Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma
Acta Pharmaceutica Sinica B
;
(6): 1492-1510, 2020.
Article
in English
| WPRIM
| ID: wpr-828794
ABSTRACT
Simultaneous inhibition of MDM2 and CDK4 may be an effective treatment against glioblastoma. A collection of chiral spirocyclic tetrahydronaphthalene (THN)-oxindole hybrids for this purpose have been developed. Appropriate stereochemistry in THN-fused spirooxindole compounds is key to their inhibitory activity selectivity differed by over 40-fold between the least and most potent stereoisomers in time-resolved FRET and KINOMEscan® assays. Studies in glioblastoma cell lines showed that the most active compound induced apoptosis and cell cycle arrest by interfering with MDM2 -P53 interaction and CDK4 activation. Cells treated with showed up-regulation of proteins involved in P53 and cell cycle pathways. The compound showed good anti-tumor efficacy against glioblastoma xenografts in mice. These results suggested that rational design, asymmetric synthesis and biological evaluation of novel tetrahydronaphthalene fused spirooxindoles could generate promising MDM2-CDK4 dual inhibitors in glioblastoma therapy.
Full text:
Available
Index:
WPRIM (Western Pacific)
Language:
English
Journal:
Acta Pharmaceutica Sinica B
Year:
2020
Type:
Article
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