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

• DOI: 10.1016/j.ejmech.2015.03.005
• Publication Date: 2015-03-05T04:56:44Z
• Authors: Barbara Parrino; Anna Carbone; Cristina Ciancimino; Virginia Spanò; Alessandra Montal...; Paola Barraja; Girolamo Cirrincione; Patrizia Diana; Claudia Sissi; Manlio Palumbo; Odra Pinato; Marzia Pennati; Giovanni Beretta; Marco Folini; Peter Matyus; Balázs Balogh; Nadia Zaffaroni
• Keywords: 0301 basic medicine; Antitubulin agents; G-quadruplex interaction; Isoindolo[2; 1-a]quinoxalin-6-imines; Topoisomerase I inhibitors; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry; Pharmacology; Cell Cycle; Water; Antineoplastic Agents; Apoptosis; Microtubules; Antitubulin agents; G-quadruplex interaction; Isoindolo[2,1-a]quinoxalin-6-imines; Topoisomerase I inhibitors; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry; Pharmacology; 3. Good health; 03 medical and health sciences; DNA Topoisomerases, Type I; Solubility; Tubulin; Cell Line, Tumor; Quinoxalines; Humans; Imines; Drug Screening Assays, Antitumor; Cell Proliferation

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.