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1.
Artigo em Inglês | MEDLINE | ID: mdl-31877429

RESUMO

A simple and fast bioanalytical method for the quantification of kavain in mice plasma was developed using liquid chromatography (LC)-tandem mass spectrometry (MS/MS). A full method validation was performed, according to regulatory guidelines, employing isotopically labeled kavain as the internal standard (racemic-kavain-d3). For the quantification, [M+H]+ was formed using an electrospray ionization (ESI) source in the positive ion mode and multiple reaction monitoring (MRM) was employed using a quadrupole-linear ion trap (4000 QTRAP®) instrument. The monitored MRM transitions were 231.0 â†’ 115.1 and 231.0 â†’ 152.8 for kavain; and 234.2 â†’ 199.2 for the internal standard. A linear response was obtained at the concentration range of 10 to 200 ng/mL with intra- and inter-day variations within the acceptable criteria for all quality control samples. After validation, the method was successfully applied for the quantification of kavain in mice plasma after oral administration of the kavain standard and Kava-kava extract. The plasma concentration over time results were applied for a pharmacokinetics study. The obtained pharmacokinetic parameters indicated a considerably higher bioavailability for kavain when Kava-kava extract was administered due to a pharmacokinetic synergism between the analyte and the other compounds present in the extract.


Assuntos
Cromatografia Líquida/métodos , Pironas/sangue , Pironas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Feminino , Kava , Limite de Detecção , Modelos Lineares , Camundongos , Extratos Vegetais , Pironas/química , Reprodutibilidade dos Testes
2.
Org Biomol Chem ; 17(40): 8943-8957, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31482157

RESUMO

Diterpene pyrones (DTPs) are a group of well-known, mainly fungal, natural products, first isolated in 1966. As the name indicates, they are composed of two main structural features: a diterpenyl moiety and a pyrone ring. Various names have been given to this class of metabolites; however, biogenetic evidence indicates that they originate through the same metabolic pathway. Based on their biosynthesis, which leads to differences in their structural architecture, the DTPs can be classified into three main types. In addition to their intriguing chemistry, these compounds demonstrate a wide range of biological activities rendering them a desirable target for total synthesis. To date, sixty-seven DTPs have been isolated from various fungal species, with one example originating from the plant kingdom. This review aims at unifying the classification of these compounds, in addition to presenting a detailed description of their isolation, bioactivities, biosynthesis, and total synthesis.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/metabolismo , Diterpenos/química , Diterpenos/metabolismo , Pironas/química , Pironas/metabolismo , Produtos Biológicos/síntese química , Diterpenos/síntese química , Estrutura Molecular , Pironas/síntese química
3.
Molecules ; 24(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370299

RESUMO

Radicinin (1), is a fungal dihydropyranopyran-4,5-dione isolated together with some analogues, namely 3-epi-radicinin, radicinol, 3-epi-radicinol, and cochliotoxin (2-5), from the culture filtrates of the fungus Cochliobolus australiensis, a foliar pathogen of buffelgrass (Cenchrus ciliaris), an invasive weed in North America. Among the different metabolites 1 showed target-specific activity against the host plant and no toxicity on zebrafish embryos, promoting its potential use to develop a natural bioherbicide formulation to manage buffelgrass. These data and the peculiar structural feature of 1 suggested to carry out a structure-activity relationship study, preparing some key hemisynthetic derivatives and to test their phytotoxicity. In particular, p-bromobenzoyl, 5-azidopentanoyl, stearoyl, mesyl and acetyl esters of radicinin were semisynthesized as well as the monoacetyl ester of 3-epi-radicinin, the diacetyl esters of radicinol and its 3 epimer, and two hexa-hydro derivatives of radicinin. The spectroscopic characterization and the activity by leaf puncture bioassay against buffelgrass of all the derivatives is reported. Most of the compounds showed phytotoxicity but none of them had comparable or higher activity than radicinin. Thus, the presence of an α,ß unsaturated carbonyl group at C-4, as well as, the presence of a free secondary hydroxyl group at C-3 and the stereochemistry of the same carbon proved to be the essential feature for activity.


