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 GI50 values in the low micromolar or submicromolar range and reached, in the case of 4c, nanomolar concentrations on88% 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.
|Rivista||Journal of Medicinal Chemistry|
|Stato di pubblicazione||Published - 2008|
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Drug Discovery
Dattolo, G., Diana, P., Martorana, A., Cirrincione, G., Montalbano, A., Barraja, P., Salvador, A., Vedaldi, D., Dall'Acqua, F., Viola, G., & Basso, G. (2008). ISOINDOLO[2,1-a]QUINOXALINE DERIVATIVES, NOVEL POTENT ANTITUMOR AGENTS WITH DUAL INHIBITION OF TUBULIN POLYMERIZATION AND TOPOISOMERASE I. Journal of Medicinal Chemistry, 51, 2387-2399.