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1.
Eur J Pharm Sci ; : 105058, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31472255

RESUMO

The biofilm formation of Pseudomonas aeruginosa (P. aeruginosa) is regulated by a phenomenon of quorum sensing (QS). With 5-hydroxyl-3,4-halogenated-5H-furan-2-ones as beginning, analogs bearing alkyl chains, vinyl bromide, or aromatic rings were designed and synthesized. The minimum inhibitory concentration (MIC) of the compounds against P. aeruginosa was assayed and the biofilm inhibition ratio was determined at different concentrations lower than the MIC. C-5 aromatic substituted furanones showed remarkable biofilm formation as well as inhibition of virulence factor production in P. aeruginosa. Fluorescence report analysis identified the QS regulatory mechanism of the most active compound 29. This study provides us a novel candidate for combating drug resistant bacteria strains by merely inhibiting biofilm formation. Without suppressing the regular life cycle of the bacteria, bacterial resistance mechanisms may not be activated.

2.
ACS Appl Mater Interfaces ; 11(36): 32769-32777, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31423772

RESUMO

The screening strategy based on α-glucosidase inhibition has been widely employed for the discovery of antidiabetic drugs, but it still faces some challenges in practical applications, such as poor stability of enzyme, high consumption of test compounds, low sensitivity of screening methods and so on. In this work, a bifunctional hybrid enzyme-catalytic metal organic framework reactor (GAA@GOx@Cu-MOF) with a flower-shaped globular structure was innovatively prepared via self-assembling of α-glucosidase (GAA), glucose oxidase (GOx), Cu2+, and 4,4'-bipyridine. It was found that GAA@GOx@Cu-MOF not only enjoyed merits of high stability, selectivity, and sensitivity but also possessed the character of assembly line work, with about 4.58 times enhanced enzyme activity compared with the free enzyme system. Based on the above characteristics, a highly sensitive screening of GAA inhibitors could be achieved with the detection limit of 7.05 nM for acarbose. Furthermore, the proposed method was successfully applied to the screening of oleanolic acid derivatives as potential antidiabetic drugs. Therefore, it was expected that this work could provide new insights and inspirations for the screening of clinical antidiabetic drugs and for further exploration of functional MOF composites.

3.
J Nanobiotechnology ; 17(1): 78, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269964

RESUMO

BACKGROUND: The construction of a multifunctional drug delivery system with a variety of advantageous features, including targeted delivery, controlled release and combined therapy, is highly attractive but remains a challenge. RESULTS: In this study, we developed a MoS2-based hyaluronic acid (HA)-functionalized nanoplatform capable of achieving targeted delivery of camptothecin (CPT) and dual-stimuli-responsive drug release. HA was connected to MoS2 via a disulfide linkage, forming a sheddable HA shell on the surface of MoS2. This unique design not only effectively prevented the encapsulated CPT from randomly leaking during blood circulation but also significantly accelerated the drug release in response to tumor-associated glutathione (GSH). Moreover, the MoS2-based generated heat upon near-infrared (NIR) irradiation could further increase the drug release rate as well as induce photothermal ablation of cancer cells. The results of in vitro and in vivo experiments revealed that MoS2-SS-HA-CPT effectively suppressed cell proliferation and inhibited tumor growth in lung cancer cell-bearing mice under NIR irradiation via synergetic chemo-photothermal therapy. CONCLUSIONS: The as-prepared MoS2-SS-HA-CPT with high targeting ability, dual-stimuli-responsive drug release, and synergistic chemo-photothermal therapy may provide a new strategy for cancer therapy.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/administração & dosagem , Dissulfetos/química , Portadores de Fármacos/química , Molibdênio/química , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Liberação Controlada de Fármacos , Feminino , Corantes Fluorescentes/química , Humanos , Ácido Hialurônico/química , Hipertermia Induzida , Raios Infravermelhos , Camundongos Nus , Transplante de Neoplasias , Oxirredução , Fotoquimioterapia/métodos
4.
J Nanobiotechnology ; 17(1): 76, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31217009

