| RRC ID |
58855
|
| 著者 |
Koyama R, Kano Y, Kikushima K, Mizutani A, Soeda Y, Miura K, Hirano T, Nishio T, Hakamata W.
|
| タイトル |
A novel Golgi mannosidase inhibitor: Molecular design, synthesis, enzyme inhibition, and inhibition of spheroid formation.
|
| ジャーナル |
Bioorg Med Chem
|
| Abstract |
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.
|
| 巻・号 |
28(11)
|
| ページ |
115492
|
| 公開日 |
2020-6-1
|
| DOI |
10.1016/j.bmc.2020.115492
|
| PII |
S0968-0896(20)30313-8
|
| PMID |
32291147
|
| MeSH |
Cell Line, Tumor
Dose-Response Relationship, Drug
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Golgi Apparatus / enzymology*
Humans
Mannosidases / antagonists & inhibitors*
Mannosidases / metabolism
Molecular Structure
Optical Imaging
Spheroids, Cellular / drug effects*
Spheroids, Cellular / metabolism
Structure-Activity Relationship
|
| IF |
3.073
|
| 引用数 |
0
|
| リソース情報 |
| ヒト・動物細胞 |
NIH:OVCAR-3(RCB2135)
HeLa(RCB0007) |
