simple naturally occurring α,ß-unsaturated ketone with biological importance, which can also be easily synthesized in laboratories by reaction between two aromatic scaffolds. In plants, chalcones occur as polyphenolic compounds of different frameworks which are bioactive molecules that have been in traditional medicinal practice for many years. Chalcone-based lead molecules have been developed, possessing varied potentials such as antimicrobial, antiviral, anti-inflammatory, anticancer, anti-oxidant, antidiabetic, antihyperurecemic, and anti-ulcer effects. Chalcones contribute considerable fragments to give important heterocyclic molecules with therapeutic utilities targeting various diseases. These characteristic features have made chalcone a topic of interest among researchers and have attracted investigations into this widely applicable structure. This review highlights the extensive exploration carried out on the synthesis, biotransformations, chemical reactions, hybridization, and pharmacological potentials of chalcones, and aims to provide an extensive, thorough, and critical review of their importance, with emphasis on their properties, chemistry, and biomedical applications to boost future investigations into this potential scaffold in medicinal chemistry.
Assuntos
Chalcona , Química Farmacêutica , Chalcona/química , Chalcona/farmacologia , Humanos , Chalconas/química , Chalconas/farmacologia , Estrutura Molecular , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologiaRESUMO
In the present study, the effect of sulfonamide-chalcone 185 (SSC185) was investigated against B16-F10 metastatic melanoma cells aggressive actions, besides migration and adhesion processes, by in silico and in vitro assays. In silico studies were used to characterize the pharmacokinetic profile and possible targets of SSC185, using the pkCSM web server, and docking simulations with AutoDock Tools. Furthermore, the antimetastatic effect of SSC185 was investigated by in vitro experiments using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide), colony, scratch, and cell adhesion assays, and atomic force microscopy (AFM). The molecular docking results show better affinity of SSC185 with the metalloproteinases-2 (MMP-2) and α5ß1 integrin. SSC185 effectively restricts the formation of colonies, migration, and adhesion of B16-F10 metastatic melanoma cells. Through the AFM images changes in cells morphology was identified, with a decrease in the filopodia and increase in the average cellular roughness. The results obtained demonstrate the potential of this molecule in inhibit the primordial steps for metastasis, which is responsible for a worse prognosis of late stage cancer, being the main cause of morbidity among cancer patients.
Assuntos
Adesão Celular , Movimento Celular , Chalcona , Simulação de Acoplamento Molecular , Sulfonamidas , Movimento Celular/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Sulfonamidas/farmacologia , Sulfonamidas/química , Camundongos , Animais , Linhagem Celular Tumoral , Chalcona/farmacologia , Chalcona/química , Chalcona/análogos & derivados , Metaloproteinase 2 da Matriz/metabolismo , Melanoma Experimental/patologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Microscopia de Força Atômica , Antineoplásicos/farmacologia , Antineoplásicos/química , Chalconas/farmacologia , Chalconas/química , HumanosRESUMO
Marine biofouling remains a huge concern for maritime industries and for environmental health. Although the current biocide-based antifouling coatings can prevent marine biofouling, their use has been associated with toxicity for the marine environment, being urgent to find sustainable alternatives. Previously, our research group has identified a prenylated chalcone (1) with promising antifouling activity against the settlement of larvae of the macrofouling species Mytilus galloprovincialis (EC50 = 16.48⯵M and LC50 > 200⯵M) and lower ecotoxicity when compared to Econea®, a commercial antifouling agent in use. Herein, a series of chalcone 1 analogues were designed and synthesized in order to obtain optimized antifouling compounds with improved potency while maintaining low ecotoxicity. Compounds 8, 15, 24, and 27 showed promising antifouling activity against the settlement of M. galloprovincialis larvae, being dihydrochalcone 27 the most potent. The effect of compound 24 was associated with the inhibition of acetylcholinesterase activity. Among the synthesized compounds, compound 24 also showed potent complementary activity against Navicula sp. (EC50 = 4.86⯵M), similarly to the lead chalcone 1 (EC50 = 6.75⯵M). Regarding the structure-activity relationship, the overall results demonstrate that the substitution of the chalcone of the lead compound 1 by a dihydrochalcone scaffold resulted in an optimized potency against the settlement of mussel larvae. Marine polyurethane (PU)-based coatings containing the best performed compound concerning anti-settlement activity (dihydrochalcone 27) were prepared, and mussel larvae adherence was reduced compared to control PU coatings.
