ISOINDOLO[2,1-a]QUINOXALINE DERIVATIVES, NOVEL POTENT ANTITUMOR AGENTS WITH DUAL INHIBITION OF TUBULIN POLYMERIZATION AND TOPOISOMERASE I

Gaetano Dattolo, Patrizia Diana, Girolamo Cirrincione, Paola Barraja, Annamaria Martorana, Alessandra Montalbano, Alessia Salvador, Daniela Vedaldi, Francesco Dall'Acqua, Giampietro Viola, Giuseppe Basso

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84 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)2387-2399
JournalJournal of Medicinal Chemistry
Volume51
Publication statusPublished - 2008

All Science Journal Classification (ASJC) codes

  • Medicine(all)
  • Molecular Medicine
  • Drug Discovery

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