Assuntos
Cenchrus/efeitos dos fármacos , Plantas Daninhas/efeitos dos fármacos , Pironas/química , Relação Estrutura-Atividade , Alcaloides/química , Alcaloides/farmacologia , Ascomicetos/química , Cenchrus/crescimento & desenvolvimento , Fungos Mitospóricos/química , Estrutura Molecular , América do Norte , Plantas Daninhas/crescimento & desenvolvimento , Pironas/farmacologia , Toxinas Biológicas/química , Toxinas Biológicas/farmacologia
4.
Molecules ; 24(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370334

RESUMO

Hyperpigmentation is considered by many to be a beauty problem and is responsible for photoaging. To treat this skin condition, medicinal cosmetics containing tyrosinase inhibitors are used, resulting in skin whitening. In this study, taraxerol methyl ether (1), spinasterol (2), 6-hydroxyflavanone (3), (+)-dihydrokaempferol (4), 3,4-dihydroxybenzoic acid (5), taraxerol (6), taraxerone (7), and lupeol acetate (8) were isolated from Manilkara zapota bark. Their chemical structures were elucidated by analysis of their nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) data, and by comparing them with data found in the literature. The in vitro antityrosinase, antioxidant, and cytotoxic activities of the isolated compounds (1-8) were evaluated. (+)-Dihydrokaempferol (4) exhibited higher monophenolase inhibitory activity than both kojic acid and α-arbutin. However, it showed diphenolase inhibitory activity similar to kojic acid. (+)-Dihydrokaempferol (4) was a competitive inhibitor of both monophenolase and diphenolase activities. It exhibited the strongest 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), and ferric reducing antioxidant power (FRAP) activities of the isolated compounds. Furthermore, (+)-dihydrokaempferol (4) also demonstrated potent cytotoxicity in breast carcinoma cell line (BT474), lung bronchus carcinoma cell line (Chago-K1), liver carcinoma cell line (HepG2), gastric carcinoma cell line (KATO-III), and colon carcinoma cell line (SW620). These results suggest that M. zapota bark might be a good potential source of antioxidants and tyrosinase inhibitors for applications in cosmeceutical products.


Assuntos
Manilkara/química , Monofenol Mono-Oxigenase/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Arbutina/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Flavonoides/química , Flavonoides/isolamento & purificação , Humanos , Hidroxibenzoatos/química , Hidroxibenzoatos/isolamento & purificação , Monofenol Mono-Oxigenase/química , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/química , Ácido Oleanólico/isolamento & purificação , Compostos Fitoquímicos/química , Pironas/química , Estigmasterol/análogos & derivados , Estigmasterol/química , Estigmasterol/isolamento & purificação
5.
Chem Biodivers ; 16(9): e1900266, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31298476

RESUMO

Two new spliceostatin analogs, designed as spliceostatins J and K (1 and 2), were isolated and identified from the culture of Pseudomonas sp., along with two known ones, FR901464 (3) and spliceostatin E (4). Their structures were elucidated by detailed interpretation of their spectroscopic data, especially 2D-NMR and HR-ESI-MS. Spliceostatin J (1) represented the first example of spliceostatins bearing an unusual hexahydrofuro[3,4-b]furan moiety. Biological assay showed all the isolated compounds except 1 displayed potent cytotoxic activities against two cancer cell lines (MDA-MB-231 and A-549). Structure-activity-relationship studies revealed that the tetrahydropyran ring in spliceostatin analogs was necessary for their bioactive retention.


Assuntos
Antineoplásicos/farmacologia , Furanos/farmacologia , Lactonas/farmacologia , Pseudomonas/química , Pironas/farmacologia , Células A549 , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/química , Furanos/isolamento & purificação , Humanos , Lactonas/química , Lactonas/isolamento & purificação , Estrutura Molecular , Piranos/química , Piranos/isolamento & purificação , Piranos/farmacologia , Pironas/química , Pironas/isolamento & purificação , Compostos de Espiro/química , Compostos de Espiro/isolamento & purificação , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
6.
Mar Drugs ; 17(7)2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31284448

RESUMO

The sponge-derived fungus Penicillium sp. SCSIO41015 cultured on solid rice medium yielded twenty-one compounds (1-21), including two new alkaloids (1 and 2) and one new pyrone derivative (3). Their structures were elucidated by analysis of 1D/2D NMR data and HR-ESI-MS. Their absolute configurations were established by single-crystal X-ray diffraction analysis and comparison of the experimental with reported specific rotation values. Compound 16 exhibited selective cytotoxic activity against the human gastric cancer cells MGC803, with IC50 value of 5.19 µM. Compounds 9 and 18 showed weak antibacterial activity against Staphylococcus aureus and Acinetobacter baumannii, respectively, both with MIC values of 57 µg/mL. Furthermore, compound 16 displayed potent antibacterial activity against S. aureus with an MIC value of 3.75 µg/mL.


