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1.
Molecules ; 26(4)2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33672072

RESUMO

Calcium (Ca2+) dependent signaling circuit plays a critical role in influenza A virus (IAV) infection. The 8-O-(E-p-methoxycinnamoyl)harpagide (MCH) exhibits pharmacological activities that exert neuroprotective, hepatoprotective, anti-inflammatory and other biological effects. However, not have reports of antiviral effects. To investigate the antiviral activity of MCH on IAV-infected human lung cells mediated by calcium regulation. We examined the inhibitory effect of MCH on IAV infections and measured the level of viral proteins upon MCH treatment using Western blotting. We also performed molecular docking simulation with MCH and IAV M2 protein. Finally, we analyzed MCH's suppression of intracellular calcium and ROS (reactive oxygen species) in IAV-infected human lung cells using a flow cytometer. The results shown that MCH inhibited the infection of IAV and increased the survival of the infected human lung cells. The levels of IAV protein M1, M2, NS1 and PA were inhibited in MCH-treated human lung cells compared to that in infected and untreated cells. Also, docking simulation suggest that MCH interacted with M2 on its hydrophobic wall (L40 and I42) and polar amino acids (D44 and R45), which formed intermolecular contacts and were a crucial part of the channel gate along with W41. Lastly, MCH inhibited IAV infection by reducing intracellular calcium and mitochondrial Ca2+/ROS levels in infected human lung cells. Taken together, these data suggest that MCH inhibits IAV infection and increases the survival of infected human lung cells by suppressing calcium levels. These results indicate that MCH is useful for developing IAV treatments.


Assuntos
Antivirais/farmacologia , Cálcio/metabolismo , Vírus da Influenza A/efeitos dos fármacos , Espaço Intracelular/metabolismo , Glicosídeos Iridoides/farmacologia , Piranos/farmacologia , Células A549 , Antivirais/uso terapêutico , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Canais Iônicos/metabolismo , Glicosídeos Iridoides/química , Glicosídeos Iridoides/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Simulação de Acoplamento Molecular , Piranos/química , Piranos/uso terapêutico , Proteínas da Matriz Viral
2.
Molecules ; 26(4)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670784

RESUMO

The fungus strain SCSIO 40433 was isolated from an Arctic-derived glacier sediment sample and characterized as Tolypocladium cylindrosporum. A new compound, cylindromicin (1), and seven known secondary metabolites (2-8) were isolated from this strain. The chemical structures of these compounds were elucidated by comprehensive spectroscopic analyses. Cylindromicin (1) featured a 3,4-dihydro-2H-pyran skeleton. The absolute configuration of compound 1 was assigned via interpretation of key Nuclear Overhauser Effect Spectroscopy (NOESY) correlations and Electronic Circular Dichroism (ECD) calculation. Cylindromicin (1) exhibited significant tyrosinase inhibition activity. This study highlights Polar fungi as a potential resource for new bioactive natural products.


Assuntos
Hypocreales/química , Piranos/isolamento & purificação , Regiões Árticas , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Testes de Sensibilidade Microbiana , Espectroscopia de Prótons por Ressonância Magnética , Piranos/química , Piranos/farmacologia , Pironas/química , Pironas/farmacologia , Relação Estrutura-Atividade
3.
Molecules ; 26(3)2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33540504

RESUMO

Counter-current chromatography (CCC) is a unique liquid-liquid partition chromatography and largely relies on the partition interactions of solutes and solvents in two-phase solvents. Usually, the two-phase solvents used in CCC include a lipophilic organic phase and a hydrophilic aqueous phase. Although a large number of partition interactions have been found and used in the CCC separations, there are few studies that address the role of water on solvents and solutes in the two-phase partition. In this study, we presented a new insight that H2O (water) might be an efficient and sensible hydrophobic agent in the n-hexane-methanol-based two-phase partition and CCC separation of lipophilic compounds, i.e., anti-cancer component mollugin from Rubia cordifolia. Although the n-hexane-methanol-based four components solvent systems of n-hexane-ethyl acetate-methanol-water (HEMWat) is one of the most popular CCC solvent systems and widely used for natural products isolation, this is an interesting trial to investigate the water roles in the two-phase solutions. In addition, as an example, the bioactive component mollugin was targeted, separated, and purified by MS-guided CCC with hexane-methanol and minor water as a hydrophobic agent. It might be useful for isolation and purification of lipophilic mollugin and other bioactive compounds complex natural products and traditional Chinese medicines.


