Synthesis, distribution analysis and mechanism studies of N-acyl glucosamine-bearing oleanolic saponins

Yu Pu Juang, You Yu Lin, She Hung Chan, Chun Kai Chang, Jiun Jie Shie, Yves S.Y. Hsieh, Jih Hwa Guh, Pi Hui Liang

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

A series of N-acyl glucosamine-bearing triterpenoid saponins has been synthesized with cytotoxic activities evaluated against HL-60, PC-3, HCT-116, and CT-26 tumor cells. Saponins incorporated an oleanolic acid (OA) triterpenoidal core exhibited the highest cytotoxic activity. To study the influence of the lengths of acyl-carbon chain on N-position of glucosamine, cells were treated with 28-propargylamides and then reacted with an azido-fluorogenic probe under CuAAC click reactions to visualize the intact distributions of these compounds by confocal microscopy and flow cytometry; it was found that cytotoxic-active compounds (30–32) located in the cytosol and inactive compounds bearing longer carbon chains (33–35) were impenetrable across cell membranes. Our study demonstrated the defined lipophilic acyl-carbon chain length can precisely regulate the cytotoxic activity of saponins, which is useful for the future development of cytotoxic agents. Furthermore, using quantitative proteomics and immunolabeling, the mechanism of cytotoxicity induced by the synthetic saponin after membrane penetration could be a result of activation of death receptor pathway and inhibition of PI3K/Akt/mTOR pathway.

Original languageEnglish
Article number103835
JournalBioorganic Chemistry
Volume99
DOIs
Publication statusPublished - Jun 2020
Externally publishedYes

Keywords

  • Apoptosis
  • Drug distribution
  • Proteomics
  • Saponins
  • Triterpene

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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