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

• 作者: Biao Wang Bo Han Fu Peng Gu He Jia Sheng Jin Zhou Nan Zhang Phensinee Haruehanroengra Wei Huang
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2020,（8）
• 所属期刊栏目: Original articles
• 页码范围: 1492-1510
• 页数: 19页
• 语种: 英文

摘要

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.