title: 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.
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Conconi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marzaro
authors.forename: Luca
authors.initials: L
authors.lastname: Urbani
authors.forename: Ilenia
authors.initials: I
authors.lastname: Zanusso
authors.forename: Rosa
authors.initials: R
authors.lastname: Di Liddo
authors.forename: Ignazio
authors.initials: I
authors.lastname: Castagliuolo
authors.forename: Paola
authors.initials: P
authors.lastname: Brun
authors.forename: Francesca
authors.initials: F
authors.lastname: Tonus
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ferrarese
authors.forename: Adriano
authors.initials: A
authors.lastname: Guiotto
authors.forename: Adriana
authors.initials: A
authors.lastname: Chilin
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011505:Protein-Tyrosine Kinases
keywords: 3-(4,5-dimethylthiazol-2-yl)-2,5-dimethyltetrazolium bromide; 3-(N-morpholino)propanesulfonic acid; 4′,6-diamidino-2-phenylindole; ADT; Angiogenesis; Anilinoquinazoline; AutoDock Tools; BSA; CAN; Cancer therapy; DAPI; DMEM; DMF; DTT; Dulbecco's modified eagle medium; EC; EDTA; EGF; EGFR; EGTA; ELISA; FBS; FCS; FGF; FGFR-1; GFR; HMTA; HUVEC; IGF; MOPS; MTT; Multi-kinase inhibitors; PDB; PDGF; PDGFRβ; Protein Data Bank; RTK; SDS-PAGE; TEA; TFA; THF; TK; TKI; VEGF; VEGFR-1 and 2; bovine serum albumin; cerium ammonium nitrate; dimethylformamide; dithiothreitol; endothelial cell; enzyme-linked immunoassorbent assay; epidermal growth factor; epidermal growth factor receptor; ethylene glycol tetraacetic acid; ethylenediaminetetraacetic acid; fetal bovine serum; fetal calf serum; fibroblast growth factor; fibroblast growth factor receptor 1; growth factor reduced; hexamethylenetetramine; human umbilical vein endothelial cell; insulin-like growth factor; platelet-derived growth factor; platelet-derived growth factor receptor β; receptor tyrosine kinase; sodium dodecyl sulfate polyacrylamide gel electrophoresis; tetrahydrofuran; triethylamine; trifluoroacetic acid; tyrosine kinase; tyrosine kinase inhibitor; vascular endothelial growth factor; vascular endothelial growth factor receptor 1 and 2