RESUMO

BACKGROUND: Molybdenum disulfide (MoS2) has been widely explored for biomedical applications due to its brilliant photothermal conversion ability. In this paper, we report a novel multifunctional MoS2-based drug delivery system (MoS2-SS-HA). By decorating MoS2 nanosheets with hyaluronic acid (HA), these functionalized MoS2 nanosheets have been developed as a tumor-targeting chemotherapeutic nanocarrier for near-infrared (NIR) photothermal-triggered drug delivery, facilitating the combination of chemotherapy and photothermal therapy into one system for cancer therapy. RESULTS: The nanocomposites (MoS2-SS-HA) generated a uniform diameter (ca. 125 nm), exhibited great biocompatibility as well as high stability in physiological solutions, and could be loaded with the insoluble anti-cancer drug erlotinib (Er). The release of Er was greatly accelerated under near infrared laser (NIR) irradiation, showing that the composites can be used as responsive systems, with Er release controllable through NIR irradiation. MTT assays and confocal imaging results showed that the MoS2-based nanoplatform could selectively target and kill CD44-positive lung cancer cells, especially drug resistant cells (A549 and H1975). In vivo tumor ablation studies prove a better synergistic therapeutic effect of the joint treatment, compared with either chemotherapy or photothermal therapy alone. CONCLUSION: The functionalized MoS2 nanoplatform developed in this work could be a potent system for targeted drug delivery and synergistic chemo-photothermal cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Dissulfetos/química , Portadores de Fármacos/química , Cloridrato de Erlotinib/farmacologia , Hipertermia Induzida , Molibdênio/química , Nanocompostos/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Cloridrato de Erlotinib/química , Feminino , Humanos , Ácido Hialurônico/química , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fototerapia
5.
J Colloid Interface Sci ; 548: 131-144, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991180

RESUMO

The construction of multifunctional theranostic nanoplatforms to integrate accurate imaging and enhanced therapy to treat tumors is highly attractive but remains a challenge. Here, we developed a molybdenum disulfide (MoS2)-based hyaluronic acid (HA)-functionalized nanoplatform capable of achieving the targeted co-delivery of the gadolinium (Gd)-based contrast agents (CAs) and the anticancer drug gefitinib (Gef) for magnetic resonance imaging (MRI) and synergetic chemo-photothermal therapy of tumors. Gd3+ ions were coupled to HA-grafted MoS2 nanosheets with diethylenetriaminepentaacetic acid (DTPA) as a linker, followed by the incorporation of Gef. The resulting MoS2-HA-DTPA-Gd/Gef exhibited enhanced relaxivity, 3.3 times greater than that of the commercial CA DTPA-Gd, which facilitated the MRI in vivo. Moreover, the nanoplatform effectively converted the absorbed near-infrared (NIR) light into heat, which not only induced the photothermal ablation of cancer cells but also triggered the release of Gef from MoS2-HA-DTPA-Gd/Gef, enabling the synergetic chemo-photothermal therapy. The results of in vitro and in vivo experiments revealed that MoS2-HA-DTPA-Gd/Gef upon NIR irradiation effectively blocked the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway and activated apoptosis-related proteins to induce cell apoptosis and suppress cell proliferation, thus inhibiting the tumor growth in lung cancer cell-bearing mice. Taken together, this multifunctional theranostic nanoplatform has significant promise for the diagnosis and treatment of cancer.

6.
Bioorg Med Chem Lett ; 29(5): 749-754, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30630718

RESUMO

Signal molecules are stimulators of multiple quroum-sensing virulence and biofilm formation. Small molecule analogues have been suspected as a potent inhibitor in therapeutic strategy. Herein, we synthesized a series of small molecule compounds from the 2, 8-bit derivatives of quinoline by Suzuki coupling reaction. We found that these compounds have the biofilm inhibitory effect in normal condition instead of phosphate limitation state. Furthermore, lacZ reporter strain assay and rhamnolipids as well as pyocyanin experiments showed that these compounds did not affect las and pqs system but reduced the expression of rhl. All these results suggest that quinoline derivatives can be treated as potent inhibitors against biofilm and reduce virulence through the rhl system. This research will be useful in designing new quorum sensing inhibitors to attenuate the infection of bacteria.

