Isoindolo[2,1-a]quinoxaline derivatives, novel potent antitumor agents with dual inhibition of tubulin polymerization and topoisomerase I.
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.
Diana
Patrizia
P
Dipartimento Farmacochimico Tossicologico e Biologico, Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy. diana@unipa.it
Martorana
Annamaria
A
Barraja
Paola
P
Montalbano
Alessandra
A
Dattolo
Gaetano
G
Cirrincione
Girolamo
G
Dall'acqua
Francesco
F
Salvador
Alessia
A
Vedaldi
Daniela
D
Basso
Giuseppe
G
Viola
Giampietro
G
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008856:Microscopy, Fluorescence; D008938:Mitosis / Q000187:drug effects; D011108:Polymers / Q000737:chemistry*; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013055:Spectrophotometry, Infrared; D059004:Topoisomerase I Inhibitors; D014404:Tubulin / Q000737:chemistry / Q000187:drug effects*
D000970:Antineoplastic Agents; D011108:Polymers; D011810:Quinoxalines; D017382:Reactive Oxygen Species; D059004:Topoisomerase I Inhibitors; D014404:Tubulin; D020169:Caspases