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

Base de dados
País como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Angew Chem Int Ed Engl ; 60(48): 25468-25476, 2021 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-34580976

RESUMO

A versatile terpene synthase (LcTPS2) producing unconventional macrocyclic terpenoids was characterized from Leucosceptrum canum. Engineered Escherichia coli and Nicotiana benthamiana expressing LcTPS2 produced six 18-/14-membered sesterterpenoids including five new ones and two 14-membered diterpenoids. These products represent the first macrocyclic sesterterpenoids from plants and the largest sesterterpenoid ring system identified to date. Two variants F516A and F516G producing approximately 3.3- and 2.5-fold, respectively, more sesterterpenoids than the wild-type enzyme were engineered. Both 18- and 14-membered ring sesterterpenoids displayed significant inhibitory activity on the IL-2 and IFN-γ production of T cells probably via inhibition of the MAPK pathway. The findings will contribute to the development of efficient biocatalysts to create bioactive macrocyclic sesterterpenoids, and also herald a new potential in the well-trodden territory of plant terpenoid biosynthesis.


Assuntos
Alquil e Aril Transferases/metabolismo , Imunossupressores/farmacologia , Interferon gama/antagonistas & inibidores , Interleucina-2/antagonistas & inibidores , Compostos Macrocíclicos/farmacologia , Terpenos/farmacologia , Humanos , Imunossupressores/química , Imunossupressores/metabolismo , Interferon gama/biossíntese , Interleucina-2/biossíntese , Lamiaceae/química , Lamiaceae/metabolismo , Compostos Macrocíclicos/química , Compostos Macrocíclicos/metabolismo , Estrutura Molecular , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Terpenos/química , Terpenos/metabolismo
2.
Molecules ; 23(2)2018 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-29425137

RESUMO

Polygala plants contain a large number of xanthones with good physiological activities. In our previous work, 18 xanthones were isolated from Polygala crotalarioides. Extented study of the chemical composition of the other species Polygala sibirica led to the separation of two new xanthones-3-hydroxy-1,2,6,7,8-pentamethoxy xanthone (A) and 6-O-ß-d-glucopyranosyl-1,7-dimethoxy xanthone (C)-together with 14 known xanthones. Among them, some xanthones have a certain xanthine oxidase (XO) inhibitory activity. Furthemore, 14 xanthones as XO inhibitors were selected to develop three-dimensional quantitative structure-activity relationship (3D-QSAR) using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. The CoMFA model predicted a q² value of 0.613 and an r² value of 0.997. The best CoMSIA model predicted a q² value of 0.608 and an r² value of 0.997 based on a combination of steric, electrostatic, and hydrophobic effects. The analysis of the contour maps from each model provided insight into the structural requirements for the development of more active XO inhibitors.


Assuntos
Extratos Vegetais/química , Traqueófitas/química , Xantina Oxidase/antagonistas & inibidores , Xantonas/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Extratos Vegetais/isolamento & purificação , Ligação Proteica , Eletricidade Estática
3.
Org Biomol Chem ; 14(45): 10705-10713, 2016 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-27805220

RESUMO

An efficient hydrogen bonding-guided ring-closing metathesis (RCM) reaction of sterically demanding homoallyl 2-(hydroxymethyl)acrylates catalyzed by the Hoveyda-Grubbs 2nd generation catalyst was developed and the reaction mechanism was explored. Adding a substituent to the hydroxymethyl group in this scaffold resulted in a class of challenging RCM substrates, although usable yields could be obtained. However, substrates bearing a 1-oxygenated alkyl group on the homoallylic carbon gave excellent RCM yields, providing a practical solution. Experimental and computational evidence indicated an unusual directing effect of OHCl hydrogen bonding between the substrate and Ru catalyst, which guides Ru to interact with the electron-deficient, more hindered acrylic C[double bond, length as m-dash]C bond and thus triggers the RCM process.

