Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.579
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Chem Biodivers ; 16(8): e1900318, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31364803

RESUMO

Sponges from freshwater environments, unlike marine's, are poorly known producers of natural compounds with medicinal purposes. Amazonian sponges produce massive large specimens and are widely spread, taxonomically diverse and their metabolites could represent a new frontier on unusual natural products to treat diseases such as Alzheimer's and Malaria. Species of Metania and Drulia (Metaniidae) genera are major contributors to the fauna of Amazonian freshwater sponges. Methanolic extracts from several species from these genera had their inhibitory activities evaluated in vitro, for parasite Plasmodium falciparum and acetyl and butyrylcholinesterase enzymes (AChE and BChE). All extracts were able to inhibit AChE, although no activity was observed towards BChE. Drulia uruguayensis extract was the most potent, inhibiting AChE with IC50 =1.04 mg/mL. For antiplasmodial activity, all species showed inhibition to P. falciparum, but Metania reticulata being the most efficient with IC50 =2.7 µg/mL. Mass spectrometry analyses evidenced the presence of fatty acids and sterols in active extracts.


Assuntos
Antiprotozoários/química , Inibidores da Colinesterase/química , Poríferos/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Antiprotozoários/isolamento & purificação , Antiprotozoários/farmacologia , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/metabolismo , Ácidos Graxos/análise , Ácidos Graxos/química , Plasmodium falciparum/efeitos dos fármacos , Poríferos/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Esteróis/química
2.
Mar Drugs ; 17(6)2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31146323

RESUMO

Pharmaceutical agents for halting the progression of Parkinson's disease (PD) are lacking. The current available medications only relieve clinical symptoms and may cause severe side effects. Therefore, there is an urgent need for novel drug candidates for PD. In this study, we demonstrated the neuroprotective activity of stellettin B (SB), a compound isolated from marine sponges. We showed that SB could significantly protect SH-SY5Y cells against 6-OHDA-induced cellular damage by inhibiting cell apoptosis and oxidative stress through PI3K/Akt, MAPK, caspase cascade modulation and Nrf2/HO-1 cascade modulation, respectively. In addition, an in vivo study showed that SB reversed 6-OHDA-induced a locomotor deficit in a zebrafish model of PD. The potential for developing SB as a candidate drug for PD treatment is discussed.


Assuntos
Apoptose/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Poríferos/química , Triterpenos/farmacologia , Animais , Organismos Aquáticos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Locomoção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Oxidopamina/toxicidade , Doença de Parkinson/tratamento farmacológico , Triterpenos/química , Triterpenos/isolamento & purificação , Peixe-Zebra
3.
Mar Drugs ; 17(6)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151240

RESUMO

So far, the Futuna Islands located in the Central Indo-Pacific Ocean have not been inventoried for their diversity in marine sponges and associated chemical diversity. As part of the Tara Pacific expedition, the first chemical investigation of the sponge Narrabeena nigra collected around the Futuna Islands yielded 18 brominated alkaloids: seven new bromotryptamine derivatives 1-7 and one new bromotyramine derivative 8 together with 10 known metabolites of both families 9-18. Their structures were deduced from extensive analyses of nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) data. In silico metabolite anticipation using the online tool MetWork revealed the presence of a key and minor biosynthetic intermediates. These 18 compounds showed almost no cytotoxic effect up to 10 µM on human neuroblastoma SH-SY5Y and microglia BV2 cells, and some of them exhibited an interesting neuroprotective activity by reducing oxidative damage.


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Poríferos/química , Alcaloides/isolamento & purificação , Alcaloides/toxicidade , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Simulação por Computador , Humanos , Internet , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Oceano Pacífico , Clima Tropical
4.
Mar Drugs ; 17(5)2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31117253

