jm8b00694_si_001.csv (1.04 kB)

Discovery of the Polyamine Conjugate with Benzo[cd]indol-2(1H)‑one as a Lysosome-Targeted Antimetastatic Agent

Download (1.04 kB)
dataset
posted on 10.07.2018, 00:00 by Jinghua Li, Runguo Tian, Chaochao Ge, Ying Chen, Xiaodan liu, Yuxia Wang, Yacheng Yang, Wen Luo, Fujun Dai, Senzhen Wang, Shuai Chen, Songqiang Xie, Chaojie Wang
Polyamine derivatives have a promising prospect in dealing with disseminated tumor cells, a major obstacle in cancer therapy. To develop a bifunctional polyamine derivative that can serve as a fluorescent probe and an antimetastatic agent, three kinds of polyamine conjugates with benzo­[cd]­indol-2­(1H)-one as a scaffold were designed and synthesized. Compound 5e was selected as a lead by in vitro screening. Two animal models demonstrated that 5e inhibited pulmonary metastasis and tumor growth. As a fluorescent probe, 5e might partially enter cells via a polyamine transporter and subsequently localize in the lysosome. Mechanistic investigations demonstrated the interdependence of 5e-triggered apoptosis and autophagy. Compound 5e modulated the expression of LC3-II, p62, cathepsins, and the expression of capases 3, caspase 8, Bcl-2, and p53. The SSAT-mediated Akt/β-catenin pathways were also inhibited by 5e. The dual features of 5e make it a worthwhile lead compound for further structural optimization.

History

Exports