4.
J Nat Prod ; 79(9): 2158-66, 2016 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-27584856

RESUMO

The new melokhanines A-J (1-10) and 22 known (11-32) alkaloids were isolated from the twigs and leaves of Melodinus khasianus. The new compounds and their absolute configurations were elucidated by extensive analysis of spectroscopic, X-ray diffraction, and computational data. Melokhanine A (1), composed of a hydroxyindolinone linked to an octahydrofuro[2,3-b]pyridine moiety, is an unprecedented monoterpenoid indole alkaloid. Melokhanines B-H (2-8) possess a new 6/5/5/6/6 pentacyclic indole alkaloid skeleton. Alkaloids 1-16, 25-27, 31, and 32 showed the best antibacterial activity against Pseudomonas aeruginosa (MIC range 2-22 µM). Among the seven dermatophytes tested, compound 1 showed significant inhibitory activity against Microsporum canis, M. ferrugineum, and Trichophyton ajelloi (MIC range 38-150 µM), i.e., half the efficacy of the positive control, griseofulvin.


Assuntos
Apocynaceae/química , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Alcaloides de Triptamina e Secologanina/química , Alcaloides de Triptamina e Secologanina/farmacologia , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/isolamento & purificação , Escherichia coli/efeitos dos fármacos , Griseofulvina/farmacologia , Testes de Sensibilidade Microbiana , Microsporum/efeitos dos fármacos , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Folhas de Planta/química , Caules de Planta/química , Pseudomonas aeruginosa/efeitos dos fármacos , Alcaloides de Triptamina e Secologanina/isolamento & purificação , Trichophyton/efeitos dos fármacos
5.
J Asian Nat Prod Res ; 17(1): 20-6, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25359634

RESUMO

Two new dopamine derivatives divesamides A (1) and B (2), along with six known N-containing compounds were isolated from the Chinese black ant (Polyrhachis dives). Their structures were determined on the basis of spectroscopic methods. Compound 1 is a racemate, and chiral HPLC separation yielded a pair of antipodes. The absolute configuration of (+)-1 was assigned by a computational method. The double signals in the (1)H and (13)C NMR spectra of 2 that resulted from the presence of a formamide group were discussed. The T- and B-lymphocytes proliferation assay showed that 2 has moderate immunosuppressive activity toward T- and B-lymphocytes proliferation at a concentration of 20 µM.


Assuntos
Formigas/química , Dopamina/análogos & derivados , Dopamina/isolamento & purificação , Imunossupressores/isolamento & purificação , Imunossupressores/farmacologia , Animais , Linfócitos B/efeitos dos fármacos , China , Cromatografia Líquida de Alta Pressão , Dopamina/química , Dopamina/farmacologia , Formamidas/química , Formamidas/farmacologia , Imunossupressores/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Estereoisomerismo , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos
6.
J Asian Nat Prod Res ; 17(10): 988-95, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26499169

RESUMO

Three new dihydroisocoumarin glucosides, termed periplanosides A-C (1-3), a known analog, pericanaside (4), and the other twenty known compounds were isolated from the insect Periplaneta americana. Their structures including absolute configurations were determined by comprehensive spectroscopic analyses and computational methods. Biological evaluation showed that compound 2 could stimulate collagen production by 31.2% in human dermal fibroblasts-adult (HDFa) at the concentration of 30 µM, indicating its significance in skin repair and ulcer.


Assuntos
Colágeno , Glucosídeos/isolamento & purificação , Isocumarinas/isolamento & purificação , Isocumarinas/farmacologia , Periplaneta/química , Adulto , Animais , Colágeno/biossíntese , Colágeno/efeitos dos fármacos , Fibroblastos/metabolismo , Glucosídeos/química , Humanos , Isocumarinas/química , Estrutura Molecular
7.
Bioorg Med Chem Lett ; 24(22): 5164-9, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25442305

RESUMO

Recent studies focusing on unveiling the biological agents of Aspongopus chinensis have led to the identification of four new norepinephrine derivatives (1-4), three new sesquiterpenoids (5-7), and one new lactam (8). In addition, twenty-three known compounds have been identified, most of which were isolated from this insect for the first time. Selected members of insect-derived substances were evaluated for their biological activities against renal protection in high-glucose-induced mesangial cells and COX-2 inhibition.


