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1.
Bioorg Med Chem Lett ; 22(1): 245-8, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22137846

RESUMO

The macrocyclic diarylether heptanoid (MDEH) natural products have been used in folk medicine for centuries. MDEHs are reported to exert anti-tumor properties by inhibiting the activation of NF-κB. Here we report the synthesis of a small MDEH library (first reported synthesis of racemic platycarynol) using a Grubbs cross metathesis/Ullmann cyclization strategy. Evaluation of the library led to the identification of MDEH 9b which sensitizes pancreatic cancer cells to gemcitabine mediated growth inhibition and apoptosis.


Assuntos
Éter/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Antineoplásicos/farmacologia , Apoptose , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Linhagem Celular , Química Farmacêutica/métodos , Desenho de Fármacos , Células HEK293 , Humanos , Modelos Químicos , NF-kappa B/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismo
2.
Cancer Biol Ther ; 11(2): 263-76, 2011 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-21088503

RESUMO

The receptor tyrosine kinase ErbB2 is overexpressed in up to a third of breast cancers, allowing targeted therapy with ErbB2-directed humanized antibodies such as Trastuzumab. Concurrent targeting of ErbB2 stability with HSP90 inhibitors is synergistic with Trastuzumab, suggesting that pharmacological agents that can inhibit HSP90 as well as signaling pathways activated by ErbB2 could be useful against ErbB2-overexpressing breast cancers. The triterpene natural product Celastrol inhibits HSP90 and several pathways relevant to ErbB2-dependent oncogenesis including the NFκB pathway and the proteasome, and has shown promising activity in other cancer models. Here, we demonstrate that Celastrol exhibits in vitro antitumor activity against a panel of human breast cancer cell lines with selectivity towards those overexpressing ErbB2. Celastrol strongly synergized with ErbB2-targeted therapeutics Trastuzumab and Lapatinib, producing higher cytotoxicity with substantially lower doses of Celastrol. Celastrol significantly retarded the rate of growth of ErbB2-overexpressing human breast cancer cells in a mouse xenograft model with only minor systemic toxicity. Mechanistically, Celastrol not only induced the expected ubiquitinylation and degradation of ErbB2 and other HSP90 client proteins, but it also increased the levels of reactive oxygen species (ROS). Our studies show that the Michael Acceptor functionality in Celastrol is important for its ability to destabilize ErbB2 and exert its bioactivity against ErbB2-overexpressing breast cancer cells. These studies suggest the potential use of Michael acceptor-containing molecules as novel therapeutic modalities against ErbB2-driven breast cancer by targeting multiple biological attributes of the driver oncogene.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Triterpenos/administração & dosagem , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Feminino , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico HSP90/uso terapêutico , Humanos , Concentração Inibidora 50 , Lapatinib , Camundongos , Camundongos SCID , Triterpenos Pentacíclicos , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/uso terapêutico , Transdução de Sinais , Trastuzumab , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
3.
Tetrahedron Lett ; 51(19): 2655-2656, 2010 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-20607147

RESUMO

Aryl and alkenyl amino acid derivatives were synthesized by a palladium catalyzed 1,4 addition of the corresponding boronic acids to 2-acetamidoacrylate.

4.
J Org Chem ; 70(2): 746-8, 2005 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-15651836

RESUMO

The Rh(II)-catalyzed coupling of chiral 2-thiopyranylindoles with vinyl diazoacetates results in the generation of indolines having quaternary substitution at C3 in high diastereoselectivity.


Assuntos
Indóis/síntese química , Compostos de Enxofre/química , Compostos Aza/química , Catálise , Indóis/química , Estrutura Molecular , Ródio/química , Estereoisomerismo , Compostos de Vinila/química
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