Assuntos
Antineoplásicos/isolamento & purificação , Cromatografia Líquida/métodos , Interações Hidrofóbicas e Hidrofílicas , Espectrometria de Massas , Piranos/isolamento & purificação , Rubia/química , Água/química , Antineoplásicos/química , Hexanos/química , Metanol/química , Piranos/química , Solventes/química
4.
Int J Mol Sci ; 22(3)2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33513799

RESUMO

The Mediterranean diet (MD) is a combination of foods mainly rich in antioxidants and anti-inflammatory nutrients that have been shown to have many health-enhancing effects. Extra-virgin olive oil (EVOO) is an important component of the MD. The importance of EVOO can be attributed to phenolic compounds, represented by phenolic alcohols, hydroxytyrosol, and tyrosol, and to secoiridoids, which include oleocanthal, oleacein, oleuropein, and ligstroside (along with the aglycone and glycosidic derivatives of the latter two). Each secoiridoid has been studied and characterized, and their effects on human health have been documented by several studies. Secoiridoids have antioxidant, anti-inflammatory, and anti-proliferative properties and, therefore, exhibit anti-cancer activity. This review summarizes the most recent findings regarding the pharmacological properties, molecular targets, and action mechanisms of secoiridoids, focusing attention on their preventive and anti-cancer activities. It provides a critical analysis of preclinical, in vitro and in vivo, studies of these natural bioactive compounds used as agents against various human cancers. The prospects for their possible use in human cancer prevention and treatment is also discussed.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Iridoides/farmacologia , Neoplasias/prevenção & controle , Azeite de Oliva/análise , Aldeídos/química , Aldeídos/farmacologia , Aldeídos/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/uso terapêutico , Antioxidantes/uso terapêutico , Monoterpenos Ciclopentânicos/química , Monoterpenos Ciclopentânicos/farmacologia , Monoterpenos Ciclopentânicos/uso terapêutico , Dieta Mediterrânea , Glucosídeos/química , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Humanos , Iridoides/química , Iridoides/isolamento & purificação , Iridoides/uso terapêutico , Neoplasias/dietoterapia , Azeite de Oliva/farmacologia , Fenóis/química , Fenóis/farmacologia , Fenóis/uso terapêutico , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Álcool Feniletílico/uso terapêutico , Piranos/química , Piranos/farmacologia , Piranos/uso terapêutico
5.
Biochem J ; 478(1): 235-245, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33346350

RESUMO

Flavonoids play beneficial roles in various human diseases. In this study, a flavonoid library was employed to probe inhibitors of d-glycero-ß-d-manno-heptose-1-phosphate adenylyltransferase from Burkholderia pseudomallei (BpHldC) and two flavonoids, epigallocatechin gallate (EGCG) and myricetin, have been discovered. BpHldC is one of the essential enzymes in the ADP-l-glycero-ß-d-manno-heptose biosynthesis pathway constructing lipopolysaccharide of B. pseudomallei. Enzyme kinetics study showed that two flavonoids work through different mechanisms to block the catalytic activity of BpHldC. Among them, a docking study of EGCG was performed and the binding mode could explain its competitive inhibitory mode for both ATP and ßG1P. Analyses with EGCG homologs could reveal the important functional moieties, too. This study is the first example of uncovering the inhibitory activity of flavonoids against the ADP-l-glycero-ß-d-manno-heptose biosynthesis pathway and especially targeting HldC. Since there are no therapeutic agents and vaccines available against melioidosis, EGCG and myricetin can be used as templates to develop antibiotics over B. pseudomallei.


