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Bioorg Chem ; 93: 103329, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31590040

RESUMO

3-Amino-1-aryl-1H-benzo[f]chromene-2-carbonitrile derivatives were synthesized from three-component reaction of arylaldehyde, malononitrile and 2-naphthol in the presence of 1, 4-bis(4-ferrocenylbutyl)piperazine as a new catalyst. Cytotoxic potencies of the compounds were tested on HT-29 cells. 3-Amino-1-(4-fluorophenyl)-1H-benzo[f]chromene-2-carbonitrile (4c) was more active among these compounds and was selected for further studies. Apoptosis was investigated by acridine orange/ethidium bromide (AO/EtBr) double staining and flow cytometry. The qRT-PCR was used to analyze the expression of pro- and anti-apoptotic genes. The binding attributes of 4c with calf thymus DNA (ctDNA) was examined using multi-spectroscopic measurements. We found that 4c had potent cytotoxic activity against HT-29 cells with an IC50 value of 60 µM through induction of cell cycle arrest in the sub-G1 phase and apoptosis. RT-PCR analysis demonstrated down-regulation of Bcl-2 expression, while the expression of Bax, caspase-3, -8 and -9 genes was up-regulated in HT-29 cells incubated with 4c compared with control cells. These studies revealed that 4c interacts with DNA through groove binding mode with the intrinsic binding constant (Kb) of 3 × 102 M-1. Thus, 4c is a valuable candidate for further evaluation as a new series of potent chemotherapeutic family in colon cancer treatment.


Assuntos
Apoptose/efeitos dos fármacos , Benzeno/química , Benzopiranos/síntese química , Benzopiranos/farmacologia , Caspases/metabolismo , Proliferação de Células/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo , Apoptose/genética , Benzopiranos/química , Células HT29 , Humanos
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