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1.
Clin Cancer Res ; 22(23): 5755-5764, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27185372

RESUMO

PURPOSE: Fulvestrant is an estrogen receptor (ER) antagonist and an approved treatment for metastatic estrogen receptor-positive (ER+) breast cancer. With the exception of ER levels, there are no established predictive biomarkers of response to single-agent fulvestrant. We attempted to identify a gene signature of response to fulvestrant in advanced breast cancer. EXPERIMENTAL DESIGN: Primary tumor samples from 134 patients enrolled in the phase III CONFIRM study of patients with metastatic ER+ breast cancer comparing treatment with either 250 mg or 500 mg fulvestrant were collected for genome-wide transcriptomic analysis. Gene expression profiling was performed using Affymetrix microarrays. An exploratory analysis was performed to identify biologic pathways and new signatures associated with response to fulvestrant. RESULTS: Pathway analysis demonstrated that increased EGF pathway and FOXA1 transcriptional signaling is associated with decreased response to fulvestrant. Using a multivariate Cox model, we identified a novel set of 37 genes with an expression that is independently associated with progression-free survival (PFS). TFAP2C, a known regulator of ER activity, was ranked second in this gene set, and high expression was associated with a decreased response to fulvestrant. The negative predictive value of TFAP2C expression at the protein level was confirmed by IHC. CONCLUSIONS: We identified biologic pathways and a novel gene signature in primary ER+ breast cancers that predicts for response to treatment in the CONFIRM study. These results suggest potential new therapeutic targets and warrant further validation as predictive biomarkers of fulvestrant treatment in metastatic breast cancer. Clin Cancer Res; 22(23); 5755-64. ©2016 AACR.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Estradiol/análogos & derivados , Receptores Estrogênicos/metabolismo , Neoplasias da Mama/metabolismo , Intervalo Livre de Doença , Método Duplo-Cego , Fator de Crescimento Epidérmico/metabolismo , Estradiol/uso terapêutico , Feminino , Fulvestranto , Perfilação da Expressão Gênica/métodos , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Pessoa de Meia-Idade , Pós-Menopausa/efeitos dos fármacos , Pós-Menopausa/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator de Transcrição AP-2/metabolismo , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética
2.
Nat Rev Cancer ; 16(5): 319-29, 2016 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-27112209

RESUMO

Genomic profiling of tumours in patients in clinical trials enables rapid testing of multiple hypotheses to confirm which genomic events determine likely responder groups for targeted agents. A key challenge of this new capability is defining which specific genomic events should be classified as 'actionable' (that is, potentially responsive to a targeted therapy), especially when looking for early indications of patient subgroups likely to be responsive to new drugs. This Opinion article discusses some of the different approaches being taken in early clinical development to define actionable mutations, and describes our strategy to address this challenge in early-stage exploratory clinical trials.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Neoplasias Pulmonares/genética , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Pirimidinonas , Proteína Supressora de Tumor p53/genética
3.
Biochem J ; 473(1): 99-107, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26508734

RESUMO

Cancer cells are capable of sphere formation (transformation) through reactive oxygen species (ROS) and glycolysis shift. Transformation is linked to tumorigenesis and therapy resistance, hence targeting regulators of ROS and glycolysis is important for cancer therapeutic candidates. Here, we demonstrate that Smac mimetic AZ58 in combination with tumour necrosis factor-α (TNF-α) was able to inhibit the production of ROS, inhibit glycolysis through Pim-1 kinase-mediated Ser-112 phosphorylation of BAD, and increase depolarization of mitochondria. We also identified mitochondrial isoforms of Pim-1 kinase that were targeted for degradation by AZ58 in combination with TNF-α or AZ58 in combination with Fas ligand (FasL) plus cycloheximide (CHX) through caspase-3 to block transformation. Our study demonstrates that Smac mimetic in combination with TNF-α is an ideal candidate to target Pim-1 expression, inhibit ROS production and to block transformation from blebbishields.