Assuntos
Burkholderia pseudomallei/enzimologia , Flavonoides/química , Manose/química , Nucleotidiltransferases/química , Piranos/química , Trifosfato de Adenosina/química , Catequina/análogos & derivados , Catequina/química , Cristalografia por Raios X , Escherichia coli/metabolismo , Concentração Inibidora 50 , Cinética , Ligantes , Simulação de Acoplamento Molecular , Nucleotidiltransferases/antagonistas & inibidores , Nucleotidiltransferases/metabolismo
6.
Molecules ; 25(24)2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33322077

RESUMO

Microtubule-targeting agents (MTAs) remain a gold standard for the treatment of several cancer types. By interfering with microtubules dynamic, MTAs induce a mitotic arrest followed by cell death. This antimitotic activity of MTAs is dependent on the spindle assembly checkpoint (SAC), which monitors the integrity of the mitotic spindle and proper chromosome attachments to microtubules in order to ensure accurate chromosome segregation and timely anaphase onset. However, the cytotoxic activity of MTAs is restrained by drug resistance and/or toxicities, and had motivated the search for new compounds and/or alternative therapeutic strategies. Here, we describe the synthesis and mechanism of action of the xanthone derivative pyranoxanthone 2 that exhibits a potent anti-growth activity against cancer cells. We found that cancer cells treated with the pyranoxanthone 2 exhibited persistent defects in chromosome congression during mitosis that were not corrected over time, which induced a prolonged SAC-dependent mitotic arrest followed by massive apoptosis. Importantly, pyranoxanthone 2 was able to potentiate apoptosis of cancer cells treated with nanomolar concentrations of paclitaxel. Our data identified the potential of the pyranoxanthone 2 as a new potent antimitotic with promising antitumor potential, either alone or in combination regimens.


Assuntos
Antimitóticos/química , Antimitóticos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Piranos/química , Xantonas/química , Xantonas/farmacologia , Antimitóticos/síntese química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Técnicas de Química Sintética , Aberrações Cromossômicas/efeitos dos fármacos , Imunofluorescência , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Microtúbulos/metabolismo , Mitose/efeitos dos fármacos , Estrutura Molecular , Paclitaxel/farmacologia
7.
PLoS Genet ; 16(12): e1009249, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33370251

RESUMO

Karrikins (KARs), smoke-derived butenolides, are perceived by the α/ß-fold hydrolase KARRIKIN INSENSITIVE2 (KAI2) and thought to mimic endogenous, yet elusive plant hormones tentatively called KAI2-ligands (KLs). The sensitivity to different karrikin types as well as the number of KAI2 paralogs varies among plant species, suggesting diversification and co-evolution of ligand-receptor relationships. We found that the genomes of legumes, comprising a number of important crops with protein-rich, nutritious seed, contain two or more KAI2 copies. We uncover sub-functionalization of the two KAI2 versions in the model legume Lotus japonicus and demonstrate differences in their ability to bind the synthetic ligand GR24ent-5DS in vitro and in genetic assays with Lotus japonicus and the heterologous Arabidopsis thaliana background. These differences can be explained by the exchange of a widely conserved phenylalanine in the binding pocket of KAI2a with a tryptophan in KAI2b, which arose independently in KAI2 proteins of several unrelated angiosperms. Furthermore, two polymorphic residues in the binding pocket are conserved across a number of legumes and may contribute to ligand binding preferences. The diversification of KAI2 binding pockets suggests the occurrence of several different KLs acting in non-fire following plants, or an escape from possible antagonistic exogenous molecules. Unexpectedly, L. japonicus responds to diverse synthetic KAI2-ligands in an organ-specific manner. Hypocotyl growth responds to KAR1, KAR2 and rac-GR24, while root system development responds only to KAR1. This differential responsiveness cannot be explained by receptor-ligand preferences alone, because LjKAI2a is sufficient for karrikin responses in the hypocotyl, while LjKAI2a and LjKAI2b operate redundantly in roots. Instead, it likely reflects differences between plant organs in their ability to transport or metabolise the synthetic KLs. Our findings provide new insights into the evolution and diversity of butenolide ligand-receptor relationships, and open novel research avenues into their ecological significance and the mechanisms controlling developmental responses to divergent KLs.