RESUMO

Among malignancies, lung cancer is the major cause of cancer death. Despite the advance in lung cancer therapy, the five-year survival rate is extremely restricted due to therapeutic failure and disease relapse. Targeted therapies selectively inhibiting certain molecules in cancer cells have been accepted as promising ways to control cancer. In lung cancer, evidence has suggested that the myeloid cell leukemia 1 (Mcl-1) protein, an anti-apoptotic member of the Bcl-2 family, is a target for drug action. Herein, we report the Mcl-1 targeting activity of renieramycin T (RT), a marine-derived tetrahydroisoquinoline alkaloid that was isolated from the Thai blue sponge Xestospongia sp. RT was shown to be dominantly toxic to lung cancer cells compared to the normal cells in the lung. The cytotoxicity of this compound toward lung cancer cells was mainly exerted through apoptosis induction. For the mechanism of action, we found that RT mediated activation of p53 protein and caspase-9 and -3 activations. While others Bcl-2 family proteins (Bcl-2, Bak, and Bax) were minimally changed in response to RT, Mcl-1 protein was dramatically diminished. We further performed the cycloheximide experiment and found that the half-life of Mcl-1 was significantly shortened by RT treatment. When MG132, a potent selective proteasome inhibitor, was utilized, it could restore the Mcl-1 level. Furthermore, immunoprecipitation analysis revealed that RT significantly increased the formation of Mcl-1-ubiquitin complex compared to the non-treated control. In conclusion, we report the potential apoptosis induction of RT with a mechanism of action involving the targeting of Mcl-1 for ubiquitin-proteasomal degradation. As Mcl-1 is critical for cancer cell survival and chemotherapeutic failure, this novel information regarding the Mcl-1-targeted compound would be beneficial for the development of efficient anti-cancer strategies or targeted therapies.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Sistemas de Liberação de Medicamentos , Neoplasias Pulmonares/fisiopatologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Tetra-Hidroisoquinolinas/farmacologia , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular , Linhagem Celular Tumoral , Neoplasias Pulmonares/tratamento farmacológico , Poríferos/química , Proteólise/efeitos dos fármacos , Tetra-Hidroisoquinolinas/uso terapêutico , Tetra-Hidroisoquinolinas/toxicidade , Ubiquitinação/efeitos dos fármacos
5.
Curr Top Med Chem ; 19(10): 812-830, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30977454

RESUMO

The developing resistance in fungi has become a key challenge, which is being faced nowadays with the available antifungal agents in the market. Further search for novel compounds from different sources has been explored to meet this problem. The current review describes and highlights recent advancement in the antifungal drug aspects from plant and marine based sources. The current available antifungal agents act on specific targets on the fungal cell wall, like ergosterol synthesis, chitin biosynthesis, sphingolipid synthesis, glucan synthesis etc. We discuss some of the important anti-fungal agents like azole, polyene and allylamine classes that inhibit the ergosterol biosynthesis. Echinocandins inhibit ß-1, 3 glucan synthesis in the fungal cell wall. The antifungals poloxins and nikkomycins inhibit fungal cell wall component chitin. Apart from these classes of drugs, several combinatorial therapies have been carried out to treat diseases due to fungal resistance. Recently, many antifungal agents derived from plant and marine sources showed potent activity. The renewed interest in plant and marine derived compounds for the fungal diseases created a new way to treat these resistant strains which are evident from the numerous literature publications in the recent years. Moreover, the compounds derived from both plant and marine sources showed promising results against fungal diseases. Altogether, this review article discusses the current antifungal agents and highlights the plant and marine based compounds as a potential promising antifungal agents.


Assuntos
Antifúngicos/farmacologia , Bactérias/química , Fungos/efeitos dos fármacos , Feófitas/química , Plantas/química , Poríferos/química , Animais , Antifúngicos/química , Antifúngicos/isolamento & purificação , Fungos/química , Humanos , Testes de Sensibilidade Microbiana
6.
Asian Pac J Cancer Prev ; 20(4): 1199-1206, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31030495

