Isoindolo[2,1-a]quinoxaline Derivatives, Novel Potent Antitumor Agents with Dual Inhibition of Tubulin Polymerization and Topoisomerase I
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- 作者：Patrizia Diana ; Annamaria Martorana ; Paola Barraja ; Alessandra Montalbano ; Gaetano Dattolo ; Girolamo Cirrincione ; Francesco Dall’ ; Acqua ; Alessia Salvador ; Daniela Vedaldi ; Giuseppe Basso ; Giampie
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：April 24, 2008
- 年：2008
- 卷：51
- 期：8
- 页码：2387 - 2399
- 全文大小：1130K
- 年卷期：v.51,no.8(April 24, 2008)
- ISSN：1520-4804
文摘
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 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.