Assuntos
Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Insetos , Animais , Produtos Biológicos/química , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Humanos , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/fisiologia , Ratos
8.
Bioorg Med Chem Lett ; 24(22): 5268-73, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25316316

RESUMO

The bioassay-guided chemical investigation of the stems of Dendrobium fimbriatum Hook led to the isolation of seven first reported bibenzyl dimers with a linkage of a methylene moiety, fimbriadimerbibenzyls A-G (1-7), together with a new dihydrophenanthrene derivative (S)-2,4,5,9-tetrahydroxy-9,10-dihydrophenanthrene (8) and thirteen known compounds (9-21). The structure of the new compound was established by spectroscopic analysis. Biological evaluation of bibenzyl derivatives against five human cell lines indicated that seven of those compounds exhibited broad-spectrum and cytotoxic activities with IC50 values ranging from 2.2 to 21.2 µM. Those rare bibenzyl dimers exhibited cytotoxic activities in vitro and the cytotoxicity decreased as the number of oxygen-containing groups in the structure decreases.


Assuntos
Bibenzilas/química , Dendrobium/química , Antioxidantes/química , Antioxidantes/isolamento & purificação , Antioxidantes/toxicidade , Bibenzilas/isolamento & purificação , Bibenzilas/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dendrobium/metabolismo , Dimerização , Humanos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Caules de Planta/química , Caules de Planta/metabolismo
9.
Nat Prod Bioprospect ; 12(1): 36, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36131216

RESUMO

11ß-Hydroxysteroid dehydrogenase 1 (11ß-HSD1) represents a promising drug target for metabolic syndrome, including obesity and type 2 diabetes. Our initial screen of a collection of natural products from Danshen led to the identification of tanshinones as the potent and selective 11ß-HSD1 inhibitors. To improve the druggability and explore the structure-activity relationships (SARs), more than 40 derivatives have been designed and synthesized using tanshinone IIA and cryptotanshinone as the starting materials. More than 10 derivatives exhibited potent in vitro 11ß-HSD1 inhibitory activity and good selectivity over 11ß-HSD2 across human and mouse species. Based on the biological results, SARs were further discussed, which was also partially rationalized by a molecular docking model of 1 bound to the 11ß-HSD1. Remarkably, compounds 1, 17 and 30 significantly inhibited 11ß-HSD1 in 3T3-L1 adipocyte and in livers of ob/ob mice, which merits further investigations as anti-diabetic agents. This study not only provides a series of novel selective 11ß-HSD1 inhibitors with promising therapeutic potentials in metabolic syndromes, but also expands the boundaries of the chemical and biological spaces of tanshinones.

10.
Org Lett ; 23(24): 9463-9467, 2021 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-34818888

RESUMO

Rhynchines A-E (1-5), five new indole alkaloids with an unprecedented skeleton, were isolated from Uncaria rhynchophylla. The new skeleton was characterized by an indole moiety and a 2-oxa-8-azatricyclo[6,5,01,5,01,8]tridecane core, forming a unique 6/5/7/5/5 ring system. Their structures were determined by nuclear magnetic resonance, high-resolution electrospray ionization mass spectrometry, infrared spectroscopy, and calculated electronic circular dichroism (ECD) and were confirmed by X-ray crystallography. Interestingly, 1 and 2 showed strong inhibitory activities against the Cav3.1 calcium channel with IC50 values of 6.86 and 10.41 µM.


Assuntos
Bloqueadores dos Canais de Cálcio
11.
J Med Chem ; 60(21): 9053-9066, 2017 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-29019670

RESUMO

Previously, vibsanin B (ViB) was found to preferentially target HSP90ß compared to HSP90α. In this study, multiple experiments, including pull-down assays of biotin-ViB with recombinant HSP90ß-NTD, MD, CTD, and full-length HSP90ß, molecular docking of ViB and its derivatives to the HSP90 CTD, and a inhibition assay of interaction of the HSP90ß CTD with GST-tagged cyclophilin 40 (Cyp40) by ViB derivatives, suggest that ViB can directly bind to the HSP90 C-terminus. On the basis of the docking predictions and primary structure-activity relationships (SARs), a series of ViB analogues devised with focus on the C18 position, along with compounds derivatized at the C4, C7, and C8 positions, were designed and chemically synthesized. Compound 12f (IC50 = 1.12 µM against SK-BR-3) exhibits great potency with drug-like properties. Overall, our findings demonstrate that compounds with the vibsanin B scaffold are a new class of HSP90 C-terminal inhibitors with considerable potential as anticancer agents.