RESUMO

Objective: Despite advanced treatment options available, drug resistance develops in breast cancer (BC) patients requiring novel effective drugs. Stylissa carteri, a marine sponge predominantly living in Indonesia territories, has not been extensively studied as anti-cancer. Therefore, this study targeted to assess the anti-tumor activity of the ethanol extract of S. carteri in BC cells. Methods: S. carteri was collected from Pramuka Island, at Kepulauan Seribu National Park, Jakarta, Indonesia and extracted using ethanol. Different BC cells including MDA MB 231, MDA MB 468, SKBR3, HCC-1954 and MCF-7 cells were treated with this extract for cytotoxic analysis using MTT assay. Spheroid growth assay and apoptosis assay were conducted in HCC-1954 cells. In addition, cell migration analysis and synergistic activity with doxorubicin or paclitaxel were conducted in MDA MB 231 cells. This extract was subjected also for GC-MS analysis. Results: The results show that ethanol extract of S. carteri demonstrated a cytotoxic activity in BC cells. The IC50 of this extract was lower 15 µg/ml in MDA MB 231, MDA MB 468, SKBR3, and HCC-1954 cells. Moreover, this extract inhibited spheroids growth and induced apoptosis in HCC-1954 cells. It inhibited cell migration and demonstrated a synergistic activity with doxorubicin or paclitaxel on triggering cell death in MDA MB 231 cells. Furthermore, GC-MS analysis indicated that this extract contained 1,2-Benzenediol, Dibutyl phthalate and 9,12-Octadecadienoic acid, ethyl ester. Conclusion: Our preliminary data indicate a potential anti-tumor activity of ethanol extract of S. carteri in breast cancer cells.


Assuntos
Alcaloides/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Etanol/química , Poríferos/química , Alcaloides/isolamento & purificação , Animais , Apoptose , Neoplasias da Mama/tratamento farmacológico , Movimento Celular , Doxorrubicina/administração & dosagem , Feminino , Humanos , Paclitaxel/administração & dosagem , Células Tumorais Cultivadas
7.
Chem Commun (Camb) ; 55(38): 5471-5474, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31012472

RESUMO

Stylissatin A, an anti-inflammatory cyclic heptapeptide, and its derivatives potently inhibited the differentiation of preadipocytes and reduced triglyceride accumulation in mature adipocytes, with little cytotoxicity. Our studies might contribute to the development of leads for new anti-inflammatory and anti-obesity agents.


Assuntos
Adipócitos/efeitos dos fármacos , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Diferenciação Celular/efeitos dos fármacos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Poríferos/química , Células 3T3-L1 , Adipócitos/citologia , Animais , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Células RAW 264.7 , Água do Mar , Relação Estrutura-Atividade
8.
Artigo em Inglês | MEDLINE | ID: mdl-30978513

RESUMO

We screened 868 marine extracts in search of hematopoietic molecules resulted in findings of several extracts that proliferated Ba/F3-HuMpl cells but not the cells expressed with other hematopoietic cytokine receptors, EPO and G-CSF. Separation of the most potent extract of a Micronesian sponge Corticium sp., guided by the cell proliferation assay using Ba/F3-HuMpl cells resulted in an isolation of thrombocorticin (ThC), a novel 14 kDa protein as an active principal. ThC displayed concentration-dependent proliferation of Ba/F3-HuMpl cells, and had a stronger activity than that of eltrombopag, a small molecule drug used to treat thrombocytopenia. ThC induced phosphorylation of STAT5, suggesting that it activates Jak/STAT pathway as in the case of TPO. These results together indicated that ThC is a specific agonist for c-Mpl, although the size and shape differs largely from TPO. Here we present isolation, characterization and biological activity of ThC.


Assuntos
Poríferos/química , Proteínas/farmacologia , Receptores de Trombopoetina/agonistas , Animais , Linhagem Celular , Camundongos , Proteínas/química , Transdução de Sinais/efeitos dos fármacos
9.
Biomater Sci ; 7(4): 1299-1310, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30821312