Assuntos
Proteínas de Arabidopsis/genética , Furanos/metabolismo , Hidrolases/genética , Hipocótilo/crescimento & desenvolvimento , Lotus/metabolismo , Reguladores de Crescimento de Planta/metabolismo , Raízes de Plantas/crescimento & desenvolvimento , Piranos/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Furanos/química , Duplicação Gênica , Regulação da Expressão Gênica de Plantas/genética , Compostos Heterocíclicos com 3 Anéis/metabolismo , Hidrolases/metabolismo , Hipocótilo/metabolismo , Lactonas/metabolismo , Ligantes , Lotus/genética , Análise em Microsséries , Filogenia , Reguladores de Crescimento de Planta/química , Reguladores de Crescimento de Planta/genética , Raízes de Plantas/metabolismo , Piranos/química
8.
J Med Chem ; 63(13): 7108-7126, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32452679

RESUMO

In the present work, a novel series of trifluoromethyl-substituted tetrahydropyran derivatives were rationally designed and synthesized as potent DPP-4 inhibitors with significantly improved duration time of action over current commercially available DPP-4 inhibitors. The incorporation of the trifluoromethyl group on the 6-position of the tetrahydropyran ring of omarigliptin with the configuration of (2R,3S,5R,6S) not only significantly improves the overall pharmacokinetic profiles in mice but also maintains comparable DPP-4 inhibition activities. Further preclinical development of compound 2 exhibited its extraordinary efficacy in vivo and good safety profile. Clinical studies of compound 2 (Haisco HSK7653) are now ongoing in China, which revealed that inhibitor 2 could serve as an efficient candidate with a once-biweekly therapeutic regimen.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Desenho de Fármacos , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Piranos/síntese química , Piranos/farmacologia , Animais , Técnicas de Química Sintética , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Macaca mulatta , Masculino , Camundongos , Piranos/química , Piranos/farmacocinética , Distribuição Tecidual
9.
Int J Nanomedicine ; 15: 2337-2349, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32308385

RESUMO

Purpose: The aim of this study was to develop an "all-in-one" nanoplatform that integrates at the second near-infrared (NIR-II) region dye IR1061 and anticancer drug paclitaxel (PTX) into an apoferritin (AFN) nanocage (IR-AFN@PTX). Simultaneously, folic acid (FA), tumor target molecule,  was conjugated onto IR-AFN@PTX to be IR-AFN@PTX-FA for tumor-targeted and pH/NIR-II-triggered synergistic photothermal-chemotherapy. Methods: IR1061 was firstly reacted with PEG and then conjugated with AFN to be IR-AFN. Then, FA was conjugated onto the surface of IR-AFN to be IR-AFN-FA. At last, PTX was incorporated into IR-AFN-FA to fabricate a nanoplatform IR-AFN@PTX-FA. The NIR-II photothermal properties and pH/NIR-II triggered drug release were evaluated. The ability of IR-AFN@PTX-FA to target tumors was estimated using optical bioluminescence. In vitro and in vivo synergistic therapeutic effects of pH/NIR-II-triggered and tumor-targeted photothermal-chemotherapy were investigated in 4T1 tumor model. Results: IR-AFN@PTX-FA showed excellent water solubility and physiological stability, which significantly enhanced the solubility of both IR1061 and PTX. After 5 min of laser irradiation at 1064 nm, IR-AFN@PTX-FA exhibited an effective photothermal effect compared with laser irradiation at 808 nm, even when blocked with 0.6 cm thick chicken breast. Cellular uptake experiments showed IR-AFN@PTX-FA utilized clathrin-mediated and caveolae-mediated endocytosis pathways to enter 4T1 cells, and was then delivered by the endosome to the lysosome. NIR-II laser irradiation and pH could synergistically trigger PTX release, inducing significant tumor inhibition in vitro and in vivo. Conclusion: As a novel "all-in-one" nanoplatform, IR-AFN@PTX-FA was found to selectively target tumors and showed very efficient NIR-II photothermal effects and pH/NIR-II triggered drug release effects, showing a remarkable, synergistic photothermal-chemotherapy effect.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Boratos/química , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/administração & dosagem , Paclitaxel/administração & dosagem , Paclitaxel/farmacologia , Piranos/química , Animais , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Apoferritinas/química , Linhagem Celular Tumoral , Corantes/química , Liberação Controlada de Fármacos , Ácido Fólico/química , Ácido Fólico/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Lasers , Camundongos Endogâmicos BALB C , Nanopartículas/química , Paclitaxel/farmacocinética , Fototerapia/métodos , Solubilidade , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Biomater Sci ; 8(8): 2245-2254, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32129330