Assuntos
Materiais Biomiméticos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transformação Genética/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Reguladoras de Apoptose , Materiais Biomiméticos/administração & dosagem , Linhagem Celular Tumoral , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/administração & dosagem , Proteínas Mitocondriais/administração & dosagem , Isoformas de Proteínas/metabolismo , Transformação Genética/efeitos dos fármacos , Fator de Necrose Tumoral alfa/administração & dosagem
4.
Pharmacol Res Perspect ; 2(6): e00081, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25505620

RESUMO

Despite recent advances in therapy, chronic lymphocytic leukaemia (CLL) remains incurable and new treatment strategies are therefore urgently required. Inhibitor of apoptosis proteins (IAPs) are over-expressed in CLL, suggesting both a role in disease pathogenesis and the potential for therapeutic targeting. To explore these questions, we evaluated the effects on primary CLL cells of AZD5582, a novel potent and selective inhibitor of IAPs. AZD5582 at nanomolar concentrations induced extensive degradation of cIAP-1 and cIAP-2, but minimally of X chromosome-linked IAP (XIAP). However, these effects of AZD5582 produced little or no direct cytotoxicity, nor did they sensitize CLL cells to p53-dependent killing by fludarabine or p53-independent killing by dexamethasone. In contrast, AZD5582 significantly enhanced apoptosis induced by the death receptor (DR) agonist tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Importantly, killing by TRAIL plus AZD5582 was independent of adverse prognostic features including TP53 deletion which is strongly associated with chemoresistance in CLL. Coculture experiments involving transfected mouse fibroblasts expressing human CD40L (CD154) to mimic the effect of T cells at sites of tissue involvement showed that CD40 stimulation almost completely prevented the killing of CLL cells by TRAIL plus AZD5582 despite up-regulating TRAIL receptors 1 and 2. In conclusion, our findings confirm the rate-limiting, upstream involvement of IAPs in the extrinsic but not intrinsic apoptotic pathway of CLL cells and suggest that drug combinations that simultaneously activate DRs and inhibit IAPs may have therapeutic potential in patients with CLL who have failed T-cell-depleting chemotherapy.

5.
Bioorg Med Chem Lett ; 24(7): 1820-4, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24631189

RESUMO

The design and synthesis of a series of novel tricyclic IAP inhibitors is reported. Rapid assembly of the core tricycle involved two key steps: Rh-catalyzed hydrogenation of an unsaturated bicyclic ring system and a Ru-catalyzed ring closing alkene metathesis reaction. The final Smac mimetics bind to cIAP1 and XIAP BIR3 domains and elicit the desired phenotype in cellular proliferation assays. Dimeric IAP inhibitors were found to possess nanomolar potency in a cellular proliferation assay and favourable in vitro drug-like properties.


Assuntos
Desenho de Drogas , Compostos Heterocíclicos com 3 Anéis/farmacologia , Proteínas Inibidoras de Apoptose/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Proteínas Inibidoras de Apoptose/síntese química , Proteínas Inibidoras de Apoptose/química , Estrutura Molecular , Relação Estrutura-Atividade
6.
PLoS One ; 9(2): e87415, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24505287

RESUMO

Fulvestrant is a selective estrogen receptor antagonist. Based on the measured growth inhibition of 60 human cancer cell lines (NCI60) in the presence of fulvestrant, as well as the baseline gene expression of the 60 cell lines, a gene expression score that predicts response to fulvestrant was developed. The score is based on 414 genes, 103 of which show increased expression in sensitive cell lines, while 311 show increased expression in the non-responding cell lines. The sensitivity genes primarily sense signaling through estrogen receptor alpha, whereas the resistance genes modulate the PI3K signaling pathway. The latter genes suggest that resistance to fulvestrant can be overcome by drugs targeting the PI3K pathway. The level of this gene expression score and its correlation with fulvestrant response was measured in a panel of 20 breast cancer cell lines. The predicted sensitivity matched the measured sensitivity well (CC = -0.63, P = 0.003). The predictor was applied to tumor biopsies obtained from a Phase II clinical trial. The sensitivity of each patient to treatment with fulvestrant was predicted based on the RNA profile of the biopsy taken before neoadjuvant treatment and without knowledge of the subsequent response. The prediction was then compared to clinical response to show that the responders had a significantly higher sensitivity prediction than the non-responders (P = 0.01). When clinical covariates, tumor grade and estrogen receptor H-score, were included in the prediction, the difference in predicted senstivity between responders and non-responders improved (P = 0.003). Using a pre-defined cutoff to separate patients into predicted sensitive and predicted resistant yielded a positive predictive value of 88% and a negative predictive value of 100% when compared to clinical data. We conclude that pre-screening patients with the new gene expression predictor has the potential to identify those postmenopausal women with locally advanced, estrogen-receptor-positive breast cancer most likely to respond to fulvestrant.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Estradiol/análogos & derivados , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Neoplasias/biossíntese , Estradiol/administração & dosagem , Feminino , Fulvestranto , Perfilação da Expressão Gênica , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Valor Preditivo dos Testes
7.
Mol Cancer Ther ; 13(2): 386-98, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24344235

