1. Academic Validation
  2. Design, synthesis, and discovery of Eudistomin Y derivatives as lysosome-targeted antiproliferation agents

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

  • Eur J Med Chem. 2023 Mar 15;250:115193. doi: 10.1016/j.ejmech.2023.115193.
Gangqiang Yang 1 Hao Xie 2 Conghui Wang 2 Chen Zhang 2 Liping Yu 2 Luyu Zhang 2 Xin Liu 2 Ruoxuan Xu 2 Zhihua Song 2 Rongxia Liu 2 Minoru Ueda 3
Affiliations

Affiliations

  • 1 School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China. Electronic address: oceanygq@ytu.edu.cn.
  • 2 School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China.
  • 3 Department of Chemistry, Graduate School of Science, Tohoku University, Sendai, 980-8578, Japan; Department of Molecular and Chemical Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, 980-8578, Japan.
Abstract

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.

Keywords

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

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-149261
    Antiproliferation Agent