RESUMO

One of the most commonly used near infrared (NIR) dyes is indocyanine green (ICG), which has been extensively used for NIR bioimaging, photothermal and photodynamic therapy. However, upon excitation this dye can react with molecular oxygen to form singlet oxygen (SO), which can then cleave ICG to form non-fluorescent debris. In order to reduce the reaction between ICG and oxygen, we used energy transfer (ET) between the former and the NIR dye IR-1061. The two dyes were encapsulated in micelles composed of biocompatible poly(ethylene glycol)-block-poly(ε-caprolactone) (PCL-PEG). Micelles were characterized for their size using dynamic light scattering (DLS) and were found to measure about 35 nm in diameter. Fluorescence emission measurements were conducted to show that the stability of ICG against photodecomposition is increased. Moreover, this increased stability allows the encapsulated dye to generate more heat and for a longer time, compared to its free form. Studies with a SO indicator showed that as more IR-1061 is added to the micelles, less SO is produced. These results show how by changing the amount of added IR-1061 it is possible to tune the heat and SO generated by the system. Cell viability studies demonstrated that while particles were nontoxic under physiological conditions, upon 808 nm irradiation they become potent at eradicating MCF7 cancer cells. Moreover, it was demonstrated that both the increase of temperature and the creation of decomposition debris play a role in the cytotoxic efficacy of the micelles. Dye-loaded micelles that were injected to live mice showed bright fluorescence in the over 1000 nm NIR (OTN-NIR) region, allowing for visualization of blood vessels and internal organs. Most importantly, the encapsulated dyes remained stable for over 30 minutes, gradually accumulating in the liver and spleen. The presence of IR-1061 in addition to the heat-generating dye ICG allowed for simultaneous temperature modification and monitoring. We were able to assess the change in temperature by measuring the change in the fluorescence intensity of IR-1061 in the OTN-NIR region, a range with deep penetration of living tissues. These features illustrate the potential use of ICG/IR-1061 in PCL-PEG micelles as promising candidates for cancer treatment and diagnosis.


Assuntos
Boratos/administração & dosagem , Corantes/administração & dosagem , Verde de Indocianina/administração & dosagem , Lactonas/administração & dosagem , Micelas , Neoplasias/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Piranos/administração & dosagem , Animais , Boratos/química , Corantes/química , Feminino , Humanos , Verde de Indocianina/química , Lactonas/química , Luz , Células MCF-7 , Camundongos Endogâmicos ICR , Imagem Óptica , Fotoquimioterapia , Polietilenoglicóis/química , Piranos/química
11.
Chemistry ; 26(33): 7369-7373, 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32083771

RESUMO

Cancer stem cells (CSC) constitute a cell subpopulation in solid tumors that is responsible for resistance to conventional chemotherapy, metastasis and cancer relapse. The natural product Salinomycin can selectively target this cell niche by directly interacting with lysosomal iron, taking advantage of upregulated iron homeostasis in CSC. Here, inhibitors of the divalent metal transporter 1 (DMT1) have been identified that selectively target CSC by blocking lysosomal iron translocation. This leads to lysosomal iron accumulation, production of reactive oxygen species and cell death with features of ferroptosis. DMT1 inhibitors selectively target CSC in primary cancer cells and circulating tumor cells, demonstrating the physiological relevance of this strategy. Taken together, this opens up opportunities to tackle unmet needs in anti-cancer therapy.


