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

Barbara Parrino, Anna Carbone, Cristina Ciancimino, Virginia Spanò, Alessandra Montalbano, Paola Barraja, Girolamo Cirrincione, Patrizia Diana, Claudia Sissi, Manlio Palumbo, Odra Pinato, Marzia Pennati, Giovanni Beretta, Marco Folini, Peter Matyus, Balázs Balogh, Nadia Zaffaroni

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Abstract

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.

Original languageEnglish
Pages (from-to)149-162
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume94
DOIs
Publication statusPublished - Apr 13 2015

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Keywords

  • Antitubulin agents
  • G-quadruplex interaction
  • Isoindolo[2,1-a]quinoxalin-6-imines
  • Topoisomerase I inhibitors

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Parrino, B., Carbone, A., Ciancimino, C., Spanò, V., Montalbano, A., Barraja, P., Cirrincione, G., Diana, P., Sissi, C., Palumbo, M., Pinato, O., Pennati, M., Beretta, G., Folini, M., Matyus, P., Balogh, B., & Zaffaroni, N. (2015). Water-soluble isoindolo[2,1-a]quinoxalin-6-imines: In vitro antiproliferative activity and molecular mechanism(s) of action. European Journal of Medicinal Chemistry, 94, 149-162. https://doi.org/10.1016/j.ejmech.2015.03.005