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

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

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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.
Lingua originaleEnglish
pagine (da-a)2387-2399
RivistaJournal of Medicinal Chemistry
Volume51
Stato di pubblicazionePublished - 2008

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Quinoxalines
Type I DNA Topoisomerase
formic acid
Tubulin
Polymerization
Antineoplastic Agents
Topoisomerase I Inhibitors
Cell Line
Mitotic Index
National Cancer Institute (U.S.)
Caspase 9
G2 Phase
Cell Cycle Checkpoints
Tumor Cell Line
Microtubules
Caspase 3
Acetic Acid
Cell Division
Reactive Oxygen Species
Cell Cycle

All Science Journal Classification (ASJC) codes

  • Medicine(all)
  • Molecular Medicine
  • Drug Discovery

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title = "ISOINDOLO[2,1-a]QUINOXALINE DERIVATIVES, NOVEL POTENT ANTITUMOR AGENTS WITH DUAL INHIBITION OF TUBULIN POLYMERIZATION AND TOPOISOMERASE I",
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.",
author = "Gaetano Dattolo and Patrizia Diana and Paola Barraja and Annamaria Martorana and Girolamo Cirrincione and Alessandra Montalbano and Alessia Salvador and Daniela Vedaldi and Francesco Dall'Acqua and Giampietro Viola and Giuseppe Basso",
year = "2008",
language = "English",
volume = "51",
pages = "2387--2399",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",

}

TY - JOUR

T1 - ISOINDOLO[2,1-a]QUINOXALINE DERIVATIVES, NOVEL POTENT ANTITUMOR AGENTS WITH DUAL INHIBITION OF TUBULIN POLYMERIZATION AND TOPOISOMERASE I

AU - Dattolo, Gaetano

AU - Diana, Patrizia

AU - Barraja, Paola

AU - Martorana, Annamaria

AU - Cirrincione, Girolamo

AU - Montalbano, Alessandra

AU - Salvador, Alessia

AU - Vedaldi, Daniela

AU - Dall'Acqua, Francesco

AU - Viola, Giampietro

AU - Basso, Giuseppe

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

UR - http://hdl.handle.net/10447/12965

M3 - Article

VL - 51

SP - 2387

EP - 2399

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

ER -