RESUMO

We demonstrated that the topical combined use of sponge Haliclona sp. spicules (SHS) and flexible liposomes (FL), referred to as SFLS (SHS-Flexible Liposomes combined System), can result in synergy to improve the skin absorption and deposition of hyaluronic acid (HA), especially in deep skin layers, both in vitro and in vivo. SHS treatment can result in skin micro-channels which are continuous, deep enough (48.6 ± 13.5 µm) and available in large quantities (850 ± 125 micro-channels per mm2). These micro-channels gradually closed up in 120 h and also allowed the intact vesicles of flexible liposomes and vesicle-bound or vesicle-encapsulated HA to penetrate into the skin-deep layers under the driving force of transdermal osmotic gradients. Specifically, SFLS topical application enhanced the penetration of FITC-HA (MW: 250 kDa) into porcine skin in vitro up to 23.2 ± 3.7%, which is 19.4 ± 3.1-fold (p < 0.001) that of a Phosphate Buffered Saline (PBS) group, 3.4 ± 0.5-fold (p < 0.01) that of an SHS group and 3.6 ± 0.6-fold (p < 0.01) that from the combined use of a Dermaroller and flexible liposomes. Moreover, SFLS can lead to significantly enhanced skin deposition of HA in all skin layers, especially in deep skin layers: up to 86.8 ± 4.1% of HA absorbed by skin was accumulated in deep skin layers. The effectiveness of SFLS topical application was also confirmed in vivo by using BALB/c mice. In addition, a skin irritation and toxicity study showed that the SFLS treatment may cause very minimal redness and the skin can recover in a short time. In sum, the combined use of SHS and FL (SFLS) offers a promising strategy to safely and effectively improve the skin delivery of hydrophilic biomacromolecules such as HA.


Assuntos
Ácido Hialurônico/química , Poríferos/química , Pele/química , Animais , Feminino , Cabelo/química , Cabelo/citologia , Ácido Hialurônico/administração & dosagem , Lipossomos/química , Camundongos , Camundongos Endogâmicos BALB C , Pele/citologia , Absorção Cutânea , Suínos
10.
Mar Drugs ; 17(3)2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30875899

RESUMO

Chemical study of the CH2Cl2-MeOH (1:1) extract of the sponge Fascaplysinopsis reticulata collected in Mayotte highlighted three new tryptophan derived alkaloids, 6,6'-bis-(debromo)-gelliusine F (1), 6-bromo-8,1'-dihydro-isoplysin A (2) and 5,6-dibromo-8,1'-dihydro-isoplysin A (3), along with the synthetically known 8-oxo-tryptamine (4) and the three known molecules from the same family, tryptamine (5), (E)-6-bromo-2'-demethyl-3'-N-methylaplysinopsin (6) and (Z)-6-bromo-2'-demethyl-3'-N-methylaplysinopsin (7). Their structures were elucidated by 1D and 2D NMR spectra and HRESIMS data. All compounds were evaluated for their antimicrobial and their antiplasmodial activities. Regarding antimicrobial activities, the best compounds are (2) and (3), with minimum inhibitory concentration (MIC) of 0.01 and 1 µg/mL, respectively, towards Vibrio natrigens, and (5), with MIC values of 1 µg/mL towards Vibrio carchariae. In addition the known 8-oxo-tryptamine (4) and the mixture of the (E)-6-bromo-2'-demethyl-3'-N-methylaplysinopsin (6) and (Z)-6-bromo-2'-demethyl-3'-N-methylaplysinopsin (7) showed moderate antiplasmodial activity against Plasmodium falciparum with IC50 values of 8.8 and 8.0 µg/mL, respectively.


Assuntos
Anti-Infecciosos/farmacologia , Antimaláricos/farmacologia , Poríferos/química , Triptaminas/química , Triptaminas/farmacologia , Alcaloides/farmacologia , Animais , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Antimaláricos/química , Antimaláricos/isolamento & purificação , Concentração Inibidora 50 , Biologia Marinha , Plasmodium falciparum/efeitos dos fármacos , Triptaminas/isolamento & purificação , Vibrio/efeitos dos fármacos
11.
Mar Drugs ; 17(3)2019 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-30884884

RESUMO

An ilimquinone (IQ) mixture isolated from Hippiospongia metachromia, consisting of IQ and epi-ilimaquinone (epi-IQ), exerts anti-HIV, anti-microbial, anti-inflammatory, and anti-cancer effects. An HPLC-MS/MS method was developed for simultaneous determination of the two epimers in rat plasma, separating them using a biphenyl column. Ascorbic acid is added during the sample preparation to ensure the stability of both isomers. The plasma concentrations of the isomers were monitored following intravenous and oral administration of the IQ mixture in rats as well as the individual epimers that were separately orally administered. Compare to IQ, epi-IQ was much more stable in rat plasma, likely due to its configurations of decalin. Both substances decayed in more than bi-exponential pattern, with an elimination rate constant of 1.2 h-1 for IQ and 1.7 h-1 for epi-IQ. The epi-IQ was distributed more widely than IQ by about two-fold. Consequently, the clearance of epi-IQ was greater than that of IQ by about three-fold. The oral absolute bioavailability for IQ was 38%, and, that for epi-IQ, was 13%. Although the systemic exposure of IQ was greater than that of epi-IQ by ~8.7-fold, the clearance of each isomer was similar when administered either orally or intravenously, when normalized for bioavailability. The stereo-specific behavior of the isomers appears to originate from differences in both their tissue distribution and gastrointestinal permeability.


