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1.
Mol Cancer Ther ; 9(3): 718-30, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20197400

RESUMO

Emerging evidence suggests that autophagic modulators have therapeutic potential. This study aims to identify novel autophagic inducers from traditional Chinese medicinal herbs as potential antitumor agents. Using an image-based screen and bioactivity-guided purification, we identified alisol B 23-acetate, alisol A 24-acetate, and alisol B from the rhizome of Alisma orientale as novel inducers of autophagy, with alisol B being the most potent natural product. Across several cancer cell lines, we showed that alisol B-treated cells displayed an increase of autophagic flux and formation of autophagosomes, leading to cell cycle arrest at the G(1) phase and cell death. Alisol B induced calcium mobilization from internal stores, leading to autophagy through the activation of the CaMKK-AMPK-mammalian target of rapamycin pathway. Moreover, the disruption of calcium homeostasis induces endoplasmic reticulum stress and unfolded protein responses in alisol B-treated cells, leading to apoptotic cell death. Finally, by computational virtual docking analysis and biochemical assays, we showed that the molecular target of alisol B is the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase. This study provides detailed insights into the cytotoxic mechanism of a novel antitumor compound.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Colestenonas/farmacologia , Retículo Endoplasmático/efeitos dos fármacos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , Estresse Fisiológico/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Retículo Endoplasmático/patologia , Inibidores Enzimáticos/farmacologia , Células HeLa , Humanos , Concentração Inibidora 50 , Camundongos , Modelos Biológicos , Resposta a Proteínas não Dobradas/efeitos dos fármacos
2.
J Org Chem ; 68(11): 4195-205, 2003 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-12762718

RESUMO

An approach toward the synthesis of the antifungal and cytotoxic pseudolaric acids based on the tandem metal carbene cyclization-cycloaddition reaction is described. Using this strategy, the advanced intermediate 3a bearing three of the four stereocenters of the target molecules has been synthesized. The substrate-controlled diastereoselectivity of the tandem carbene cyclization-cycloaddition was preferential for the undesired diastereomer, but reagent control through the use of Hashimoto's chiral rhodium catalyst Rh(2)(S-BPTV)(4) reversed the selectivity in favor of 3a. Ring opening of the oxabicyclic nucleus to give a hydroxycycloheptene has been demonstrated in a model study.


Assuntos
Antifúngicos/síntese química , Antineoplásicos/síntese química , Técnicas de Química Combinatória , Diterpenos/síntese química , Metano/análogos & derivados , Metano/química , Modelos Moleculares , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Catálise , Ciclização , Diterpenos/farmacologia , Hidrocarbonetos , Indicadores e Reagentes , Estereoisomerismo
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