Assuntos
Incrustação Biológica , Larva , Mytilus , Animais , Incrustação Biológica/prevenção & controle , Larva/efeitos dos fármacos , Mytilus/efeitos dos fármacos , Chalconas/farmacologia , Chalconas/química , Relação Estrutura-Atividade , Chalcona/farmacologia , Chalcona/análogos & derivados , Chalcona/química , Desinfetantes/toxicidade , Desinfetantes/farmacologiaRESUMO
The aberrant assembly of amyloid-ß (Aß) is implicated in Alzheimer's disease (AD). Recent clinical outcomes of Aß-targeted immunotherapy reinforce the notion that clearing Aß burden is a potential therapeutic approach for AD. Herein, to develop drug candidates for chemically driven clearance of Aß aggregates, we synthesized 51 novel polyfunctionalized furo[2,3-b:4,5-b']dipyridine-chalcone hybrid compounds. After conducting two types of cell-free anti-Aß functional assays, Aß aggregation prevention and Aß aggregate clearance, we selected YIAD-0336, (E)-8-((1H-pyrrol-2-yl)methylene)-10-(4-chlorophenyl)-2,4-dimethyl-7,8-dihydropyrido[3',2':4,5]furo[3,2-b]quinolin-9(6H)-one, for further in vivo investigations. As YIAD-0336 exhibited a low blood-brain barrier penetration profile, it was injected along with aggregated Aß directly into the intracerebroventricular region of ICR mice and ameliorated spatial memory in Y-maze tests. Next, YIAD-0336 was orally administered to 5XFAD transgenic mice with intravenous injections of mannitol, and YIAD-0336 significantly removed Aß plaques from the brains of 5XFAD mice. Collectively, YIAD-0336 dissociated toxic aggregates in the mouse brain and hence alleviated cognitive deterioration. Our findings indicate that chemically driven clearance of Aß aggregates is a promising therapeutic approach for AD.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Modelos Animais de Doenças , Camundongos Transgênicos , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Camundongos , Peptídeos beta-Amiloides/metabolismo , Chalcona/química , Chalcona/farmacologia , Chalcona/análogos & derivados , Chalconas/química , Chalconas/farmacologia , Chalconas/administração & dosagem , Masculino , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Humanos , Memória/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Piridinas/química , Piridinas/farmacologia , Piridinas/administração & dosagemRESUMO
More women die of breast cancer than of any other malignancy. The resistance and toxicity of traditional hormone therapy created an urgent need for potential molecules for treating breast cancer effectively. Novel biphenyl-substituted pyrazole chalcones linked to a pyrrolidine ring were designed by using a hybridization approach. The hybrids were assessed against MCF-7 and MDA-MB-231 cells by NRU assay. Among them, 8 k, 8 d, 8 m, 8 h, and 8 f showed significantly potent IC50 values: 0.17, 5.48, 8.13, 20.51, and 23.61â µM) respectively, on MCF-7 cells compared to the positive control Raloxifene and Tamoxifen. Furthermore, most active compound 8 k [3-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1-(2-(2-(pyrrolidin-1-yl)-ethoxy)-phenyl)-chalcone] showed cell death induced through apoptosis, cell cycle arrest at the G2/M phase, and demonstrated decrease of ER-α protein in western blotting study. Docking studies of 8 k and 8 d established adequate interactions with estrogen receptor-α as required for SERM binding. The active hybrids exhibited good pharmacokinetic properties for oral bioavailability and drug-likeness. Whereas, RMSD, RMSF, and Rg values from Molecular dynamics studies stipulated stability of the complex formed between compound 8 k and receptor. All of these findings strongly indicate the antiproliferative potential of pyrazole-chalcone hybrids for the treatment of breast cancer.
Assuntos
Antineoplásicos , Apoptose , Neoplasias da Mama , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Pirazóis , Humanos , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Feminino , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Apoptose/efeitos dos fármacos , Estrutura Molecular , Chalconas/química , Chalconas/farmacologia , Chalconas/síntese química , Simulação de Acoplamento Molecular , Chalcona/química , Chalcona/farmacologia , Linhagem Celular Tumoral , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/antagonistas & inibidores , Relação Dose-Resposta a Droga , Animais , RatosRESUMO
Purpose: Lung adenocarcinoma currently ranks the leading causes of cancer-related mortality worldwide. Many anti-inflammation herbs, like tetramethylpyrazine, have shown their anti-tumor potentials. Here, we evaluated the role of a novel chalcone derivative of tetramethylpyrazine ((E) -1- (E) -1- (2-hydroxy-5-chlorophenyl) -3- (3,5,6-trimethylpyrazin-2-yl) -2-propen-1, HCTMPPK) in lung adenocarcinoma. Methods: The effects of HCTMPPK on cell proliferation, apoptosis, and invasion were investigated by in-vitro assays, including CCK-8, colony formation assay, flow cytometry, transwell assay, and wound-healing assay. The therapeutic potential of HCTMPPK in vivo was evaluated in xenograft mice. To figure out the target molecules of HCTMPPK, a network pharmacology approach and molecular docking studies were employed, and subsequent experiments were conducted to confirm these candidate molecules. Results: HCTMPPK effectively suppressed the proliferative activity and migration, as well as enhanced the apoptosis of A549 cells in a concentration-dependent manner. Consistent with this, tumor growth was inhibited by HCTMPPK significantly in vivo. Regarding the mechanisms, HCTMPPK down-regulated Bcl-2 and MMP-9 and up-regulating Bax and cleaved-caspase-3. Subsequently, we identified 601 overlapping DEGs from LUAD patients in TCGA and GEO database. Then, 15 hub genes were identified by PPI network and CytoHubba. Finally, MELK was verified to be the HCTMPPK targeted site, through the molecular docking studies and validation experiments. Conclusion: Overall, our study indicates HCTMPPK as a potential MELK inhibitor and may be a promising candidate for the therapy of lung cancer.