7.
Int J Nanomedicine ; 13: 7457-7472, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30532533

RESUMO

Background: Gefitinib (Gef), an important epidermal growth factor receptor (EGFR), is used to treat lung cancer, but low water solubility and poor bioavailability severely limit its application in cancer therapy. Methods: In this study, nanographene oxide (NGO) was decorated with hyaluronic acid (HA) by a linker cystamine dihydrochloride containing disulfide bonds (-SS-), followed by the incorporation of gefitinib, thus, constructing a HA-functionalized GO-based gefitinib delivery system (NGO-SS-HA-Gef). Subsequently, studies of biological experiments in vitro and in vivo were performed to investigate the therapeutic effect of the system in lung cancer. Results: The HA-grafted GO nanosheets possessed enhanced physiological stability, admirable biocompatibility, and no obvious side effects in mice and could act as a nanocarrier for the delivery of gefitinib to tumor. Cellular uptake and intracellular cargo release assays showed that the uptake of NGO-SS-HA by A549 cells was facilitated via CD44 receptor-mediated endocytosis, and that more drug was released from NGO-SS-HA in the presence of GSH than in the absence of GSH. The target-specific binding of NGO-SS-HA to cancer cells with redox-responsive cargo release significantly enhanced the abilities of gefitinib-loaded GO nanosheets to induce cell apoptosis, suppress cell proliferation, and inhibit tumor growth in lung cancer cell-bearing mice. Conclusion: The results demonstrated the potential utility of NGO-SS-HA-Gef for therapeutic applications in the treatment of lung cancer.


Assuntos
Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Grafite/química , Ácido Hialurônico/química , Nanopartículas/química , Água/química , Células A549 , Animais , Apoptose/efeitos dos fármacos , Materiais Biocompatíveis/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dissulfetos/química , Liberação Controlada de Fármacos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oxirredução , Solubilidade , Distribuição Tecidual
8.
Data Brief ; 21: 1591-1597, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30480072

RESUMO

Plumula nelumbinis is widely consumed as tea for its pharmacological properties, which is related to its chemical composition, so the identification of the major compounds of P. nelumbinis is valuable. The data described in this article is supported by the research article entitled "Chemical composition of alkaloids of Plumula nelumbinis and their antioxidant activity from different habitats in China" (Tian et al., 2018). Included are the MS-MS Spectrograms of seven alkaloid standards and thirty alkaloids identified in the P. nelumbinis, which is based on ultra-performance liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry method. Also included are the total alkaloids content and the antioxidant activity of total alkaloid in P. nelumbinis from 13 habitats in China, which was accomplished with three different antioxidant assays.

9.
Data Brief ; 21: 321-327, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30364612

RESUMO

Plumula nelumbinis is a well-known health food and a traditional Chinese medicine, is used in many countries around the world. For its pharmacological properties are related to its chemical composition, a ultra-performance liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOF-MS) method was used to identify the flavonoids in P. nelumbinis. The first set of data shows the MS-MS Spectrograms of 12 flavonoid standards and 38 flavonoids detected in the P. nelumbinis from Xiangtan, Hunan province. The second set of data shows the total flavonoids content and the antioxidant activity of total flavonoid in P. nelumbinis from 13 habitats. The antioxidant activity were accomplished with 1,1-diphenyl-2-picrylhydrazyl (DPPH), oxygen radical absorbance capacity (ORAC) and ferric reducing ability of plasma (FRAP) assays.

