Reference - Detail
| RRC ID | 39846 |
|---|---|
| Author | Jimbo M, Yamagishi K, Yamaki T, Nunomura K, Kabayama K, Igarashi Y, Inokuchi JI. |
| Title | Development of a new inhibitor of glucosylceramide synthase. |
| Journal | 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. |
| Volume | 127(3) |
| Pages | 485-91 |
| Published | 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 |
| Times Cited | 17 |
| WOS Category | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| Altmetric score |
オルトメトリクス指標項目
|
| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 70 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | MRC-5 |