Assuntos
Poríferos/química , Quinonas/química , Quinonas/farmacocinética , Sesquiterpenos/química , Sesquiterpenos/farmacocinética , Animais , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão/métodos , Isomerismo , Masculino , Quinonas/administração & dosagem , Quinonas/sangue , Ratos , Ratos Sprague-Dawley , Sesquiterpenos/administração & dosagem , Sesquiterpenos/sangue , Espectrometria de Massas em Tandem/métodos
12.
Mar Drugs ; 17(2)2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30813373

RESUMO

Sponges are a valuable source of natural compounds and biomaterials for many biotechnological applications. Marine sponges belonging to the order Verongiida are known to contain both chitin and biologically active bromotyrosines. Aplysina archeri (Aplysineidae: Verongiida) is well known to contain bromotyrosines with relevant bioactivity against human and animal diseases. The aim of this study was to develop an express method for the production of naturally prefabricated 3D chitin and bromotyrosine-containing extracts simultaneously. This new method is based on microwave irradiation (MWI) together with stepwise treatment using 1% sodium hydroxide, 20% acetic acid, and 30% hydrogen peroxide. This approach, which takes up to 1 h, made it possible to isolate chitin from the tube-like skeleton of A. archeri and to demonstrate the presence of this biopolymer in this sponge for the first time. Additionally, this procedure does not deacetylate chitin to chitosan and enables the recovery of ready-to-use 3D chitin scaffolds without destruction of the unique tube-like fibrous interconnected structure of the isolated biomaterial. Furthermore, these mechanically stressed fibers still have the capacity for saturation with water, methylene blue dye, crude oil, and blood, which is necessary for the application of such renewable 3D chitinous centimeter-sized scaffolds in diverse technological and biomedical fields.


Assuntos
Quitina/isolamento & purificação , Poríferos/química , Animais , Materiais Biocompatíveis/análise , Materiais Biocompatíveis/química , Materiais Biocompatíveis/isolamento & purificação , Quitina/análise , Quitina/química , Espectroscopia de Infravermelho com Transformada de Fourier , Tirosina/análogos & derivados , Tirosina/análise , Tirosina/química , Tirosina/isolamento & purificação
13.
Mar Drugs ; 17(3)2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30857135

RESUMO

Sponges are a well-known bioresource for bioactive compounds. In this study, antibacterial activity-guided fractionation of the extract from an Indonesian marine Dactylospongia elegans sponge led to the discovery of four merosesquiterpenoids, namely, a new sesquiterpenoid aminoquinone nakijiquinone V (1), along with illimaquinone (2), smenospongine (3), and dyctioceratine C (4). The structure of compound 1 was elucidated by 1D and 2D NMR as well as by LC-HRESIMS data analysis. Compounds 2⁻4 showed moderate to low antimicrobial activity against Bacillus megaterium DSM32 with a minimum inhibitory concentration (MIC) of 32 µg/mL, 32 µg/mL, and 64 µg/mL, respectively. Furthermore, compounds 2 and 3 both inhibited Micrococcus luteus ATCC 4698 with a MIC of 32 µg/mL. In conclusion, the isolated merosesquiterpenoids, which are known for their cytotoxic effects, showed antibacterial activity and prompt future structure activity relationship (SAR) studies concerning the various bioactivities observed for this group of natural products.


