Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma.
10.1016/j.apsb.2019.12.013
- Author:
Biao WANG
1
;
Fu PENG
2
;
Wei HUANG
1
;
Jin ZHOU
1
;
Nan ZHANG
1
;
Jia SHENG
3
;
Phensinee HARUEHANROENGRA
3
;
Gu HE
2
;
Bo HAN
1
Author Information
1. Hospital of Chengdu University of Traditional Chinese Medicine, State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
3. Department of Chemistry and the RNA Institute, University at Albany, State University of New York, Albany, NY 12222, USA.
- Publication Type:Journal Article
- Keywords:
Apoptosis;
Cell cycle arrest;
Chiral tetrahydronaphthalene-fused spirooxindoles;
Glioblastoma;
MDM2-CDK4 dual inhibitors;
Structure–activity relationship;
Synthesis
- From:
Acta Pharmaceutica Sinica B
2020;10(8):1492-1510
- CountryChina
- Language:English
-
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.