10.
ACS Omega ; 3(3): 2855-2864, 2018 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30221223

RESUMO

Herein, we developed a natural surface-enhanced Raman scattering (SERS) substrate based on size-tunable Au@Ag nanoparticle-coated mussel shell to form large-scale three-dimensional (3D) supercrystals (up to 10 cm2) that exhibit surface-laminated structures and crossed nanoplates and nanochannels. The high content of CaCO3 in the mussel shell results in superior hydrophobicity for analyte enrichment, and the crossed nanoplates and nanochannels provided rich SERS hot spots, which together lead to high sensitivity. Finite-difference time-domain simulations showed that nanoparticles in the channels exhibit apparently a higher electromagnetic field enhancement than nanoparticles on the platelets. Thus, under optimized conditions (using Au@AgNPs with 5 nm shell thickness), highly sensitive SERS detection with a detection limit as low as 10-9 M for rhodamine 6G was obtained. Moreover, the maximum electromagnetic field enhancement of different types of 3D supercrystals shows no apparent difference, and Au@AgNPs were uniformly distributed such that reproducible SERS measurements with a 6.5% variation (613 cm-1 peak) over 20 spectra were achieved. More importantly, the as-prepared SERS substrates can be utilized for the fast discrimination of Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa by discriminant analysis. This novel Au@Ag self-assembled mussel shell template holds considerable promise as low-cost, durable, sensitive, and reproducible substrates for future SERS-based biosensors.

11.
Medchemcomm ; 9(1): 181-188, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30108912

RESUMO

Strigolactones (SLs) are a novel class of plant hormones with enormous potential for the prevention and treatment of inflammation. To further investigate the anti-inflammatory activities of SLs, a representative SL, GR24, and the reductive products of its D-ring were synthesized and their anti-inflammatory activities were fully evaluated on both in vitro and in vivo models. Among these compounds, the two most active optical isomers (2a and 6a) demonstrated strong inhibitory activity on the release of inflammatory cytokines, including nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) by blocking the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways; they also greatly inhibited the migration of neutrophils and macrophages in fluorescent protein labeled zebrafish larvae. These results identified the promising anti-inflammatory effects of SLs, and suggested that both the absolute configuration of SL and the α,ß-unsaturated D-ring structure are essential for the observed anti-inflammatory activity.

12.
Sci Rep ; 7(1): 11525, 2017 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-28912450

RESUMO

Drug resistance caused by excessive and indiscriminate antibiotic usage has become a serious public health problem. The need of finding new antibacterial drugs is more urgent than ever before. Tyrosyl-tRNA synthase was proved to be a potent target in combating drug-resistant bacteria. In silico methodologies including molecular docking and 3D-QSAR were employed to investigate a series of newly reported tyrosyl-tRNA synthase inhibitors of furanone derivatives. Both internal and external cross-validation were conducted to obtain high predictive and satisfactory CoMFA model (q 2 = 0.611, r 2pred = 0.933, r 2m = 0.954) and CoMSIA model (q 2 = 0.546, r 2pred = 0.959, r 2m = 0.923). Docking results, which correspond with CoMFA/CoMSIA contour maps, gave the information for interactive mode exploration. Ten new molecules designed on the basis of QSAR and docking models have been predicted more potent than the most active compound 3-(4-hydroxyphenyl)-4-(2-morpholinoethoxy)furan-2(5H)-one (15) in the literatures. The results expand our understanding of furanones as inhibitors of tyrosyl-tRNA synthase and could be helpful in rationally designing of new analogs with more potent inhibitory activities.