Assuntos
Alcaloides/química , Organismos Aquáticos/química , Fungos/química , Penicillium/química , Policetídeos/química , Poríferos/microbiologia , Células A549 , Alcaloides/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Testes de Sensibilidade Microbiana/métodos , Policetídeos/farmacologia , Pironas/química , Pironas/farmacologia
7.
Mar Drugs ; 17(7)2019 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-31284571

RESUMO

Ochrazepines A-D (1-4), four new conjugates dimerized from 2-hydroxycircumdatin C (5) and aspyrone (6) by a nucleophilic addition to epoxide, were isolated from the fermentation broth of the coral-associated Aspergillus ochraceus strain LCJ11-102. Their structures including absolute configurations were determined based on spectroscopic analysis and chemical methods. Compounds 1-4 were also obtained by the semisynthesis from a nucleophilic addition of 2-hydroxycircumdatin C (5) to aspyrone (6). New compound 1 exhibited cytotoxic activity against 10 human cancer cell lines while new compounds 2 and 4 selectively inhibited U251 (human glioblastoma cell line) and compound 3 was active against A673 (human rhabdomyoma cell line), U87 (human glioblastoma cell line), and Hep3B (human liver cancer cell line) with IC50 (half maximal inhibitory concentration) values of 2.5-11.3 µM among 26 tested human cancer cell lines.


Assuntos
Antozoários/microbiologia , Aspergillus ochraceus/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Fermentação/fisiologia , Humanos , Concentração Inibidora 50 , Pironas/química , Pironas/farmacologia
8.
Molecules ; 24(13)2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31288458

RESUMO

BACKGROUND/AIM: Plants play an important role in anti-cancer drug discovery, therefore, the current study aimed to evaluate the biological activity of Alpinia zerumbet (A. zerumbet) flowers. METHODS: The phytochemical and biological criteria of A. zerumbet were in vitro investigated as well as in mouse xenograft model. RESULTS: A. zerumbet extracts, specially CH2Cl2 and MeOH extracts, exhibited the highest potent anti-tumor activity against Ehrlich ascites carcinoma (EAC) cells. The most active CH2Cl2 extract was subjected to bioassay-guided fractionation leading to isolatation of the naturally occurring 5,6-dehydrokawain (DK) which was characterized by IR, MS, 1H-NMR and 13C-NMR. A. zerumbet extracts, specially MeOH and CH2Cl2 extracts, exhibited significant inhibitory activity towards tumor volume (TV). Furthermore, A. zerumbet extracts declined the high level of malonaldehyde (MDA) as well as elevated the levels of superoxide dismutase (SOD) and catalase (CAT) in liver tissue homogenate. Moreover, DK showed anti-proliferative action on different human cancer cell lines. The recorded IC50 values against breast carcinoma (MCF-7), liver carcinoma (Hep-G2) and larynx carcinoma cells (HEP-2) were 3.08, 6.8, and 8.7 µg/mL, respectively. CONCLUSION: Taken together, these findings open the door for further investigations in order to explore the potential medicinal properties of A. zerumbet.


Assuntos
Alpinia/química , Antineoplásicos Fitogênicos/química , Extratos Vegetais/química , Pironas/química , Animais , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Catalase/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Clorofórmio/química , Flores/química , Xenoenxertos , Humanos , Malondialdeído/metabolismo , Metanol/química , Camundongos , Transplante de Neoplasias , Extratos Vegetais/farmacologia , Plantas Medicinais , Pironas/farmacologia , Solventes , Superóxido Dismutase/metabolismo
9.
J Agric Food Chem ; 67(32): 9050-9059, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31339697

