Design, Synthesis, and Antitumor Activity Evaluation of Novel 2,4,7-Trisubstituted Quinazoline Derivatives Containing an Aminomethyl Piperidine Moiety

Abstract

Objective: In order to discover new antitumor small molecules, research has been conducted on quinazoline derivatives to explore potential new compounds. Methods: A series of 2,4,7-trisubstituted quinazoline derivatives containing an aminomethyl piperidine moiety were designed and synthesized. The MTT assay was used to evaluate the inhibitory effect of the compounds on the proliferation of various tumor cell lines (Eca-109, A549, PC-3, MGC-803), and the IC₅₀ values were calculated. Cell cycle analysis, cell migration assays, colony formation assays, and apoptosis assays were performed to investigate the antitumor mechanism of compound (XVIe). Results and Discussion: Compound (XVIe) exhibited the most potent antiproliferative activity against MGC-803 cells, with an IC₅₀ value of 0.74 μM, significantly lower than that of 5-fluorouracil. Additionally, compound (XVIe) effectively inhibited the migration and colony formation of MGC-803 cells, induced G0/G1 phase arrest, and increased ROS accumulation, ultimately leading to apoptosis of MGC-803 cells. Meta-substituents in the benzene ring demonstrated superior antiproliferative activity compared to para- and ortho-substituents. The sequence of antiproliferative activity for the meta-substituted compounds against the four cancer cell lines was: methyl > ethoxy > fluorine ≈ methoxy > chlorine. Conclusions: Compound (XVIe) demonstrated significant antitumor activity and holds potential for further development as an antitumor drug.