Assuntos
Antineoplásicos , Chalcona , Regulação para Baixo , Neoplasias Pulmonares , Pirazinas , Animais , Humanos , Camundongos , Células A549 , Antineoplásicos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalcona/farmacologia , Chalcona/química , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Neoplasias Experimentais/metabolismo , Pirazinas/farmacologia , Pirazinas/química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
In this study, UV-vis spectroscopy was employed to investigate the interaction between formylphenoxyacetic acid (FPAA) and its derivatives (chalcone and flavones) with ionic surfactants (SDS, CTAB, and DTAB) in different physiological environments. Changes in the physiochemical properties of FPAA chalcone and flavones including binding constants, partitioning constants, and Gibbs free energy were observed which were influenced by the presence of ionic surfactants computed using mathematical models. The solubilization of the targeted compounds in the ionic surfactants was determined through the binding constant (Kb). The results of the present study indicated that electrostatic interactions played a significant role in the solubilization of the targeted compounds in SDS, CTAB, and DTAB. At pH 4.1, FPAA chalcone exhibited stronger binding affinity with SDS compared to CTAB and DTAB. However, at pH 7.4, chalcone showed stronger binding with DTAB compared to SDS, while negligible interaction with CTAB was observed at pH 7.4. The flavones demonstrated stronger binding with DTAB at pH 7.4 compared to SDS and CTAB and it exhibited strong bonding with CTAB at pH 4.1. The negative values of the Gibbs free energy for binding (ΔGbË) and partitioning (ΔGpË) constants displayed the spontaneity of the process. However, FPAA chalcone with SDS and FPAA flavones with DTAB furnished positive ΔGbË, indicating a non-spontaneous process.
Assuntos
Flavonas , Solubilidade , Tensoativos , Tensoativos/química , Flavonas/química , Flavonas/metabolismo , Concentração de Íons de Hidrogênio , Cetrimônio/química , Termodinâmica , Íons/química , Chalcona/química , Chalconas/química , Chalconas/metabolismo , Dodecilsulfato de Sódio/química , Eletricidade EstáticaRESUMO
A series of novel near-infrared (NIR) xanthene-chalcone fluorophores were constructed through a modular synthesis with the electron-donating xanthene moiety and the electron-withdrawing chalcone moiety. These fluorophores are convenient for fluorescence imaging in living cells, benefiting from their NIR emissions (650-710 nm), large Stokes shifts (>100 nm), moderate quantum yields and low cytotoxicity. The substituted hydroxyl group of the xanthene-chalcone fluorophore HCA-E facilitates the development of multifunctional fluorescent probes. As an example, a highly sensitive and selective probe N-HCA-E for glutathione (GSH) detection was developed based on the fluorophore HCA-E. A 4-nitrobenzenesulfonyl (4-Ns) group was introduced to cage the hydroxyl group of HCA-E, which was used as a selective recognition site for the thiol of GSH and an effective fluorescence quencher. Probe N-HCA-E revealed NIR "turn-on" fluorescence (709 nm) for endogenous and exogenous GSH detection in lysosomes with a large Stokes shift (129 nm) and high anti-interference ability.