RESUMO

The control of 2,3-dihydro-3,5-dihydroxy-6-methyl-4(H)-pyran-4-one (DDMP) formation in the Maillard reaction is important to improve the thermally treated food quality as a result of its intense bitterness and potential toxicity. In this work, phenolic acids, such as gallic, protocatechuic, caffeic, and ferulic acids, were applied to modulate DDMP formation in a microaqueous glucose-proline model. The formation of DDMP was inhibited at low concentrations (from 0.1 to 5.0 mM) while enhanced at 10.0 mM gallic, protocatechuic, and caffeic acids. Ferulic acid always inhibited DDMP formation as a result of the absence of catechol groups on its benzene ring. The result indicated that the control of DDMP formation depended upon the concentration and chemical structures of phenolic acids, such as the number of hydroxyl groups. Further studies indicated that the hydroxyl distribution of phenolic acids regulated the peroxide formation in the model reaction system and further changed the development of the oxidation reaction, which affected the degradation of glucose via caramel or Maillard reaction, Amadori rearrangement product oxidation, and 1-deoxyglucosone degradation to form the intermediates.


Assuntos
Glucose/química , Hidroxibenzoatos/química , Prolina/química , Pironas/química , Reação de Maillard , Modelos Químicos , Oxirredução
11.
ACS Chem Biol ; 14(7): 1536-1545, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31184855

RESUMO

Diversity-oriented synthesis (DOS) has historically focused on the development of small-molecule collections with considerable chemical diversity with the hypothesis that chemical diversity will lead to diverse biological activities. We took a systematic approach to DOS to develop a focused library of reduced flavones from γ-pyrones with diversity of appendage, stereochemistry, and chemical properties to determine which features of small molecules are most predictive of biological performance diversity. The effects of these systematic modifications on biodiversity were determined using Cell Painting and cytotoxicity assays to compare the results of multiple methods of assessment. We observed that a greater fraction of sp3 hybridized atoms (fsp3) does not always lead to enhanced biodiversity, that stereochemistry and appendage diversity both contribute to biodiversity, and that lipophilicity of the pyrone class of compounds correlates with biodiversity. These results will contribute to the development of a general algorithm to predict which chemical features should be considered during the synthesis of DOS libraries to create biological performance-diverse collections of small molecules for probe and drug discovery.


Assuntos
Antineoplásicos/química , Flavonas/química , Pironas/química , Bibliotecas de Moléculas Pequenas/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas/métodos , Flavonas/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Oxirredução , Pironas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia
12.
Mar Drugs ; 17(6)2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185700

RESUMO

Four 4-hydroxy-α-pyrones including three new ones named nipyrones A-C (1-3) together with one known analogue germicidin C (4) were discovered from a marine sponge-derived fungus Aspergillus niger cultivated in a solid rice culture. Their structures and absolute configurations were elucidated through a combination of spectroscopic data and electronic circular dichroism (ECD) calculations as well as comparison with literature data. Compounds 1-4 were evaluated for their antibacterial activities against five pathogenic bacteria (Staphylococcus aureus, Escherichia coli, Bacillus subtilis, methicillin-resistant Staphylococcus aureus, and Mycobacterium tuberculosis). Compound 3 showed promising activity against S. aureus and B. subtilis, with minimum inhibitory concentration (MIC) values of 8 µg/mL and 16 µg/mL, respectively, and displayed weak antitubercular activities against M. tuberculosis, with MIC value of 64 µg/mL, while compounds 1 and 2 exhibited moderate antibacterial efficacy against four pathogenic bacteria with MIC values of 32-64 µg/mL.


Assuntos
Antibacterianos/farmacologia , Organismos Aquáticos/química , Aspergillus niger/química , Bactérias/efeitos dos fármacos , Descoberta de Drogas , Pironas/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Testes de Sensibilidade Microbiana , Pironas/química , Pironas/isolamento & purificação
13.
Org Biomol Chem ; 17(25): 6119-6121, 2019 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-31168541

RESUMO

Anaerobic bacteria represent an underexplored source of bioactive natural products with unusual structural features. Here we report the isolation and structure elucidation of an antimycobacterial natural product, clostroindolin, produced by Clostridium beijerinckii. Furthermore, we provide first insights into structure activity relationships, which might guide the development of novel antibiotics against mycobacteria.


