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

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 nonreceptor 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 favorable interaction energies with the target proteins: this feature is favored 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 noncytotoxic concentrations, acted as antiangiogenic agents both in in vitro and in vivo assays.
AuthorsMaria Teresa Conconi, Giovanni Marzaro, Luca Urbani, Ilenia Zanusso, Rosa Di Liddo, Ignazio Castagliuolo, Paola Brun, Francesca Tonus, Alessandro Ferrarese, Adriano Guiotto, Adriana Chilin
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 67 Pg. 373-83 (Sep 2013) ISSN: 1768-3254 [Electronic] France
PMID23900004 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Masson SAS. All rights reserved.
Chemical References
  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Quinazolines
  • Protein-Tyrosine Kinases
Topics
  • Angiogenesis Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Animals
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • HT29 Cells
  • HeLa Cells
  • Humans
  • MCF-7 Cells
  • Mice
  • Models, Molecular
  • Molecular Structure
  • NIH 3T3 Cells
  • Neovascularization, Pathologic (drug therapy)
  • Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
  • Quinazolines (chemical synthesis, chemistry, pharmacology)
  • Structure-Activity Relationship

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