Assuntos
Corantes Fluorescentes , Glutationa , Imagem Óptica , Xantenos , Corantes Fluorescentes/química , Corantes Fluorescentes/toxicidade , Corantes Fluorescentes/síntese química , Xantenos/química , Humanos , Glutationa/química , Imagem Óptica/métodos , Chalconas/química , Células HeLa , Lisossomos/química , Lisossomos/metabolismo , Raios Infravermelhos , Chalcona/químicaRESUMO
Chemotherapy toxicity and tumor multidrug resistance remain the main reasons for clinical treatment failure in cervical cancer. In this study, 79 novel chalcone derivatives were designed and synthesized using the principle of active substructure splicing with the parent nucleus of licorice chalcone as the lead compound and VEGFR-2 and P-gp as the target of action and their potentials for anticervical cancer activity were preliminarily evaluated. The results showed that the IC50 values of candidate compound B20 against HeLa and HeLa/DDP cells were 3.66 ± 0.10 and 4.35 ± 0.21 µΜ, respectively, with a resistance index (RI) of 1.18, which was significantly higher than that of the positive drug cisplatin (IC50:13.60 ± 1.63, 100.03 ± 7.94 µΜ, RI:7.36). In addition, B20 showed significant inhibitory activity against VEGFR-2 kinase and P-gp-mediated rhodamine 123 efflux, as well as the ability to inhibit the phosphorylation of VEGFR-2 and downstream PI3K/AKT signaling pathway proteins, inducing apoptosis, blocking cells in the S-phase, and inhibiting invasive migration and tubule generation by HUVEC cells. Acceptable safety was demonstrated in acute toxicity tests when B20 was at 200 mg/kg. In the nude mouse HeLa/DDP cell xenograft tumor model, the inhibition rate of transplanted tumors was 39.2 % and 79.2 % when B20 was at 10 and 20 mg/kg, respectively. These results suggest that B20 is a potent VEGFR-2 and P-gp inhibitor with active potential for treating cisplatin-resistant cervical cancer.
Assuntos
Antineoplásicos , Proliferação de Células , Relação Dose-Resposta a Droga , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias do Colo do Útero , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/metabolismo , Feminino , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Chalconas/farmacologia , Chalconas/química , Chalconas/síntese química , Animais , Chalcona/química , Chalcona/farmacologia , Chalcona/síntese química , Células HeLa , Apoptose/efeitos dos fármacos , CamundongosRESUMO
24 chalcone derivatives containing 1,3,4-thiadiazole were synthesized. The results of bioactivity tests indicated that some of the target compounds exhibited superior antifungal activities inâ vitro. Notably, the EC50 value of D4 was 14.4â µg/mL against Phomopsis sp, which was significantly better than that of azoxystrobin (32.2â µg/mL) and fluopyram (54.2â µg/mL). The inâ vivo protective activity of D4 against Phomopsis sp on kiwifruit (71.2 %) was significantly superior to azoxystrobin (62.8 %) at 200â µg/mL. The inâ vivo protective activities of D4 were 74.4 and 57.6 % against Rhizoctonia solani on rice leaf sheaths and rice leaves, respectively, which were slightly better than those of azoxystrobin (72.1 and 49.2 %) at 200â µg/mL. Scanning electron microscopy (SEM) results showed that the mycelial surface collapsed, contracted and grew abnormally after D4 treatment. Finally, the results were further verified by inâ vivo antifungal assay, fluorescence microscopy (FM) observation, determination of relative conductivity, membrane lipid peroxidation degree assay, and determination of cytoplasmic content leakage. Molecular docking results suggested that D4 could be a potential SDHI.
Assuntos
Antifúngicos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Rhizoctonia , Tiadiazóis , Tiadiazóis/química , Tiadiazóis/farmacologia , Tiadiazóis/síntese química , Antifúngicos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Rhizoctonia/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Ascomicetos/efeitos dos fármacos , Chalconas/farmacologia , Chalconas/química , Chalconas/síntese química , Chalcona/farmacologia , Chalcona/química , Chalcona/síntese química , Oryza/microbiologia , Relação Dose-Resposta a DrogaRESUMO
The study focuses on the anxiolytic potential of chalcone (2E,4E)-1-(2-hydroxyphenyl)-5-phenylpenta-2,4-dien-1-one (CHALCNM) in adult zebrafish. Successfully synthesized in 58 % yield, CHALCNM demonstrated no toxicity after 96â h of exposure. In behavioral tests, CHALCNM (40â mg/kg) reduced locomotor activity and promoted less anxious behavior in zebrafish, confirmed by increased permanence in the light zone of the aquarium. Flumazenil reversed its anxiolytic effect, indicating interaction with GABAA receptors. Furthermore, CHALCNM (4 and 20â mg/kg) preserved zebrafish memory in inhibitory avoidance tests. Virtual screening and ADMET profile studies suggest high oral bioavailability, access to the CNS, favored by low topological polarity (TPSA≤75â Å2) and low incidence of hepatotoxicity, standing out as a promising pharmacological agent against the GABAergic system. In molecular coupling, CHALCNM demonstrated superior affinity to diazepam for the GABAA receptor. These results reinforce the therapeutic potential of CHALCNM in the treatment of anxiety, highlighting its possible future clinical application.