Assuntos
Antibacterianos/farmacologia , Clostridium beijerinckii/química , Alcaloides Indólicos/farmacologia , Pironas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Linhagem Celular Tumoral , Células Endoteliais da Veia Umbilical Humana , Humanos , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Estrutura Molecular , Mycobacteriaceae/efeitos dos fármacos , Pironas/síntese química , Pironas/química , Relação Estrutura-Atividade
14.
Mar Drugs ; 17(6)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31159234

RESUMO

Three novel monomeric naphtho-γ-pyrones, peninaphones A-C (compounds 1-3), along with two known bis-naphtho-γ-pyrones (compounds 4 and 5) were isolated from mangrove rhizosphere soil-derived fungus Penicillium sp. HK1-22. The absolute configurations of compounds 1 and 2 were determined by electronic circular dichroism (ECD) spectra, and the structure of compound 3 was confirmed by single-crystal X-ray diffraction analysis. Compounds 4 and 5 are a pair of hindered rotation isomers. A hypothetical biosynthetic pathway for the isolated monomeric and dimeric naphtho-γ-pyrones is also discussed in this study. Compounds 1-3 showed antibacterial activity against Staphylococcus aureus (ATCC 43300, 33591, 29213, and 25923) with minimum inhibitory concentration (MIC) values in the range of 12.5-50 µg/mL. Compound 3 exhibited significant activity against the rice sheath blight pathogen Rhizoctonia solani.


Assuntos
Organismos Aquáticos/química , Basidiomycota/efeitos dos fármacos , Penicillium/química , Pironas/química , Pironas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Dicroísmo Circular , Testes de Sensibilidade Microbiana , Estrutura Molecular , Difração de Raios X
15.
J Microbiol Biotechnol ; 29(9): 1412-1423, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31216791

RESUMO

The filamentous fungus Aspergillus tubingensis that belongs to the black Aspergillus section has the capacity to produce high-value metabolites, for instance, Naphtho-Gamma-Pyrones (NGPs). For these fungal secondary metabolites, numerous biological properties of industrial interest have been demonstrated, such as antimicrobial, antioxidant and anti-cancer capacities. It has been observed that these secondary metabolites production is linked with the fungal sporulation. The aim of this research was to apply environmental stresses to trigger the production of NGPs in liquid cultures with CYB (Czapek Dox Broth): osmotic and oxidative stresses. In addition, numerous parameters were tested during the experiments, such as pH value, incubation time, container geometry, and static and agitation conditions. Results demonstrate that the produced amount of NGPs can be enhanced by decreasing the water activity (aw) or by adding an oxidative stress factor. In conclusion, this study can contribute to our knowledge regarding A. tubingensis to present an effective method to increase NGPs's production, which may support the development of current industrial processes.


Assuntos
Aspergillus/metabolismo , Naftalenos/metabolismo , Pironas/metabolismo , Aspergillus/crescimento & desenvolvimento , Biomassa , Meios de Cultura , Concentração de Íons de Hidrogênio , Cinética , Estrutura Molecular , Naftalenos/química , Pressão Osmótica , Estresse Oxidativo , Pironas/química
16.
Org Biomol Chem ; 17(22): 5526-5532, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31041978

RESUMO

Marine-derived fungi have been regarded as an under-explored and promising reservoir of structurally novel and bioactive natural products. In this study, five new γ-pyrone-containing polyketides, fusaresters A-E (1-5), were isolated and identified from the culture extracts of a marine-derived fungus Fusarium sp. Hungcl. The structures of compounds 1-5 were elucidated on the basis of their HRESIMS and NMR spectroscopic data as well as 13C NMR calculation and electronic circular dichroism (ECD) analyses. Remarkably, the structure of fusariumin D was revised to (9S*,11S*)-3. All these isolates were tested for the cytotoxicity against seven human cancer cell lines, including SW480, HL-60, A549, MCF-7, HepG2, HeLa and SMMC-7721, and the inhibitory activity against protein tyrosine phosphatase 1B (PTP1B). The results revealed that only compound 2 showed a weak inhibition rate of 56% at 40 µM.


