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.

同时抑制MDM2和CDK4可能是针对胶质母细胞瘤的有效治疗方法。为此目的，已经开发了手性螺环四氢萘（THN）-羟吲哚杂化物的集合。THN融合的螺氧基吲哚化合物中适当的立体化学是其抑制活性的关键：在时间分辨的FRET和KINOMEscan®体外测定中，最小和最有效的立体异构体之间的选择性相差40倍以上。对胶质母细胞瘤细胞系的研究表明，活性最高的ent- 4g通过干扰MDM2-P53相互作用和CDK4活化而诱导凋亡和细胞周期停滞。ent- 4g处理过的细胞显示参与P53和细胞周期途径的蛋白质上调。该化合物对小鼠胶质母细胞瘤异种移植物显示出良好的抗肿瘤功效。这些结果表明，新颖的四氢萘稠合螺硫醇的合理设计，不对称合成和生物学评估可在成胶质细胞瘤治疗中产生有前景的MDM2-CDK4双重抑制剂。