In this work the synthesis and the biological evaluation of some novel anilinoquinazoline derivatives carrying modifications in the quinazoline scaffold and in the aniline moiety were reported. Preliminary cytotoxicity studies identified three derivatives, carrying dioxygenated rings fused on the quinazoline portion and the biphenylamino substituent as aniline portion, as the most effective compounds. Further investigations revealed that these compounds exhibited antiproliferative activity on a wide panel of human tumor cell lines through the inhibition of both receptor and non receptor TKs. Furthermore, the compound bearing the dioxolane nucleus was also able to inhibit in vivo tumor growth. Molecular modeling of these compounds into kinase domain suggested that the phenyl group allows favourable interaction energies with the target proteins: this feature is favoured by fused dioxygenated ring at the 6,7 positions, whereas free rotating functions do not allow the correct placement of the molecule, thus impairing the inhibitory potency. Finally, the biphenylamino derivatives, at non cytotoxic concentrations, acted as antiangiogenic agents both in in vitro and in vivo assays.

Quinazoline-based multi-tyrosine kinase inhibitors: synthesis, modeling, antitumor and antiangiogenic properties

CONCONI, MARIA TERESA;MARZARO, GIOVANNI;URBANI, LUCA;ZANUSSO, ILENIA;DI LIDDO, ROSA;CASTAGLIUOLO, IGNAZIO;BRUN, PAOLA;TONUS, FRANCESCA;FERRARESE, ALESSANDRO;GUIOTTO, ADRIANO;CHILIN, ADRIANA
2013

Abstract

In this work the synthesis and the biological evaluation of some novel anilinoquinazoline derivatives carrying modifications in the quinazoline scaffold and in the aniline moiety were reported. Preliminary cytotoxicity studies identified three derivatives, carrying dioxygenated rings fused on the quinazoline portion and the biphenylamino substituent as aniline portion, as the most effective compounds. Further investigations revealed that these compounds exhibited antiproliferative activity on a wide panel of human tumor cell lines through the inhibition of both receptor and non receptor TKs. Furthermore, the compound bearing the dioxolane nucleus was also able to inhibit in vivo tumor growth. Molecular modeling of these compounds into kinase domain suggested that the phenyl group allows favourable interaction energies with the target proteins: this feature is favoured by fused dioxygenated ring at the 6,7 positions, whereas free rotating functions do not allow the correct placement of the molecule, thus impairing the inhibitory potency. Finally, the biphenylamino derivatives, at non cytotoxic concentrations, acted as antiangiogenic agents both in in vitro and in vivo assays.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/2666452
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