Assuntos
Diterpenos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Simulação de Acoplamento Molecular , Antineoplásicos/química , Sítios de Ligação , Diterpenos/síntese química , Desenho de Fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Ligação Proteica , Relação Estrutura-Atividade
12.
Org Lett ; 18(9): 2166-9, 2016 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-27075046

RESUMO

Euphorbia peplus has been used in traditional medicine to treat asthma and psoriasis. Three highly modified diterpenoids, namely, pepluacetal (1) and pepluanol A-B (2-3), have been isolated and identified from this plant. Compounds 1-3 exhibit unprecedented 5/4/7/3, 5/6/7/3, and 5/5/8/3 ring systems, respectively. Their structures with absolute configurations were determined by spectroscopic analyses, X-ray crystallography, and electronic circular dichroism calculations. Since Kv1.3 is a validated target for the treatment of autoimmune diseases, such as multiple sclerosis, type-1 diabetes, asthma, and psoriasis, Kv1.3 was studied in terms of its response to the new compounds. All three compounds inhibit Kv1.3, with compound 3 being the most effective with an IC50 value of 9.50 µM.


Assuntos
Diterpenos/farmacologia , Euphorbia/química , Canal de Potássio Kv1.3/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/farmacologia , Cristalografia por Raios X , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Humanos , Canal de Potássio Kv1.3/metabolismo , Modelos Moleculares , Conformação Molecular , Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/isolamento & purificação , Relação Estrutura-Atividade
13.
Phytochemistry ; 114: 155-62, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25882500

RESUMO

Ganoderma lingzhi is a valuable, edible and medicinal fungus that has been widely used for the prevention and treatment of a broad range of diseases. In this study, spirolingzhines A-D, four meroterpenoids with a spiro[benzofuran-2,10-cyclopentane] motif, lingzhines A-F, six meroterpenoids with diverse ring systems, along with two known compounds were isolated from the fruiting bodies of this fungus. The structures and stereochemistry of these substances were determined by using spectroscopic, X-ray crystallographic and computational methods. Chiral HPLC was used to separate (-)- and (+)-antipodes of seven of ten meroterpenoids, which were isolated from the fungus as racemic mixtures. Several of the metabolites were found to promote proliferation of neural stem cells (NSCs) and, as such, they constitute a class of NSC stimulators. The most potent member of this series, (-)-spirolingzhine A, was shown to affect NSC cell cycle progression using the 5-bromo-2-deoxyuridine (BrdU) incorporation assay.


Assuntos
Proliferação de Células/efeitos dos fármacos , Ganoderma/química , Células-Tronco Neurais/efeitos dos fármacos , Terpenos/isolamento & purificação , Humanos , Estrutura Molecular , Terpenos/química , Terpenos/farmacologia
14.
J Ethnopharmacol ; 176: 385-93, 2015 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-26571087

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Several Ganoderma fungi are well-known for their medical uses to treat cancer, insomnia and kidney disease in East Asia. Triperpenoids and polysaccharides have been considered for a long time to be the major active components of the genus Ganoderma. The present study is to examine the effects of lingzhilactones from G. lingzhi on adriamycin-induced nephropathy in mice. MATERIALS AND METHODS: A combination of various chromatography led to the isolation of lingzhilactones A-C, their structures were identified by spectroscopic and computational methods. The intracellular reactive oxygen species (ROS) was detected with the carboxymethyl-H2-dichlorofluorescein diacetate fluoroprobe. The fibrotic markers were analyzed by real-time RT-PCR and Western blot analyses. Detection of SEAP was conducted with the chemiluminescent. Urine albumin was measured using an ELISA assay. Histology and immunohistochemical staining was used to assess fibrotic lesions in mice. RESULTS: Three new lingzhilactones A-C (1-3) containing a fused lactone moiety were isolated from G. lingzhi. We found that 2 could inhibit ROS generation in a dose-dependent manner, inhibit mRNA expression of collagen IV, fibronectin, IL-6 and increase expression of Nrf2 in rat tubular epithelial cells. Furthermore, we found that 2 could reduce urinary albumin levels, abrogate myofibroblastic activation and inhibit the phosphorylation of Smad3 in adriamycin-induced mice. CONCLUSIONS: The in vitro and in vivo results suggested that lingzhilactone B could protect against renal injuries by increasing the activities of antioxidants and inhibiting inflammation. The inhibition of Smad3 phosphorylation suggested that this substance displays in vivo antifibrotic activity by a mechanism that is dependent on disruption of Smad3. These results promote understanding of the traditional usage of G. lingzhi and provide promising findings which may be beneficial for anti-kidney disease drug design.