Assuntos
Proteínas de Transporte de Cátions/química , Ferro/química , Lisossomos/química , Células-Tronco Neoplásicas/química , Piranos/química , Espécies Reativas de Oxigênio/química , Proteínas de Transporte de Cátions/metabolismo , Morte Celular , Homeostase , Humanos , Ferro/metabolismo , Lisossomos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima
12.
Chemistry ; 26(33): 7416-7424, 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32083773

RESUMO

Salinomycin (1) exhibits a large spectrum of biological activities including the capacity to selectively eradicate cancer stem cells (CSC), making it and its derivatives promising candidates for the development of drug leads against CSC. It has been previously shown that salinomycin and its C20-propargylamine derivative (Ironomycin (2)) accumulate in lysosomes and sequester iron in this organelle. Herein, a library of salinomycin derivatives is reported, including products of C20-amination, C1-esterification, C9-oxidation, and C28-dehydration. The biological activity of these compounds is evaluated against transformed human mammary epithelial HMLER CD24low /CD44high cells, a well-established model of breast CSC, and HMLER CD24high /CD44low cells deprived of CSC properties. Unlike other structural alterations, derivative 4, which displays a cyclopropylamine at position C20, showed a strikingly low IC50 value of 23 nm against HMLER CD24low /CD44high cells. This study provides highly selective molecules to target the CSC niche, a potential interesting advance for drug development to prevent cancer resistance.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Receptores de Hialuronatos/química , Ferro/agonistas , Lisossomos/química , Células-Tronco Neoplásicas/química , Piranos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Lisossomos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Piranos/química
13.
Molecules ; 25(4)2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32059518

RESUMO

In continuation of our efforts to identify promising antileishmanial agents based on the chroman scaffold, we synthesized several substituted 2H-thiochroman derivatives, including thiochromenes, thichromanones and hydrazones substituted in C-2 or C-3 with carbonyl or carboxyl groups. Thirty-two compounds were thus obtained, characterized, and evaluated against intracellular amastigotes of Leishmania (V) panamensis. Twelve compounds were active, with EC50 values lower than 40 µM, but only four compounds displayed the highest antileishmanial activity, with EC50 values below 10 µM; these all compounds possess a good Selectivity Index > 2.6. Although two active compounds were thiochromenes, a clear structure-activity relationship was not detected since each active compound has a different substitution pattern.


Assuntos
Antiprotozoários/farmacologia , Proliferação de Células/efeitos dos fármacos , Leishmania/efeitos dos fármacos , Piranos/farmacologia , Compostos de Sulfidrila/farmacologia , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Humanos , Leishmania/patogenicidade , Estrutura Molecular , Testes de Sensibilidade Parasitária , Piranos/síntese química , Piranos/química , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química
14.
Nat Commun ; 11(1): 793, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034152

RESUMO

Fluorescence-based technologies have revolutionized in vivo monitoring of biomolecules. However, significant technical hurdles in both probe chemistry and complex cellular environments have limited the accuracy of quantifying these biomolecules. Herein, we report a generalizable engineering strategy for dual-emission anti-Kasha-active fluorophores, which combine an integrated fluorescein with chromene (IFC) building block with donor-π-acceptor structural modification. These fluorophores exhibit an invariant near-infrared Kasha emission from the S1 state, while their anti-Kasha emission from the S2 state at around 520 nm can be finely regulated via a spirolactone open/closed switch. We introduce bio-recognition moieties to IFC structures, and demonstrate ratiometric quantification of cysteine and glutathione in living cells and animals, using the ratio (S2/S1) with the S1 emission as a reliable internal reference signal. This de novo strategy of tuning anti-Kasha-active properties expands the in vivo ratiometric quantification toolbox for highly accurate analysis in both basic life science research and clinical applications.


Assuntos
Bioquímica/métodos , Corantes Fluorescentes/química , Imagem Molecular/métodos , Células A549 , Animais , Benzopiranos/química , Cisteína/análise , Feminino , Fluoresceína/química , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Glutationa/análise , Células Hep G2 , Humanos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Neoplasias Experimentais/diagnóstico por imagem , Piranos/química , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Espironolactona/química
15.
Chemistry ; 26(24): 5419-5433, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31958176

RESUMO

A series of 16 dinuclear thiopyridone-based organometallics with excellent water solubility, increased stability and remarkable cytotoxicity were synthesized and characterized. The complexes of this work formed dimeric species featuring a double positive charge in polar protic solvents, accounting for their outstanding solubility in aqueous solution. Most of them displayed higher antiproliferative activity than their parental thiomaltol complex, with unexpected cytotoxicity trends depending on the employed metal center, ligand modification, and cell line. Insights into their behavior in biological systems were gathered by means of amino-acid interaction studies, cytotoxicity tests in 3D spheroid models, laser ablation, cellular accumulation measurements, as well as cell cycle experiments.