13.
Oncotarget ; 8(13): 21177-21186, 2017 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-28416753

RESUMO

Renal cell carcinoma (RCC) management has undergone a major transformation over the past decade; immune checkpoint inhibitors are currently undergoing clinical trials and show promising results. However, the effectiveness of immune checkpoint inhibitors in patients with metastatic RCC (mRCC) is still limited. Lycorine, an alkaloid extracted from plants of the Amaryllidaceae family, is touted as a potential anti-cancer drug because of its demonstrative growth inhibition capacity (induction of cell cycle arrest and inhibition of vasculogenic mimicry formation). Moreover, T cell checkpoint blockade therapy with antibodies targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) has improved outcomes in cancer patients. However, the anti-tumor efficacy of combined lycorine and anti-CTLA-4 therapy remains unknown. Thus, we investigated a combination therapy of lycorine hydrochloride and anti-CTLA-4 using a murine RCC model. As a means of in vitro confirmation, we found that lycorine hydrochloride inhibited the viability of various RCC cell lines. Furthermore, luciferase-expressing Renca cells were implanted in the left kidney and the lung of BALB/c mice to develop a RCC metastatic mouse model. Lycorine hydrochloride and anti-CTLA-4 synergistically decreased tumor weight, lung metastasis, and luciferin-staining in tumor images. Importantly, the observed anti-tumor effects of this combination were dependent on significantly suppressing regulatory T cells while upregulating effector T cells; a decrease in regulatory T cells by 31.43% but an increase in effector T cells by 31.59% were observed in the combination group compared with those in the control group). We suggest that a combination of lycorine hydrochloride and anti-CTLA-4 is a viable therapeutic option for RCC patients.


Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Carcinoma de Células Renais/terapia , Inibidores do Crescimento/farmacologia , Fenantridinas/farmacologia , Extratos Vegetais/farmacologia , Alcaloides de Amaryllidaceae/uso terapêutico , Animais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Terapia Combinada , Sinergismo Farmacológico , Feminino , Inibidores do Crescimento/uso terapêutico , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais , Fenantridinas/uso terapêutico , Extratos Vegetais/uso terapêutico , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Resultado do Tratamento
14.
Biochem Biophys Res Commun ; 483(1): 197-202, 2017 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-28042037

RESUMO

Lycorine, an alkaloid extracted from Amaryllidaceae genera, exhibits antitumor activities against several human solid-tumor and leukemia cells with extensive influence on various cell signaling molecules. However, the effect of lycorine on bladder cancer has not yet been investigated. In this study, we demonstrated that lycorine induced apoptosis in human bladder cancer T24 cells, an effect that is mediated via inhibition of phospho-Akt expression and the consequent activation of caspase-3 and Bax in vitro. In an in vivo experiment, T24 cells were subcutaneously implanted in the right rear flank of nu/nu mice. Lycorine treatment for 14 days significantly inhibited tumor growth compared with that in controls. Collectively, our findings suggest that lycorine suppressed the Akt pathway and activated the intrinsic apoptotic cascade, leading to the apoptosis of bladder cancer cells. We suggest that lycorine can be a viable therapeutic option for bladder cancer patients.


Assuntos
Alcaloides de Amaryllidaceae/farmacologia , Apoptose/efeitos dos fármacos , Fenantridinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/farmacologia , Caspase 3/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos Nus , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Bexiga Urinária/citologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
PLoS One ; 9(4): e93704, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24722522

RESUMO

Several small-molecule CDK inhibitors have been identified, but none have been approved for clinical use in the past few years. A new series of 4-[(3-hydroxybenzylamino)-methylene]-4H-isoquinoline-1,3-diones were reported as highly potent and selective CDK4 inhibitors. In order to find more potent CDK4 inhibitors, the interactions between these novel isoquinoline-1,3-diones and cyclin-dependent kinase 4 was explored via in silico methodologies such as 3D-QSAR and docking on eighty-one compounds displaying potent selective activities against cyclin-dependent kinase 4. Internal and external cross-validation techniques were investigated as well as region focusing, bootstraping and leave-group-out. A training set of 66 compounds gave the satisfactory CoMFA model (q2 = 0.695, r2 = 0.947) and CoMSIA model (q2 = 0.641, r2 = 0.933). The remaining 15 compounds as a test set also gave good external predictive abilities with r2pred values of 0.875 and 0.769 for CoMFA and CoMSIA, respectively. The 3D-QSAR models generated here predicted that all five parameters are important for activity toward CDK4. Surflex-dock results, coincident with CoMFA/CoMSIA contour maps, gave the path for binding mode exploration between the inhibitors and CDK4 protein. Based on the QSAR and docking models, twenty new potent molecules have been designed and predicted better than the most active compound 12 in the literatures. The QSAR, docking and interactions analysis expand the structure-activity relationships of constrained isoquinoline-1,3-diones and contribute towards the development of more active CDK4 subtype-selective inhibitors.