Assuntos
Anti-Inflamatórios/uso terapêutico , Ganoderma , Nefropatias/tratamento farmacológico , Lactonas/uso terapêutico , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Linhagem Celular , Colágeno Tipo IV/genética , Doxorrubicina , Fibronectinas/genética , Interleucina-6/genética , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Lactonas/isolamento & purificação , Lactonas/farmacologia , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/genética , RNA Mensageiro/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo
15.
Org Lett ; 17(12): 3082-5, 2015 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-26024438

RESUMO

T-type calcium channel (TTCC) inhibitors hold great potential for the treatment of a variety of neurological disorders. Cochlearoids A-E (1-5), five pairs of dimeric meroterpenoid enantiomers, and cochlearines A (6) and B (7), two pairs of enantiomeric hybrid metabolites, were isolated and characterized from Ganoderma cochlear. Biological evaluation found that compounds (+)-1, (-)-3, and (±)-6 significantly inhibited Cav3.1 TTCC and showed noticeable selectivity against Cav1.2, Cav2.1, Cav2.2, and Kv11.1 (hERG) channels.


Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/química , Canais de Cálcio Tipo T/química , Ganoderma/química , Inibição Neural/efeitos dos fármacos , Terpenos/síntese química , Terpenos/farmacologia , Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio Tipo N/metabolismo , Canais de Cálcio Tipo T/metabolismo , Humanos , Estrutura Molecular , Inibição Neural/fisiologia , Terpenos/química
16.
Nat Prod Bioprospect ; 5(3): 129-157, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26085282

RESUMO

The unusual fused ß-lactone vibralactone was isolated from cultures of the basidiomycete Boreostereum vibrans and has been shown to significantly inhibit pancreatic lipase. In this study, a structure-based lead optimization of vibralactone resulted in three series of 104 analogs, among which compound C1 exhibited the most potent inhibition of pancreatic lipase, with an IC50 value of 14 nM. This activity is more than 3000-fold higher than that of vibralactone. The effect of compound C1 on obesity was investigated using high-fat diet (HFD)-induced C57BL/6 J obese mice. Treatment with compound C1 at a dose of 100 mg/kg significantly decreased HFD-induced obesity, primarily through the improvement of metabolic parameters, such as triglyceride levels.

17.
Nat Prod Bioprospect ; 4(5): 285-95, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25159896

RESUMO

Coiled-coils are well known protein-protein interaction motifs, with the leucine zipper region of activator protein-1 (AP-1) consisting of the c-Jun and c-Fos proteins being a typical example. Molecular dynamics (MD) simulations using the MM/GBSA method have been used to predict the free energy of interaction of these proteins. The influence of force field polarisation and capping on the predicted free energy of binding of complexes with different electrostatic environments (net charge) were investigated. Although both force field polarisation and peptide capping are important for the prediction of the absolute free energy of binding, peptide capping has the largest influence on the predicted free energy of binding. Polarisable simulations appear better suited to determine structural properties of the complexes of these proteins while non-polarisable simulations seem to give better predictions of the associated free energies of binding.