RESUMO

The hedgehog pathway has been implicated in the tumorigenesis, tumor progression, and metastasis of numerous human cancers. We generated the first fully human hedgehog antibody MEDI-5304 and characterized its antitumor activity and preclinical toxicology. MEDI-5304 bound sonic hedgehog (SHH) and Indian hedgehog (IHH) with low picomolar affinity and neutralized SHH and IHH activity in cellular mGLI1 reporter assays. The antibody inhibited transcription of hedgehog target genes and osteoblast differentiation of C3H10T1/2 cells. We evaluated the activity of MEDI-5304 in vivo in model systems that allowed us to evaluate two primary hypotheses of hedgehog function in human cancer, paracrine signaling between tumor and stromal cells and cancer stem cell (CSC) self-renewal. MEDI-5304 displayed robust pharmacodynamic effects in stromal cells that translated to antitumor efficacy as a single agent in an HT-29/MEF coimplantation model of paracrine hedgehog signaling. MEDI-5304 also improved responses to carboplatin in the HT-29/MEF model. The antibody, however, had no effect as a single agent or in combination with gemcitabine on the CSC frequency or growth of several primary pancreatic cancer explant models. These findings support the conclusion that hedgehog contributes to tumor biology via paracrine tumor-stromal signaling but not via CSC maintenance or propagation. Finally, the only safety study finding associated with MEDI-5304 was ondontodysplasia in rats. Thus, MEDI-5304 represents a potent dual hedgehog inhibitor suitable for continued development to evaluate efficacy and safety in human patients with tumors harboring elevated levels of SHH or IHH.


Assuntos
Anticorpos Neutralizantes/farmacologia , Antineoplásicos/farmacologia , Proteínas Hedgehog/antagonistas & inibidores , Comunicação Parácrina/efeitos dos fármacos , Animais , Anticorpos Monoclonais Humanizados , Anticorpos Neutralizantes/imunologia , Antineoplásicos/imunologia , Antineoplásicos/farmacocinética , Linhagem Celular , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Células HT29 , Proteínas Hedgehog/imunologia , Humanos , Cinética , Macaca fascicularis , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Células NIH 3T3 , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Comunicação Parácrina/imunologia , Ligação Proteica/imunologia , Ratos Wistar , Células Estromais/efeitos dos fármacos , Células Estromais/imunologia , Células Estromais/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Med Chem ; 56(24): 9897-919, 2013 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-24320998

RESUMO

A series of dimeric compounds based on the AVPI motif of Smac were designed and prepared as antagonists of the inhibitor of apoptosis proteins (IAPs). Optimization of cellular potency, physical properties, and pharmacokinetic parameters led to the identification of compound 14 (AZD5582), which binds potently to the BIR3 domains of cIAP1, cIAP2, and XIAP (IC50 = 15, 21, and 15 nM, respectively). This compound causes cIAP1 degradation and induces apoptosis in the MDA-MB-231 breast cancer cell line at subnanomolar concentrations in vitro. When administered intravenously to MDA-MB-231 xenograft-bearing mice, 14 results in cIAP1 degradation and caspase-3 cleavage within tumor cells and causes substantial tumor regressions following two weekly doses of 3.0 mg/kg. Antiproliferative effects are observed with 14 in only a small subset of the over 200 cancer cell lines examined, consistent with other published IAP inhibitors. As a result of its in vitro and in vivo profile, 14 was nominated as a candidate for clinical development.


Assuntos
Alquinos/farmacologia , Antineoplásicos/farmacologia , Materiais Biomiméticos/farmacologia , Descoberta de Drogas , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Oligopeptídeos/farmacologia , Alquinos/síntese química , Alquinos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dimerização , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Camundongos , Conformação Molecular , Neoplasias/patologia , Oligopeptídeos/síntese química , Oligopeptídeos/química , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Cancer Biol Ther ; 14(9): 812-22, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23792592

RESUMO

Cisplatin-based chemotherapy is considered the gold standard for patients with advanced bladder cancer. However, despite initial response, many patients will relapse; therefore, novel salvage treatment strategies are desperately needed. Herein, we studied a mechanism based treatment combination using a Smac mimetic with standard chemotherapy. Using a panel of 10 urothelial cancer cell lines, we exposed them to a combination of gemcitabine, cisplatin, and a Smac mimetic. Sensitivity was determined using a DNA fragmentation assay. We determined that three cell lines (UMUC-3, UMUC-13, and RT4v6) were considered sensitive to the combination of gemcitabine and cisplatin and an additional three cell lines were sensitized to gemcitabine and cisplatin with the addition of the Smac mimetic (UMUC-6, UMUC-12, and UMUC-18). We next explored the constitutive expression of selected members of the IAP family (XIAP, cIAP-1, cIAP-2, and Survivin), the BCL family (BCL-2, BCLXL, and BAX) and Smac using gene expression profiling and western blotting. We determined that RNA and protein expression of SMAC, selected members of the IAP family and members of the BCL family did not correlate to drug sensitivity. Lastly, using an in vivo mouse model, we determined that treatment with the Smac mimetic in combination with gemcitabine and cisplatin resulted in increased apoptosis, decreased microvessel density and decreased cellular proliferation. This novel treatment strategy may be effective in patients with advanced urothelial carcinoma and warrants further investigation.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Desoxicitidina/análogos & derivados , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Mitocondriais/metabolismo , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologia , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose , Proliferação de Células/efeitos dos fármacos , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Feminino , Genes bcl-2 , Xenoenxertos , Humanos , Camundongos Nus , Mimetismo Molecular , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/tratamento farmacológico
10.
Mol Pharmacol ; 83(6): 1247-56, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23558446

RESUMO

Platelet-derived growth factor receptor α (PDGFRα) is a receptor tyrosine kinase that promotes cell survival and is expressed in both the tumor and the stromal components of human cancers. We have developed a fully human monoclonal antibody, MEDI-575, that selectively binds to human PDGFRα with high affinity, with no observable affinity for murine PDGFRα. To more fully characterize the role of PDGFRα in the regulation of tumor stroma, we evaluated the in vivo antitumor effects of MEDI-575 in tumor-bearing severe combined immunodeficient (SCID) mice and in genetically altered SCID mice expressing human PDGFRα in place of murine PDGFRα. We used the Calu-6 non-small cell lung cancer model because it lacks an in vitro proliferative response to PDGFRα activation. Antitumor activity was observed when the study was performed in mice expressing the human receptor, but no activity was observed in the mice expressing the murine receptor. Immunohistologic analysis of the tumors from mice expressing human PDGFRα showed a highly significant reduction in stromal fibroblast content and only minor changes in tumor proliferative index in tumors exposed to MEDI-575 compared with the results seen in vehicle-treated tumors or in tumors from mice expressing murine PDGFRα. Additional in vitro studies indicated that exposure of primary cancer-associated fibroblasts to MEDI-575 can directly affect proliferation and key signaling pathways in these cells. These results highlight the potential for observing antitumor activity with MEDI-575 through modulation of the stromal component of tumors and confirm that the PDGFRα pathway can play a role in maintaining a tumor microenvironment conducive to tumor growth.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Fibroblastos/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Animais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Camundongos SCID , Células NIH 3T3 , Transplante de Neoplasias , Fosforilação , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia , Transplante Heterólogo
11.
Bioorg Med Chem Lett ; 22(4): 1690-4, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22264476

