Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma

• Main Authors: Biao Wang, Fu Peng, Wei Huang, Jin Zhou, Nan Zhang, Jia Sheng, Phensinee Haruehanroengra, Gu He, Bo Han
• Format: Article
• Language: English
• Published: Elsevier 2020-08-01
• Series: Acta Pharmaceutica Sinica B
• Subjects: Chiral tetrahydronaphthalene-fused spirooxindoles; Synthesis; MDM2-CDK4 dual inhibitors; Glioblastoma; Structure–activity relationship; Apoptosis
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211383519308706
• ISSN: 2211-3835

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® in vitro assays. Studies in glioblastoma cell lines showed that the most active compound ent-4g induced apoptosis and cell cycle arrest by interfering with MDM2 -P53 interaction and CDK4 activation. Cells treated with ent-4g 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.