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

摘要

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 Se was selected as a lead by in vitro screening. Two animal models demonstrated that Se inhibited pulmonary metastasis and tumor growth. As a fluorescent probe, Se might partially enter cells via a polyamine transporter and subsequently localize in the lysosome. Mechanistic investigations demonstrated the interdependence of Se-triggered apoptosis and autophagy. Compound Se modulated the expression of LC3-II, p62, cathepsins, and the expression of capases 3, caspase 8, Bcl-2, and p53. The SSAT-mediated Akt/beta-catenin pathways were also inhibited by 5e. The dual features of Se make it a worthwhile lead compound for further structural optimization.