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Natural products play an important role in drug development and lead compound synthesis. Neocryptolepine is a polycyclic quinoline compound isolated from <i>Cryptolepis sanguinolent</i>. 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 <b>C5</b> and <b>C8</b> exhibited strong cytotoxicity to AGS cells. The cell colony formation and cell migration experiments suggested that compounds <b>C5</b> and <b>C8</b> could inhibit the proliferation and cell migration of AGS and HGC27 cells. Cell cycle and apoptosis experiments showed that compounds <b>C5</b> and <b>C8</b> did not cause the apoptosis of AGS and HGC27 cells but, mainly, caused cell necrosis. Compound <b>C5</b> 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 <b>C5</b> could significantly arrest the AGS cell cycle in the G2/M phase. Compound <b>C8</b> had no significant effect on the AGS and HGC27 cell cycles. The results of molecular docking and Western blot showed that compounds <b>C5</b> and <b>C8</b> might induce cytotoxicity through the PI3K/AKT signaling pathway. Therefore, compounds <b>C5</b> and <b>C8</b> may be promising lead compounds for the treatment of gastric cancer.