Assuntos
Complexos de Coordenação/síntese química , Piranos/síntese química , Tionas/síntese química , Ciclo Celular , Linhagem Celular Tumoral , Complexos de Coordenação/química , Biblioteca Gênica , Humanos , Ligantes , Piranos/química , Solubilidade , Tionas/química
16.
Food Chem ; 314: 126183, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31972407

RESUMO

Phenolic compounds largely contribute to the nutraceutical properties of virgin olive oil (VOO), the organoleptic attributes and the shelf life due to their antioxidant capabilities. Due to the relevance of malaxation in the oil extraction process, we tested the effects of malaxation time on the concentrations of relevant phenolic compounds in VOO, and we evaluated the influence of performing malaxation under vacuum. An increase in malaxation time significantly decreased the concentrations of aglycone isomers of oleuropein and ligstroside but, conversely, increased the oleocanthal and oleacein contents. Additionally, malaxation under vacuum led to an increase in phenolic contents compared to standard conditions carried out at atmospheric pressure. Finally, we explored the possibility of predicting the VOO oxidative stability on the basis of the phenolic profile, and a model (R2 = 0.923; p < 0.0001) was obtained by combining the concentration of the VOO phenolic compounds and the main fatty acids.


Assuntos
Manipulação de Alimentos/métodos , Azeite de Oliva/química , Fenóis/análise , Fenóis/química , Aldeídos/análise , Aldeídos/química , Monoterpenos Ciclopentânicos/análise , Monoterpenos Ciclopentânicos/química , Ácidos Graxos/análise , Ácidos Graxos/química , Glucosídeos/análise , Glucosídeos/química , Iridoides/análise , Iridoides/química , Azeite de Oliva/análise , Oxirredução , Piranos/análise , Piranos/química , Temperatura , Fatores de Tempo
17.
Molecules ; 25(3)2020 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-31991882

RESUMO

Polyether ionophore salinomycin (SAL) and its semi-synthetic derivatives are recognized as very promising anticancer drug candidates due to their activity against various types of cancer cells, including multidrug-resistant populations. Ovarian cancer is the deadliest among gynecologic malignancies, which is connected with the development of chemoresistant forms of the disease in over 70% of patients after initial treatment regimen. Thus, we decided to examine the anticancer properties of SAL and selected SAL derivatives against a series of drug-sensitive (A2780, SK-OV-3) and derived drug-resistant (A2780 CDDP, SK-OV-3 CDDP) ovarian cancer cell lines. Although SAL analogs showed less promising IC50 values than SAL, they were identified as the antitumor agents that significantly overcome the resistance to platinum-based drugs in ovarian cancer, more potent than unmodified SAL and commonly used anticancer drugs-5-fluorouracil, gemcitabine, and cisplatin. Moreover, when compared with SAL used alone, our experiments proved for the first time increased selectivity of SAL-based dual therapy with 5-fluorouracil or gemcitabine, especially towards A2780 cell line. Looking closer at the results, SAL acted synergistically with 5-fluorouracil towards the drug-resistant A2780 cell line. Our results suggest that combinations of SAL with other antineoplastics may become a new therapeutic option for patients with ovarian cancer.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Organoplatínicos/farmacologia , Piranos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Estrutura Molecular , Compostos Organoplatínicos/química , Neoplasias Ovarianas , Piranos/química
18.
J Am Chem Soc ; 142(7): 3472-3478, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-31986250

RESUMO

Amphidinol 3 (AM3) is a potent antifungal produced by the dinoflagellate Amphidinium klebsii. It was difficult to determine the absolute configuration of AM3 by using the scarce natural product due to the presence of numerous stereogenic centers on the acyclic carbon chain. Since the absolute configuration was partially determined on the basis of insufficient evidence, the originally proposed structure has been revised three times. Although recent progress on structure determination by computational analysis is remarkable, total synthesis is still the most reliable way to confirm structures. The first total synthesis of AM3 was achieved via expeditious assembly of three components in five steps, confirming the revised structure of AM3 after more than 20 years since its first discovery. The established synthetic route would be a general strategy for synthesizing amphidinol congeners. An artificial and simplified analogue of AM3, which elicited antifungal activity comparable to that of AM3, was designed and synthesized. This is the first example of a biologically active artificial analogue possessing a shorter polyol moiety, providing insight on the antifungal mode-of-action.