18.
Oncotarget ; 5(22): 11354-64, 2014 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-25404639

RESUMO

As an ent-kaurene diterpenoid isolated from Isodon eriocalyx var. Laxiflora, Eriocalyxin B (EriB) possesses potent bioactivity of antitumor and anti-autoimmune inflammation, which has been suggested to work through inhibition of NF-kappaB (NF-κB) signaling. However, the direct target of EriB remains elusive. In this study, we showed that EriB induced apoptosis is associated with the inhibition of NF-κB signaling in SMMC-7721 hepatocellular carcinoma cells. With activity-based probe profiling, we identified p50 protein as the direct target of EriB. We showed that cysteine 62 is the critical residue of p50 for EriB binding through the α, ß-unsaturated ketones. As the result, EriB selectively blocks the binding between p50 and the response elements, whereas having no effect on the dimerization or the nuclear translocation of p50 and p65. SiRNA mediated knockdown of p50 attenuated the apoptosis induced by EriB in SMMC-7721 cells. Taken together, our studies illustrated that EriB induces cancer cell apoptosis through interfering with the binding between NF-κB and the response elements by targeting the cysteine 62 of p50, which highlights its potential for the development of p50 targeted cancer therapeutic agents.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Diterpenos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Subunidade p50 de NF-kappa B/antagonistas & inibidores , Sequência de Aminoácidos , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Neoplasias Hepáticas/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Terapia de Alvo Molecular , Subunidade p50 de NF-kappa B/genética , Subunidade p50 de NF-kappa B/metabolismo , Elementos de Resposta , Transdução de Sinais , Relação Estrutura-Atividade
19.
Org Lett ; 16(2): 532-5, 2014 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-24383883

RESUMO

(±)-Aspongamide A (1), an unusual trimer of N-acetyldopamine (NADA) bearing a novel tetrahydrobenzo[a]dibenzo[b,e][1,4]dioxine structure, and a pair of NADA dimeric enantiomers (2) were isolated from Aspongopus chinensis. The structures of compounds 1 and 2 were assigned using spectroscopic methods. Compound 1 was found to be an inhibitor of Smad3 phosphorylation in transforming growth factor-ß1 (TGF-ß1) induced rat renal proximal tubular cells and suppressed extracellular matrix expression in mesangial cells under diabetic conditions.


Assuntos
Dopamina/análogos & derivados , Hemípteros/química , Proteína Smad3/antagonistas & inibidores , Animais , Dopamina/química , Dopamina/isolamento & purificação , Dopamina/farmacologia , Células Mesangiais/metabolismo , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Fosforilação , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo
20.
Mol Pharmacol ; 70(5): 1593-601, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16914642

RESUMO

Salvicine, a structurally modified diterpenoid quinone derived from Salvia prionitis, is a nonintercalative topoisomerase II (topo II) poison. The compound possesses potent in vitro and in vivo antitumor activity with a broad spectrum of anti-multidrug resistance activity and is currently in phase II clinical trials. To elucidate the distinct antitumor properties of salvicine and obtain valuable structural information of salvicine-topo II interactions, we characterized the effects of salvicine on human topo IIalpha (htopo IIalpha), including possible binding sites and molecular interactions. The enzymatic assays disclosed that salvicine mainly inhibits the catalytic activity with weak DNA cleavage action, in contrast to the classic topo II poison etoposide (VP16). Molecular modeling studies predicted that salvicine binds to the ATP pocket in the ATPase domain and superimposes on the phosphate and ribose groups. In a surface plasmon resonance binding assay, salvicine exhibited higher affinity for the ATPase domain of htopo IIalpha than ATP and ADP. Competitive inhibition tests demonstrated that ATP competitively and dose-dependently blocked the interactions between salvicine and ATPase domain of htopo IIalpha. The data illustrate that salvicine shares a common binding site with ATP and functions as an ATP competitor. To our knowledge, this is the first report to identify an ATP-binding pocket as the structural binding motif for a nonintercalative eukaryotic topo II poison. These findings collectively support the potential value of an ATP competitor of htopo IIalpha in tumor chemotherapy.


Assuntos
Trifosfato de Adenosina/metabolismo , Antígenos de Neoplasias/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Naftoquinonas/metabolismo , Naftoquinonas/farmacologia , Inibidores da Topoisomerase II , Adenosina Trifosfatases/isolamento & purificação , Adenosina Trifosfatases/metabolismo , Antígenos de Neoplasias/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Sítios de Ligação , Catálise , DNA/química , DNA Topoisomerases Tipo II/química , Proteínas de Ligação a DNA/química , Relação Dose-Resposta a Droga , Humanos , Hidrólise , Modelos Moleculares , Naftoquinonas/química , Conformação de Ácido Nucleico , Estrutura Terciária de Proteína
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa