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RESEARCH PRODUCT
Water-soluble isoindolo[2,1-a]quinoxalin-6-imines: In vitro antiproliferative activity and molecular mechanism(s) of action
Claudia SissiPaola BarrajaPatrizia DianaMarzia PennatiOdra PinatoGirolamo CirrincioneVirginia SpanòCristina CianciminoManlio PalumboBarbara ParrinoNadia ZaffaroniAlessandra MontalbanoPéter MátyusMarco FoliniAnna CarboneGiovanni Luca BerettaBalázs Baloghsubject
StereochemistryStrecker amino acid synthesisAntineoplastic AgentsApoptosisIsoindolo[21-a]quinoxalin-6-imineTopoisomerase I inhibitorsTopoisomerase-I InhibitorMicrotubulesTubulinCell Line TumorQuinoxalinesDrug DiscoveryHumansCytotoxic T cellCell ProliferationPharmacologyTopoisomerase I inhibitorChemistryAntitubulin agents; G-quadruplex interaction; Isoindolo[2; 1-a]quinoxalin-6-imines; Topoisomerase I inhibitors; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry; PharmacologyAntitubulin agentsDrug Discovery3003 Pharmaceutical ScienceCell CycleOrganic ChemistryWaterGeneral MedicineSettore CHIM/08 - Chimica FarmaceuticaIn vitroTelomereAntitubulin agentAntitubulin agents; G-quadruplex interaction; Isoindolo[21-a]quinoxalin-6-imines; Topoisomerase I inhibitors; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry; Pharmacology1-a]quinoxalin-6-iminesDNA Topoisomerases Type ISolubilityBiochemistryCell cultureApoptosisIsoindolo[2Cancer cellIminesG-quadruplex interactionDrug Screening Assays Antitumordescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2015-01-01 |