Design and Synthesis of Structurally Tailored 4H-Pyran Derivatives as Potent Therapeutics for Precision Gastric Cancer Targeting

Abstract

Objective: To discover novel small-molecule anticancer agents, we designed and synthesized a series of structurally diverse 4H-pyran derivatives 2a–2g and evaluated their antiproliferative activity against human gastric cancer cells. Methods: A one-pot multicomponent reaction strategy was systematically optimized by screening solvents, catalyst loadings, reaction times, and reactant molar ratios. The optimized protocol—utilizing 4-dimethylaminopyridine (DMAP) as an organocatalyst in ethanol—afforded the target heterocycles under mild conditions within 20 min in high yields (80–91%). Structure–activity relationship (SAR) analysis revealed that the electronic properties and regiochemistry of the phenyl ring substituents heavily dictated both synthetic efficiency and cytotoxicity. Results and Discussion: Notably, the para-fluoro 2a and para-methyl 2d derivatives exhibited the most potent antiproliferative effects against SGC-7901 cells, with half-maximal inhibitory concentrations (IC₅₀) values of 10.81 ± 0.32 and 12.73 ± 0.24 μM, respectively, significantly outperforming the reference flavonoid apigenin (IC₅₀ = 29.47 ± 0.27 μM). These findings underscore the dual role of electronic effects in modulating chemical reactivity and biological efficacy. Conclusions: establishing a rapid, sustainable synthetic framework and identifying promising lead candidates for preclinical anticancer drug development.