A novel Golgi mannosidase inhibitor: Molecular design, synthesis, enzyme inhibition, and inhibition of spheroid formation

Ryosuke Koyama, Yui Kano, Kaori Kikushima, Ayaka Mizutani, Yuta Soeda, Kazuki Miura, Takako Hirano, Toshiyuki Nishio, Wataru Hakamata

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)


Effective chemotherapy for solid cancers is challenging due to a limitation in permeation that prevents anticancer drugs from reaching the center of the tumor, therefore unable to limit cancer cell growth. To circumvent this issue, we planned to apply the drugs directly at the center by first collapsing the outer structure. For this, we focused on cell–cell communication (CCC) between N-glycans and proteins at the tumor cell surface. Mature N-glycans establish CCC; however, CCC is hindered when numerous immature N-glycans are present at the cell surface. Inhibition of Golgi mannosidases (GMs) results in the transport of immature N-glycans to the cell surface. This can be employed to disrupt CCC. Here, we describe the molecular design and synthesis of an improved GM inhibitor with a non-sugar mimic scaffold that was screened from a compound library. The synthesized compounds were tested for enzyme inhibition ability and inhibition of spheroid formation using cell-based methods. Most of the compounds designed and synthesized exhibited GM inhibition at the cellular level. Of those, AR524 had higher inhibitory activity than a known GM inhibitor, kifunensine. Moreover, AR524 inhibited spheroid formation of human malignant cells at low concentration (10 µM), based on the disruption of CCC by GM inhibition.

Original languageEnglish
Article number115492
JournalBioorganic and Medicinal Chemistry
Issue number11
Publication statusPublished - 2020 Jun 1


  • Cancer stem cell
  • Cell-cell communication
  • Golgi mannosidase
  • Non-sugar mimic inhibitor
  • Spheroid formation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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