Design, Synthesis and Biological Evaluation of Neocryptolepine Derivatives as Potential Anti-Gastric Cancer Agents.

Natural products play an important role in drug development and lead compound synthesis. Neocryptolepine is a polycyclic quinoline compound isolated from . The cytotoxicity of neocryptolepine to gastric cancer cells AGS, MKN45, HGC27, and SGC7901 was not very strong, and it also had certain toxicity to gastric mucosa cells GES-1. Therefore, a series of neocryptolepine derivatives were synthesized by the modification of the structure of neocryptolepine, and their cytotoxicity was evaluated. The results showed that compounds and exhibited strong cytotoxicity to AGS cells. The cell colony formation and cell migration experiments suggested that compounds and could inhibit the proliferation and cell migration of AGS and HGC27 cells. Cell cycle and apoptosis experiments showed that compounds and did not cause the apoptosis of AGS and HGC27 cells but, mainly, caused cell necrosis. Compound had no significant effect on AGS and HGC27 cell cycles at low concentration. After treatment with AGS cells for 24 h at high concentration, compound could significantly arrest the AGS cell cycle in the G2/M phase. Compound had no significant effect on the AGS and HGC27 cell cycles. The results of molecular docking and Western blot showed that compounds and might induce cytotoxicity through the PI3K/AKT signaling pathway. Therefore, compounds and may be promising lead compounds for the treatment of gastric cancer.