Design and green synthesis of asymmetric 3,4,5-trimethoxyphenyl-inspired 1,5-diaryl-1,4-pentadien-3-ones as potent anti-gastric cancer agents through ROS and JNK-triggered apoptosis

Asymmetric 1,5-diheteroarylpenta-1,4-dien-3-one skeleton and 3,4,5-trimethoxy- phenyl group could be regarded as potent elements for designing chemotherapy agents, respectively. With the disadvantages of previous synthesis, a greener and simple procedure was developed for one-step synthesis of (E)-4(3,4,5- trimethoxypheyl)but-3-en-2-one intermediate under the Cs₂CO₃/EtOH/H₂O system. Hence, a series of asymmetric 1,5-diaryl-1,4-pentadien-3-ones inspired 3,4,5-trimethoxyphenyl were designed, optimized synthesized and investigated the anti-gastric cancer activity. Among them, most compounds showed good anti-gastric cancer activity. The quantitative structure-activity relationship models (QSAR) of compounds were constructed through by random forest algorithm and R² in two tumor cells were greater than 0.88. Compound 7c was elucidated to inhibit tumor growth, migration, and trigger death of SGC-7901 cells by up-regulating the generation of ROS and JNK-related apoptosis. In total, a greener system for synthesizing intermediates is provided, and compound 7c may serve as a potential chemotherapy agent for gastric cancer.