| RRC ID |
39846
|
| 著者 |
Jimbo M, Yamagishi K, Yamaki T, Nunomura K, Kabayama K, Igarashi Y, Inokuchi JI.
|
| タイトル |
Development of a new inhibitor of glucosylceramide synthase.
|
| ジャーナル |
J Biochem
|
| Abstract |
Analogs of the potent inhibitor of glucosylceramide (GlcCer) synthase, D-threo-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (P4), based on substitutions in the palmitoyl group were made by means of a stereo-selective synthetic method in order to elucidate the role of the hydrophobic portion in both the inhibitory action toward the enzyme and the biological effects. While P4 strongly inhibited GlcCer synthase with an IC(50) of 0.5 microM in vitro, it also inhibited cell growth by 50% at the concentration of 7 microM. The shorter N-acyl chain analogs including decanoyl, octanoyl, and hexanoyl groups showed similar IC(50) values for GlcCer synthase (around 2 microM) but the hexanoyl analog exhibited only a slight inhibitory effect on cell growth, showing the dissociation between GlcCer depletion and cell growth. Several compounds which exhibit similar hydrophobicity to the hexanoyl analog of P4 were subsequently designed. We found that D-threo-1-phenyl-2-benzyloxycarbonylamino-3-pyrrolidino-1-pr opanol (PBPP) was a most potent inhibitor, showing an IC50 of 0.3 microM. In cultured cells, PBPP was able to deplete glycosphingolipids without affecting cell growth or the ceramide level.
|
| 巻・号 |
127(3)
|
| ページ |
485-91
|
| 公開日 |
2000-3-1
|
| DOI |
10.1093/oxfordjournals.jbchem.a022631
|
| PMID |
10731721
|
| MeSH |
Animals
Cell Line
Cell Survival / drug effects
Chromatography, High Pressure Liquid
Dose-Response Relationship, Drug
Fibroblasts / drug effects
Glucosyltransferases / antagonists & inhibitors*
Humans
Magnetic Resonance Spectroscopy
Morpholines / chemistry
Procyclidine / analogs & derivatives*
Procyclidine / chemical synthesis
Propanolamines / chemistry
Pyrrolidines / chemistry
Rats
Sphingolipids / metabolism
Tumor Cells, Cultured
|
| IF |
2.476
|
| 引用数 |
17
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
|
