Novel promising 4-anilinoquinazoline-based derivatives as multi-target RTKs inhibitors: Design, molecular docking, synthesis, and antitumor activities in vitro and vivo

摘要

4-Anilinoquinazoline derivatives function as tyrosine kinase inhibitors (TKIs). Novel TKIs are needed for cancer mutations and drug-resistant cells. We designed and synthesized 4-anilinoquinazoline derivatives with substitutions at quinazoline positions 6, 7 and 4 using a binding model with multi-target receptor tyrosine kinases, and assessed their antitumor activity against five human tumor cell lines (HepG2, A549, MCF-7, DU145, SH-SY5Y). The majority of the compounds inhibited the proliferation of all the cancer cell types, with some compounds displaying selective inhibition. Compounds 21, 25, 27, and 37 displayed IC50 values of 7.588, 8.619, 6.936, and 8.516 mu M, respectively, for A549 cells, which were much lower than that of Gefitinib (14.803 mu M). Compound 32 displayed an IC50 value of 2.756 mu M for DU145 cells. The representative compound 40 had unexceptionable broad-spectrum inhibition for all cancer cell types, and demonstrate inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFR-beta), and epidermal growth factor receptor (EGFR) with IC50 values of 46.4, 673.6 and 384.8 nM, respectively, which were similar to those of Sorafenib for VEGFR-2 and PDGFR-beta (140.6 and 582.7 nM, respectively). Molecular docking results supported the molecular level assay results. Data for production of reactive oxygen species and assessment of matrix metalloproteinase corroborated the strong anti-proliferative effect of compound 40. The compound also displayed robust antitumor efficacy and relativity lower toxicity in a xenograft model. These attributes were similar to those of Sorafenib. Compound 40 drug warrants further study as a candidate.