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

European Journal of Medicinal Chemistry
Barbara ParrinoNadia Zaffaroni

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.

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Citations

Aug 22, 2015·European Journal of Medicinal Chemistry·Virginia SpanòPaola Barraja
Dec 25, 2015·Journal of Photochemistry and Photobiology. B, Biology·Soňa JantováZuzana Barbieriková
Mar 18, 2015·European Journal of Medicinal Chemistry·Barbara ParrinoPatrizia Diana
Jul 19, 2016·Journal of Medicinal Chemistry·Virginia SpanòNadia Zaffaroni
Sep 20, 2016·European Journal of Medicinal Chemistry·Virginia SpanòPaola Barraja
Nov 22, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Barbara ParrinoPatrizia Diana
Aug 8, 2018·Marine Drugs·Anna CarboneStella Cascioferro
Jan 11, 2019·Marine Drugs·Stella CascioferroBarbara Parrino
Jan 18, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Stella CascioferroPatrizia Diana
Jan 25, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ahmed T A BoraeiAssem Barakat
Feb 7, 2020·Future Medicinal Chemistry·Barbara ParrinoStella Cascioferro
Mar 6, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Wenzhi WangQingguo Meng
Dec 5, 2018·European Journal of Medicinal Chemistry·M MontanaP Vanelle
Oct 10, 2020·European Journal of Medicinal Chemistry·Barbara ParrinoPatrizia Diana
Nov 24, 2020·Bioorganic & Medicinal Chemistry·Sandeep SundriyalVibhudutta Awasthi
Jun 3, 2021·International Journal of Molecular Sciences·Irene AlessandriniMarco Folini

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