Assuntos
Quinase 4 Dependente de Ciclina/genética , Isoquinolinas/química , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Trifosfato de Adenosina/química , Algoritmos , Biologia Computacional , Humanos , Ligações de Hidrogênio , Concentração Inibidora 50 , Ligantes , Modelos Estatísticos , Ligação Proteica , Inibidores de Proteínas Quinases/química , Eletricidade Estática , Relação Estrutura-Atividade
16.
Fitoterapia ; 88: 25-30, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23583437

RESUMO

Four steroidal saponins were isolated from the anti-anoxic fraction of the 60% EtOH extract of Selaginella uncinata, including two new compounds, (3ß, 7ß, 12ß, 25R)-spirost-5-ene-3, 7, 12-triol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl-(1→4)]-O-ß-D-glucopyranoside (1), (2α, 3ß, 12ß, 25R)-spirost-5-ene-2, 3, 12-triol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl-(1→4)]-O-ß-D-glucopyranoside (2) and two known compounds, (3ß, 12ß, 25R)-spirost-5-ene-3,12-diol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl-(1→4)]-O-ß-D-glucopyranoside, (3), (1α, 3ß, 25R)-spirost-5-ene-2-diol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl(1→4)]-O-ß-D-glucopyranoside (4). The four compounds showed potent protective effect against anoxia in the anoxic PC12 cells assay, among which compounds 1 and 2 were the most active. To our knowledge, this is the first study to report the steroidal saponins in the plant S. uncinata and demonstrate their protective effect against anoxia in PC12 cell assay.


Assuntos
Hipóxia/prevenção & controle , Extratos Vegetais/uso terapêutico , Saponinas/uso terapêutico , Selaginellaceae/química , Animais , Células PC12 , Fitoterapia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Saponinas/isolamento & purificação , Saponinas/farmacologia
17.
Int J Mol Sci ; 12(10): 6502-16, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22072901

RESUMO

Selective S1P(1) receptor agonists have therapeutic potential to treat a variety of immune-mediated diseases. A series of 2-imino-thiazolidin-4-one derivatives displaying potent S1P(1) receptor agonistic activity were selected to establish 3D-QSAR models using CoMFA and CoMSIA methods. Internal and external cross-validation techniques were investigated as well as some measures including region focusing, progressive scrambling, bootstraping and leave-group-out. The satisfactory CoMFA model predicted a q(2) value of 0.751 and an r(2) value of 0.973, indicating that electrostatic and steric properties play a significant role in potency. The best CoMSIA model, based on a combination of steric, electrostatic, hydrophobic and H-bond donor descriptors, predicted a q(2) value of 0.739 and an r(2) value of 0.923. The models were graphically interpreted using contour plots which gave more insight into the structural requirements for increasing the activity of a compound, providing a solid basis for future rational design of more active S1P(1) receptor agonists.


Assuntos
Relação Quantitativa Estrutura-Atividade , Receptores de Lisoesfingolipídeo/agonistas , Tiazolidinas/química , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Receptores de Lisoesfingolipídeo/metabolismo , Eletricidade Estática
18.
Molecules ; 16(8): 6206-14, 2011 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-21788929