Assuntos
Alcenos/síntese química , Piranos/síntese química , Alcenos/química , Alcenos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Modelos Moleculares , Piranos/química , Piranos/farmacologia , Relação Estrutura-Atividade
19.
J Infect Public Health ; 13(5): 791-799, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31813834

RESUMO

BACKGROUND: The development of bacterial biofilm can cause severe chronic infections and antibiotic resistance. Therefore, it poses a significant threat to public health. Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa) are two major pathogens that can cause biofilm-associated infections, which leads to the urgent necessity of developing new agents with biofilm-forming inhibitory ability. METHODS: A series of pyran derivatives were synthesized and characterized, and their in vitro anti-biofilm activity against S. aureus and P. aeruginosa were measured by minimal biofilm inhibitory concentration assay and FITC dye staining. The in vivo antibiofilm therapeutical effects were evaluated in S. aureus induced tissue cage infection mice model and P. aeruginosa induced urinary tract catheter infection rat model. RESULTS: Several pyran derivatives showed the in vitro anti-biofilm activity against S. aureus and P. aeruginosa, and the activity of these compounds was not mediated through the accessory gene regulator (agr) quorum sensing system of S. aureus. One of these pyran derivatives, namely 2-amino-4-(2,6-dichlorophenyl)-3-cyano-5-oxo-4H,5H-pyrano[3,2c]chromene, exhibited significant inhibitory biofilm-formation activity in S. aureus tissue cage infection mice model and in the P. aeruginosa-infected urinary tract catheters of experimental rats. CONCLUSIONS: The data indicated that this pyran derivative is a possible lead compound that can be used for the development of novel anti-biofilm agents against S. aureus and P. aeruginosa infection.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Piranos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/química , Infecções Relacionadas a Cateter/microbiologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/microbiologia , Piranos/química , Percepção de Quorum , Infecções Estafilocócicas/microbiologia , Infecções Urinárias/microbiologia
20.
J Pharm Pharmacol ; 72(2): 236-248, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31743446

RESUMO

OBJECTIVES: In this study, the pharmacological properties of six spirocyclic piperidines 1-6 showing very high σ1 receptor affinity (Ki  = 0.2-16 nm) were investigated. METHODS: In vitro receptor binding studies, retinal ganglion assay and in vivo capsaicin assay were used to determine the affinity, selectivity and activity. Influence on human tumour cell growth (cell lines A427, LCLC-103H, 5637 and DAN-G) was determined in different assays. The effect on the ergosterol and cholesterol biosynthesis was determined by GLC/MS analysis. KEY FINDINGS: Receptor binding studies demonstrated high selectivity for the σ1 receptor. The increased Ca2+ influx mediated by 2 and the analgesic activity of 1, 4, 5 and 6 confirm σ1 receptor antagonistic activity. Inhibition of human tumour cell growth further supports the σ1 antagonistic effects. Treatment of A427 tumour cells with 2 led to cell detachment and cell degradation. Whereas the ergosterol biosynthesis was not affected, the sterol C14-reductase, a key enzyme in the cholesterol biosynthesis, was weakly inhibited. CONCLUSIONS: Due to the high selectivity, off-target effects are not expected. The antiallodynic activity underlines the clinical potential of the spirocyclic piperidines for the treatment of neuropathic pain. Due to the antiproliferative activity, the spirocyclic σ1 antagonists represent promising antitumour agents.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Piperidinas/farmacologia , Receptores sigma/antagonistas & inibidores , Animais , Antineoplásicos/química , Cálcio/metabolismo , Linhagem Celular Tumoral , Furanos/química , Furanos/farmacologia , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/patologia , Piperidinas/química , Piranos/química , Piranos/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
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