Assuntos
Antibacterianos/farmacologia , Produtos Biológicos/farmacologia , Poríferos/química , Quinonas/farmacologia , Sesquiterpenos/farmacologia , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Bacillus megaterium/efeitos dos fármacos , Produtos Biológicos/isolamento & purificação , Indonésia , Testes de Sensibilidade Microbiana , Micrococcus luteus/efeitos dos fármacos , Estrutura Molecular , Quinonas/química , Quinonas/isolamento & purificação , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação
14.
Molecules ; 24(5)2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30818810

RESUMO

Three furan-containing scalarane sesterterpenoids (1⁻3) and a novel pyrrole-containing analog (4) were isolated from the sponge Scalarispongia species. Compound 3, reported in the literature as a synthetic derivative of furoscalarol 2, was for the first time isolated from a natural source. During the separation performed using a silica column in the presence of methanol, 16-methoxy derivatives (5, 6) were obtained from the unintended reaction of 2. The isolated natural products 3 and 4 and the artifact 5 showed moderate to high cytotoxicity against six human cancer cell lines, whereas compound 6, the C-16 epimer of 5, showed no cytotoxicity at a concentration of 60 µΜ.


Assuntos
Antineoplásicos/farmacologia , Furanos/química , Neoplasias/patologia , Poríferos/química , Sesterterpenos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Sobrevivência Celular , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Sesterterpenos/química , Sesterterpenos/isolamento & purificação , Células Tumorais Cultivadas
15.
Mar Drugs ; 17(2)2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30759808

RESUMO

The nuclear receptors (NRs) RARα, RXRα, PPARα, and PPARγ represent promising pharmacological targets for the treatment of neurodegenerative diseases. In the search for molecules able to simultaneously target all the above-mentioned NRs, we screened an in-house developed molecular database using a ligand-based approach, identifying (-)-Muqubilin (Muq), a cyclic peroxide norterpene from a marine sponge, as a potential hit. The ability of this compound to stably and effectively bind these NRs was assessed by molecular docking and molecular dynamics simulations. Muq recapitulated all the main interactions of a canonical full agonist for RXRα and both PPARα and PPARγ, whereas the binding mode toward RARα showed peculiar features potentially impairing its activity as full agonist. Luciferase assays confirmed that Muq acts as a full agonist for RXRα, PPARα, and PPARγ with an activity in the low- to sub-micromolar range. On the other hand, in the case of RAR, a very weak agonist activity was observed in the micromolar range. Quite surprisingly, we found that Muq is a positive allosteric modulator for RARα, as both luciferase assays and in vivo analysis using a zebrafish transgenic retinoic acid (RA) reporter line showed that co-administration of Muq with RA produced a potent synergistic enhancement of RARα activation and RA signaling.


Assuntos
PPAR alfa/agonistas , PPAR gama/agonistas , Peróxidos/farmacologia , Receptor alfa de Ácido Retinoico/agonistas , Terpenos/farmacologia , Regulação Alostérica , Animais , Animais Geneticamente Modificados , Sinergismo Farmacológico , Ensaios de Triagem em Larga Escala , Humanos , Larva , Modelos Moleculares , Simulação de Acoplamento Molecular , Poríferos/química , Tretinoína/farmacologia , Peixe-Zebra
16.
Mar Drugs ; 17(2)2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30795557

RESUMO

Gukulenin A is a bis-tropolone tetraterpenoid isolated from the marine sponge Phorbas gukhulensis. In this study, we examined the anticancer activities of gukulenin A in ovarian cancer cell lines (A2780, SKOV3, OVCAR-3, and TOV-21G) and in an ovarian cancer mouse model generated by injecting A2780 cells. We found that gukulenin A suppressed tumor growth in A2780-bearing mice. Gukulenin A markedly inhibited cell viability in four ovarian cancer cell lines, including the A2780 cell line. Gukulenin A treatment increased the fraction of cells accumulated at the sub G1 phase in a dose-dependent manner and the population of annexin V-positive cells, suggesting that gukulenin A induces apoptotic cell death in ovarian cancer cells. In addition, gukulenin A triggered the activation of caspase-3, -8, and -9, and caspase inhibitors attenuated gukulenin A-induced A2780 cell death. The results suggest that gukulenin A may be a potential therapeutic agent for ovarian cancer.


