Isoindolo[2,1-a]quinoxaline derivatives, novel potent antitumor agents with dual inhibition of tubulin polymerization and topoisomerase I
| Autor: | Alessia Salvador, Paola Barraja, Daniela Vedaldi, Gaetano Dattolo, Giampietro Viola, Alessandra Montalbano, Girolamo Cirrincione, Giuseppe Basso, Annamaria Martorana, Francesco Dall'Acqua, Patrizia Diana |
|---|---|
| Přispěvatelé: | DIANA P, MARTORANA A, BARRAJA P, MONTALBANO A, DATTOLO G, CIRRINCIONE G, DALL'ACQUA F, SALVADOR A, VEDALDI D, BASSO G, VIOLA G |
| Rok vydání: | 2008 |
| Předmět: |
Mitotic index
Magnetic Resonance Spectroscopy Spectrophotometry Infrared Polymers FLUORESCENT-PROBE LIGAND-DNA SYSTEMS Mitosis CELL-LINES Antineoplastic Agents ACRIDINE-ORANGE Topoisomerase-I Inhibitor MITOCHONDRIA Tubulin Cell Line Tumor Quinoxalines Drug Discovery Humans Cytotoxicity biology Chemistry Topoisomerase B-DNA Cell Cycle Cell cycle APOPTOSIS CD Enzyme Activation MICROTUBULES Biochemistry Microscopy Fluorescence Cell culture Apoptosis Enzyme inhibitor LINEAR DICHROISM SPECTROSCOPY Caspases biology.protein Molecular Medicine Drug Screening Assays Antitumor Topoisomerase I Inhibitors Reactive Oxygen Species |
| Zdroj: | Journal of medicinal chemistry. 51(8) |
| ISSN: | 0022-2623 |
| Popis: | Isoindoloquinoxalines 4 and 5 were obtained by refluxing 2-(2'-aminoaryl)-1-cyanoisoindoles 3a- e in acetic or formic acid. All derivatives were screened by the National Cancer Institute (Bethesda, MD) for the in vitro one dose primary anticancer assay against a 3-cell line panel. Compounds 4a- e, screened against a panel of about 60 human tumor cell lines, showed remarkable antineoplastic activity; they had GI 50 values in the low micromolar or submicromolar range and reached, in the case of 4c, nanomolar concentrations on 88% of the 59 tested cell lines. Flow cytometric analysis of cell cycle after treatment with 4c demonstrated an arrest of the cell cycle in G2/M phase. This effect was accompanied with apoptosis of the cells, mitochondrial depolarization, generation of reactive oxygen species, and activation of caspase-3 and caspase-9. Moreover, 4c induced a clear increase in the mitotic index, inhibited microtubule assembly in vitro, and interestingly also acted as a topoisomerase I inhibitor. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|