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

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.

聚胺衍生物在应对癌症治疗的主要障碍——播散性肿瘤细胞方面具有可观的应用前景。为开发一种可同时充当荧光探针(fluorescent probe)与抗转移剂的双功能聚胺衍生物，本研究设计并合成了三种以苯并[cd]吲哚-2(1H)-酮(benzo[cd]indol-2(1H)-one)为母核的聚胺缀合物。经体外筛选，将化合物5e选为先导化合物。两种动物模型实验证实，5e可抑制肺转移与肿瘤生长。作为荧光探针，5e可通过聚胺转运体部分进入细胞，并随后定位于溶酶体。机制研究表明，5e诱导的细胞凋亡与细胞自噬存在相互依存关系。化合物5e可调控LC3-II、p62、组织蛋白酶(cathepsins)的表达，同时对半胱天冬酶3(caspase 3)、半胱天冬酶8(caspase 8)、B细胞淋巴瘤因子2(Bcl-2)及p53的表达具有调节作用。此外，5e还可抑制SSAT(多胺乙酰基转移酶)介导的Akt/β-连环蛋白通路。5e的双重功能特性使其成为极具研究价值的先导化合物，可用于后续的结构优化研究。