Assuntos
Cumarínicos/química , Fusarium/química , Policetídeos/isolamento & purificação , Pironas/isolamento & purificação , Estrutura Molecular , Policetídeos/química , Pironas/química
17.
Molecules ; 24(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052538

RESUMO

In the course of investigations on the complex phenomenon of bee decline, Aspergillus flavus was isolated from the haemocoel of worker bees. Observations on the metabolomic profile of this strain showed kojic acid to be the dominant product in cultures on Czapek-Dox broth. However, an accurate review of papers documenting secondary metabolite production in A. flavus also showed that an isomer of kojic acid, identified as 5-(hydroxymethyl)-furan-3-carboxylic acid and named flufuran is reported from this species. The spectroscopic data of kojic acid were almost identical to those reported in the literature for flufuran. This motivated a comparative study of commercial kojic acid and 5-(hydroxymethyl)-furan-3-carboxylic acid, highlighting some differences, for example in the 13C-NMR and UV spectra for the two compounds, indicating that misidentification of the kojic acid as 5-(hydroxymethyl)-furan-3-carboxylic acid has occurred in the past.


Assuntos
Aspergillus flavus/química , Furanos/química , Pironas/química , Aspergillus flavus/metabolismo , Furanos/metabolismo , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Pironas/metabolismo
18.
Fitoterapia ; 136: 104169, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31075488

RESUMO

Sopherone A (1) and B (2), two new biologically relevant dibenzo-α-pyrones, were isolated from the stems of Cassia sophera Linn. (Caesalpiniaceae). Their structures were elucidated by detailed analysis of their spectroscopic data, including 1D and 2D NMR.


Assuntos
Cassia/química , Caules de Planta/química , Pironas/química , Índia , Estrutura Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Pironas/isolamento & purificação
19.
Eur J Med Chem ; 177: 105-115, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129449

RESUMO

Human lactate dehydrogenase A (LDHA) plays a critical role in the glycolytic process, making the enzyme an ideal of anti-cancer drug target. Herein, we report the discovery of novel potent LDHA inhibitors by screening an in-house library. The hit-to-lead modification enabled us to identify compound 24c, which inhibited LDHA activity with an EC50 value of 90 nM, and reduced MiaPaCa-2 cancer cell proliferation with an IC50 value of 2.1 µM. In line with the in vitro anticancer activity, 24c suppressed the tumor growth at a dose of 10 mg/kg in a MiaPaCa-2 cells xenograft model, but with little effect to the mice weight. Moreover, 24c strongly inhibited MiaPaCa-2 cell colonies formation, induced MiaPaCa-2 cell apoptosis, and arrested MiaPaCa-2 cell cycle at G2 phase. In addition, the mitochondrial bioenergetics analysis suggested that 24c could reprogram cancer cell metabolic pathways from glycolysis to oxidation phosphorylation, which verified by decreasing the extracellular acidification rates and lactate formation, and increasing oxygen consumption rate in cancer cell. All these results indicate 24c is a promising metabolic modulator for the anticancer drug development.


Assuntos
Antineoplásicos/farmacologia , L-Lactato Desidrogenase/antagonistas & inibidores , Piperazinas/farmacologia , Pironas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Domínio Catalítico , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos , L-Lactato Desidrogenase/química , L-Lactato Desidrogenase/metabolismo , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Simulação de Acoplamento Molecular , Fosforilação Oxidativa , Piperazinas/síntese química , Piperazinas/química , Piperazinas/metabolismo , Ligação Proteica , Pironas/síntese química , Pironas/química , Pironas/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Enzyme Inhib Med Chem ; 34(1): 990-998, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31072148

RESUMO

The novel kojic acid derivatives KAD1 and KAD2 have been demonstrated that they exhibited potent anti-melanogenesis activity in our previous report. In this study, we further study the inhibitory mechanism on mushroom tyrosinase. The inhibitory types of both KADs on diphenolase were classified as mixed type based on the results of the kinetic model. The interaction between KADs and tyrosinase was illustrated by fluorescence quenching, molecular docking and copper chelate activity. The KADs were also evaluated with respect to their antioxidant activities by DPPH and ABTS+ assays. The results showed that KADs have more potent antioxidant activities than kojic acid. Our study could provide new ideas for the development of new anti-tyrosinase and antioxidant agents.


Assuntos
Antioxidantes/farmacologia , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase/antagonistas & inibidores , Pironas/farmacologia , Agaricales/enzimologia , Antioxidantes/química , Benzotiazóis/antagonistas & inibidores , Compostos de Bifenilo/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Cinética , Monofenol Mono-Oxigenase/metabolismo , Picratos/antagonistas & inibidores , Pironas/química , Espectrometria de Fluorescência , Relação Estrutura-Atividade , Ácidos Sulfônicos/antagonistas & inibidores
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