title: Water-soluble isoindolo[2,1-a]quinoxalin-6-imines: in vitro antiproliferative activity and molecular mechanism(s) of action.
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.
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Parrino
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Carbone
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ciancimino
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Spanò
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Montalbano
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Barraja
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy.
authors.forename: Girolamo
authors.initials: G
authors.lastname: Cirrincione
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy. Electronic address: diana@unipa.it.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Diana
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, Via Marzolo 5, 35131 Padova, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sissi
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, Via Marzolo 5, 35131 Padova, Italy.
authors.forename: Manlio
authors.initials: M
authors.lastname: Palumbo
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, Via Marzolo 5, 35131 Padova, Italy.
authors.forename: Odra
authors.initials: O
authors.lastname: Pinato
authors.affiliation: Dept. of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, Milano, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Pennati
authors.affiliation: Dept. of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, Milano, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Beretta
authors.affiliation: Dept. of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Folini
authors.affiliation: Department of Organic Chemistry, Semmelweis University, Högyes E. u. 7, H-1092 Budapest, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Matyus
authors.affiliation: Department of Organic Chemistry, Semmelweis University, Högyes E. u. 7, H-1092 Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Balogh
authors.affiliation: Dept. of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, Milano, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D007097:Imines / Q000737:chemistry; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D011810:Quinoxalines / Q000737:chemistry; D012995:Solubility; D014404:Tubulin / Q000378:metabolism; D014867:Water
chemical_list: D000970:Antineoplastic Agents; D007097:Imines; D011810:Quinoxalines; D014404:Tubulin; D014867:Water; D004264:DNA Topoisomerases, Type I
keywords: Antitubulin agents; G-quadruplex interaction; Isoindolo[2,1-a]quinoxalin-6-imines; Topoisomerase I inhibitors