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Water-soluble isoindolo[2,1-a]quinoxalin-6-imines: in vitro antiproliferative activity and molecular mechanism(s) of action.

Authors: Barbara B. Parrino, Anna A. Carbone, Cristina C. Ciancimino, Virginia V. Spanò, Alessandra A. Montalbano, Paola P. Barraja, Girolamo G. Cirrincione, Patrizia P. Diana, Claudia C. Sissi, Manlio M. Palumbo, Odra O. Pinato, Marzia M. Pennati, Giovanni G. Beretta, Marco M. Folini, Peter P. Matyus, Balázs B. Balogh, Nadia N. Zaffaroni
Published: 03/05/2015, European journal of medicinal chemistry


Water-soluble isoindoloquinoxalin (IIQ) imines and the corresponding acetates were conveniently prepared from the key intermediates 2-(2'-aminophenyl)-2H-isoindole-1-carbonitriles obtained by a Strecker reaction between substituted 1,2-dicarbaldehydes and 1,2-phenylenediamines. Both series were screened by the National Cancer Institute (Bethesda, MD) and showed potent antiproliferative activity against a panel of 60 human tumor cell lines. Several of the novel compounds showed GI50 values at a nanomolar level on the majority of the tested cell lines. Among IIQ derivatives, methoxy substituents at positions 3 and 8 or/and 9 were especially effective in impairing cell cycle progression and inducing apoptosis in cancer cells. These effects were associated to IIQ-mediated impairment of tubulin polymerization at pharmacologically significant concentrations of tested compounds. In addition, impaired DNA topoisomerase I functions and perturbation in telomere architecture were observed in cells exposed to micromolar concentrations of IIQ derivatives. The above results suggest that IIQ derivatives exhibit multi-target cytotoxic activities.

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