RESUMO

A series of structurally unique Smac mimetics that act as antagonists of inhibitor of apoptosis proteins (IAPs) has been discovered. While most previously described Smac mimetics contain the proline ring (or a similar cyclic motif) found in Smac, a key feature of the compounds described herein is that this ring has been removed. Despite this, compounds in this series potently bind to cIAP1 and elicit the expected phenotype of cIAP1 inhibition in cancer cells. Marked selectivity for cIAP1 over XIAP is observed for these compounds, which is attributed to a slight difference in the binding groove between the two proteins and the resulting steric interactions with the inhibitors. XIAP binding can be improved by constraining the inhibitor so that these unfavorable steric interactions are minimized.


Assuntos
Aminas/síntese química , Desenho de Drogas , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/química , Proteínas Mitocondriais/química , Piperidinas/síntese química , Aminas/química , Aminas/farmacologia , Proteínas Reguladoras de Apoptose , Biomimética , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Piperidinas/química , Piperidinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
12.
Invest New Drugs ; 28(5): 561-74, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19626278

RESUMO

Despite the widespread use of rituximab, a chimeric monoclonal antibody with demonstrated efficacy in the treatment of non-Hodgkin's lymphomas, there is a recognized need to develop new agents with improved efficacy. Towards this end, using XenoMouse technology, a fully human IgG1 anti-CD20 monoclonal antibody was generated. This antibody, denoted mAb 1.5.3, evoked enhanced pro-apoptotic activity in vitro, as compared to rituximab, in the Ramos lymphoma cell line. Also, mAb 1.5.3 mediated both complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) similar to rituximab in human B-lymphoma lines. Interestingly, mAb 1.5.3 demonstrated superior ADCC compared to rituiximab when FcgammaRIIIa F/F allotype donors were profiled and superior cytolytic activity across multiple human B-lymphoma and chronic B-cell leukemia lines in an in vitro whole blood assay. Furthermore, mAb 1.5.3 exhibited enhanced anti-tumor activity in Ramos, Daudi, and Namalwa tumour xenograft models. Lastly, mAb 1.5.3 produced a superior B-cell depletion profile in lymph node organs and bone marrow as compared to rituximab in a primate pharmacodynamic (PD) model. These findings underscore the potential of mAb 1.5.3 to exhibit improved clinical activity in the treatment of B-cell malignancies compared to rituximab.


Assuntos
Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais/uso terapêutico , Antígenos CD20/imunologia , Linfoma de Células B/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Murinos , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Mapeamento de Epitopos , Humanos , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Macaca fascicularis , Camundongos , Camundongos SCID , Dados de Sequência Molecular , Peptídeos/química , Peptídeos/imunologia , Rituximab
13.
J Nat Prod ; 67(11): 1911-4, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15568789

RESUMO

Activity-guided fractionation of a chloroform-soluble extract of the leaves of Ormosia sumatrana, using a proteasome inhibition assay, led to the isolation of a new A-type proanthocyanidin derivative, 3'-O-cinnamoylprocyanidin A-2 (1), and a new cerebroside, sumatranoside (2). The structures of these two isolates were determined as epicatechin-(2 beta-->O-->7',4 beta-->8')-epicatechin-3'-O-cinnamate (1) and 1-O-(beta-d-glucopyranosyl)-(2S,3S,4R)-2N-[(2'R)-2'-hydroxy-tetracosanoyl]-9Z-octadecene-1,3,4-triol (2), respectively, by spectroscopic and chemical methods. Sumatranoside (2) exhibited proteasome inhibitory activity with an IC(50) value of 30 microM.


Assuntos
Catequina/análogos & derivados , Catequina/isolamento & purificação , Cerebrosídeos/isolamento & purificação , Inibidores Enzimáticos/isolamento & purificação , Fabaceae/química , Inibidores de Proteassoma , Catequina/química , Catequina/farmacologia , Cerebrosídeos/química , Cerebrosídeos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Indonésia , Concentração Inibidora 50 , Estrutura Molecular , Folhas de Planta/química , Estereoisomerismo
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