TY - JOUR
T1 - Design, Synthesis and Biological Evaluation of Neocryptolepine Derivatives as Potential Anti-Gastric Cancer Agents
AU - Ma, Yunhao
AU - Tian, Yanan
AU - Zhou, Zhongkun
AU - Chen, Shude
AU - Du, Kangjia
AU - Zhang, Hao
AU - Jiang, Xinrong
AU - Lu, Juan
AU - Niu, Yuqing
AU - Tu, Lixue
AU - Wang, Jie
AU - Liu, Huanxiang
AU - Zhu, Hongmei
AU - Chen, Peng
AU - Liu, Yingqian
N1 - Publisher Copyright:
© 2022 by the authors.
PY - 2022/10
Y1 - 2022/10
N2 - 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.
AB - 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.
KW - AGS cell
KW - AKT
KW - HGC27 cell
KW - PI3K/AKT signaling pathway
KW - neocryptolepine derivatives
UR - http://www.scopus.com/inward/record.url?scp=85139941892&partnerID=8YFLogxK
U2 - 10.3390/ijms231911924
DO - 10.3390/ijms231911924
M3 - Article
C2 - 36233226
AN - SCOPUS:85139941892
SN - 1661-6596
VL - 23
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 19
M1 - 11924
ER -