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.

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.