RESUMO

Seven 3',8''-linked bioflavonoids, including one new compound, (2''S)-2'', 3''-dihydroamentoflavone-4'-methyl ether and six known compounds: (2S)-2,3- dihydroamentoflavone-4'-methyl ether, (2S,2''S)-2,3,2'',3''-tetrahydroamento- flavone-4'-methyl ether, (2S,2''S)-tetrahydroamentoflavone, (2S)-2,3-dihydro- amentoflavone and (2''S)-2'',3''-dihydroamentoflavone (6) and amentoflavone, were isolated from the 60% ethanolic extract of Selaginella uncinata (Desv.) Spring. The structures of these compounds were elucidated mainly by analysis of their 1D and 2D NMR spectroscopic data, and their absolute configurations were determined by circular-dichroism (CD) spectroscopy. All the seven compounds showed protective effect against anoxia in the anoxic PC12 cells assay, in which compound 6 displayed particularly potent activity.


Assuntos
Doença da Altitude/tratamento farmacológico , Biflavonoides , Hipóxia/tratamento farmacológico , Extratos Vegetais , Selaginellaceae/química , Doença da Altitude/fisiopatologia , Doença da Altitude/prevenção & controle , Animais , Biflavonoides/análise , Biflavonoides/química , Biflavonoides/farmacologia , Configuração de Carboidratos , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Etanol/química , Flavonoides/farmacologia , Humanos , Hipóxia/fisiopatologia , Hipóxia/prevenção & controle , Espectroscopia de Ressonância Magnética , Células PC12 , Extratos Vegetais/análise , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Azul Tripano/análise
19.
Chem Biol Drug Des ; 78(2): 314-21, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21599857

RESUMO

A series of indole and related benzo[g]indole compounds displaying potent activities against 5-lipoxygenase were selected to establish three-dimensional quantitative structure-activity relationships using comparative molecular field analysis and comparative molecular similarity indices analysis methods. A training set of 37 active compounds was used to develop the models, which were then valuated by a series of internal and external cross-validation techniques. A test set of seven compounds was used for the external validation. Models with greater than 70% predictive ability, as determined by external validation, and high internal validity (cross-validated q(2)>0.5) have been developed. The satisfactory comparative molecular field analysis model predicted a q(2) value of 0.779 and an r(2) value of 0.957 and revealed that electrostatic and steric properties play a significant role in potency. The best comparative molecular similarity indices analysis model, based on a combination of steric, hydrophobic, and H-bond donor effects, predicted a q(2) value of 0.816 and an r(2) value of 0.953. The models were graphically interpreted using comparative molecular field analysis and comparative molecular similarity indices analysis contour plots that provided insight into the structural requirements for increasing the activity of a compound. The results obtained from this study provide a solid basis for future rational design of more active 5-lipoxygenase inhibitors.


Assuntos
Araquidonato 5-Lipoxigenase/metabolismo , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Desenho de Drogas , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/farmacologia , Modelos Biológicos , Ácidos Carboxílicos/química , Ativação Enzimática/efeitos dos fármacos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Inibidores de Lipoxigenase/química , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade
20.
J Mol Model ; 17(8): 2113-30, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21416222

RESUMO

Seventy-five 1,5,6,7-tetrahydro-pyrrolo[3,2-C]pyridinone derivatives displaying potent activities against Cdc7 kinase were selected to establish 3D-QSAR models using CoMFA and CoMSIA methods. Internal and external cross-validation techniques were investigated as well as some measures including region focusing, progressive scrambling, bootstraping and leave-group-out. The satisfactory CoMFA model predicted a q (2) value of 0.836 and an r (2) value of 0.950, indicating that electrostatic and steric properties play a significant role in potency. The best CoMSIA model, based on a combination of steric, electrostatic and H-bond acceptor effects, predicted a q (2) value of 0.636 and an r (2) value of 0.907. The models were graphically interpreted using contour plots which provided insight into the structural requirements for increasing the activity of a compound. The final 3D-QSAR results could be used for rational design of potent inhibitors against Cdc7 kinase.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridonas/química , Relação Quantitativa Estrutura-Atividade , Ciclo Celular/efeitos dos fármacos , Simulação por Computador , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Piridonas/metabolismo , Piridonas/farmacologia
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