Design, synthesis, and discovery of Eudistomin Y derivatives as lysosome-targeted antiproliferation agents

Gangqiang Yang, Hao Xie, Conghui Wang, Chen Zhang, Liping Yu, Luyu Zhang, Xin Liu, Ruoxuan Xu, Zhihua Song, Rongxia Liu, Minoru Ueda

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


Eudistomin Y is a novel class of β-carbolines of marine origin with potential antiproliferation activity against MDA-MB-231 cells (triple-negative breast carcinoma). However, the subcellular target or the detailed mechanism against cancer cell proliferation has not yet been identified. In this study, based on its special structure, a novel series of Eudistomin Y fluorescent derivatives were designed and synthesized by enhancing the electron-donor effect of N-9 to endow it with fluorescent properties through N-alkylation. The structure–activity relationships against the proliferation of cancer cells were also analyzed. A quarter of Eudistomin Y derivatives showed much higher potency against cancer cell proliferation than the original Eudistomin Y1. Fluorescent derivative H1k with robust antiproliferative activity could arrest MDA-MB-231 cells in the G2–M phase. The subcellular localization studies of the probes, including H1k, and Eudistomin Y1 were performed in MDA-MB-231 cells, and the co-localization and competitive inhibition assays revealed their lysosome-specific localization. Moreover, H1k could dose-dependently increase the autophagy signal and downregulate the expression of cyclin-dependent kinase (CDK1) and cyclin B1 which principally regulated the G2–M transition. Furthermore, the specific autophagy inhibitor 3-methyladenine significantly inhibited the H1k-triggered antiproliferation of cancer cells and the downregulation of CDK1 and cyclin B1. Overall, the lysosome is identified as the subcellular target of Eudistomin Y for the first time, and derivative H1k showed robust antiproliferative activity against MDA-MB-231 cells by decreasing Cyclin B1–CDK1 complex via a lysosome-dependent pathway.

Original languageEnglish
Article number115193
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 2023 Mar 15


  • Anti-proliferative activity
  • Autophagy
  • Fluorescent probe synthesis
  • Subcellular target identification
  • β-Carbolines


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