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

**Yunhao Ma 1,†, Yanan Tian 1,†, Zhongkun Zhou 1, Shude Chen 2, Kangjia Du 1, Hao Zhang 1, Xinrong Jiang 1, Juan Lu 1, Yuqing Niu 1, Lixue Tu 1, Jie Wang 1, Huanxiang Liu 1, Hongmei Zhu 1, Peng Chen 1,\* and Yingqian Liu 1,\***

	- † These authors contributed equally to this work.

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

**Keywords:** neocryptolepine derivatives; AKT; AGS cell; HGC27 cell; PI3K/AKT signaling pathway