Assuntos
Neoplasias Ovarianas/tratamento farmacológico , Poríferos/química , Terpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Distribuição Aleatória , Terpenos/isolamento & purificação , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Agric Food Chem ; 67(10): 2774-2781, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30794394

RESUMO

The marine natural product neopeltolide was isolated from a deep-water sponge specimen of the family Neopeltidae. Neopeltolide has been proven to be a new type of inhibitor of the cytochrome bc1 complex in the mitochondrial respiration chain. However, its detailed inhibition mechanism has remained unknown. In addition, neopeltolide is difficult to synthesize because of its very complex chemical structure. In the present work, the binding mode of neopeltolide was determined for the first time by integrating molecular docking, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area calculations, which showed that neopeltolide is a Qo site inhibitor of the bc1 complex. Then, according to guidance via inhibitor-protein interaction analysis, structural modification was carried out with the aim to simplify the chemical structure of neopeltolide, leading to the synthesis of a series of new neopeltolide derivatives with much simpler chemical structures. The calculated binding energies (Δ Gcal) of the newly synthesized analogues correlated very well ( R2 = 0.90) with their experimental binding free energies (Δ Gexp), which confirmed that the computational protocol was reliable. Compound 45, bearing a diphenyl ether fragment, was successfully designed and synthesized as the most potent candidate (IC50 = 12 nM) against porcine succinate cytochrome c reductase. The molecular modeling results indicate that compound 45 formed a π-π interaction with Phe274 and two hydrogen bonds with Glu271 and His161. The present work provides a new starting point for future fungicide discovery to overcome the resistance that the existing bc1 complex inhibitors are facing.


Assuntos
Produtos Biológicos/química , Complexo III da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Inibidores Enzimáticos/química , Macrolídeos/química , Animais , Sítios de Ligação , Complexo III da Cadeia de Transporte de Elétrons/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Poríferos/química
18.
Mar Drugs ; 17(2)2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30736370

RESUMO

A new acylic jasplakinolide congener (2), another acyclic derivative requiring revision (4), together with two jasplakinolide derivatives including the parent compound jasplakinolide (1) were isolated from the Indonesian marine sponge Jaspis splendens. The chemical structures of the new and known compounds were unambiguously elucidated based on HRESIMS and exhaustive 1D and 2D NMR spectral analysis as well as a comparison of their NMR data with those of jasplakinolide (1). The isolated jasplakinolides inhibited the growth of mouse lymphoma (L5178Y) cells in vitro with IC50 values in the low micromolar to nanomolar range.


Assuntos
Depsipeptídeos/química , Depsipeptídeos/farmacologia , Poríferos/química , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Depsipeptídeos/isolamento & purificação , Leucemia L5178/tratamento farmacológico , Leucemia L5178/patologia , Camundongos , Espectroscopia de Prótons por Ressonância Magnética
19.
Mar Drugs ; 17(2)2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30736491

RESUMO

Bengazoles A⁻G from the marine sponge Jaspis sp. exhibit potent in vitro antifungal activity against Candida spp. and other pathogenic fungi. The mechanism of action (MOA) of bengazole A was explored in Candida albicans under both liquid culture and surface culture on Mueller-Hinton agar. Pronounced dose-dependent synergistic antifungal activity was observed with bengazole A in the presence of bengamide A, which is also a natural product from Jaspis sp. The MOA of bengazole A was further explored by monitoring the sterol composition of C. albicans in the presence of sub-lethal concentrations of bengazole A. The GCMS of solvent extracts prepared from liquid cultures of C. albicans in the presence of clotrimazole-a clinically approved azole antifungal drug that suppresses ergosterol biosynthesis by the inhibition of 14α-demethylase-showed reduced cellular ergosterol content and increased concentrations of lanosterol and 24-methylenedihydrolanosterol (a shunt metabolite of ergosterol biosynthesis). No change in relative sterol composition was observed when C. albicans was cultured with bengazole A. These results eliminate an azole-like MOA for the bengazoles, and suggest that another as-yet unidentified mechanism is operative.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Oxazóis/farmacologia , Poríferos/química , Animais , Antifúngicos/isolamento & purificação , Azóis/química , Azóis/isolamento & purificação , Azóis/farmacologia , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Sinergismo Farmacológico , Ergosterol/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazóis/química , Oxazóis/isolamento & purificação
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA