Synthesis and Antitumor Activity of 1,5-Disubstituted 1,2,4-Triazoles as Cis-Restricted Combretastatin Analogues
| Autor: | Maria Dora Carrion, Olga Cruz-Lopez, Giampietro Viola, Roberta Bortolozzi, Longchuan Chen, Pier Giovanni Baraldi, Andrea Brancale, Ernest Hamel, Carlota Lopez Cara, Romeo Romagnoli, Giuseppe Basso |
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| Rok vydání: | 2010 |
| Předmět: |
G2 Phase
Models Molecular Angiogenesis Inhibitors Antineoplastic Agents Apoptosis Chick Embryo Jurkat cells Article HeLa Structure-Activity Relationship chemistry.chemical_compound Tubulin Cell Line Tumor Bibenzyls Drug Discovery Animals Humans Cell Shape Cells Cultured Membrane Potential Mitochondrial Combretastatin biology Caspase 3 Endothelial Cells Depolarization Triazoles Cell cycle biology.organism_classification Tubulin Modulators Mitochondria Enzyme Activation Endothelial stem cell Proto-Oncogene Proteins c-bcl-2 Biochemistry chemistry Cell culture Molecular Medicine Drug Screening Assays Antitumor Poly(ADP-ribose) Polymerases Colchicine Reactive Oxygen Species Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 53:4248-4258 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm100245q |
| Popis: | A series of 1-aryl-5-(3',4',5'-trimethoxyphenyl) derivatives and their related 1-(3',4',5'-trimethoxyphenyl)-5-aryl-1,2,4-triazoles, designed as cis-restricted combretastatin analogues, were synthesized and evaluated for antiproliferative activity, inhibitory effects on tubulin polymerization, cell cycle effects, and apoptosis induction. Their activity was greater than, or comparable with, that of the reference compound CA-4. Flow cytometry studies showed that HeLa and Jurkat cells treated with the most active compounds 4l and 4o were arrested in the G2/M phase of the cell cycle in a concentration dependent manner. This effect was accompanied by apoptosis of the cells, mitochondrial depolarization, generation of reactive oxygen species, activation of caspase-3, and PARP cleavage. Compound 4l was also shown to have potential antivascular activity, since it induced endothelial cell shape change in vitro and disrupted the sprouting of endothelial cells in the chick aortic ring assay. |
| Databáze: | OpenAIRE |
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