期刊
ACTA PHARMACEUTICA SINICA B
卷 10, 期 8, 页码 1492-1510出版社
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2019.12.013
关键词
Chiral tetrahydronaphthalene-fused spirooxindoles; Synthesis; MDM2-CDK4 dual inhibitors; Glioblastoma; Structure-activity relationship; Apoptosis; Cell cycle arrest
资金
- National Natural Science Foundation of China [81573588, 81630101, 81773889, 21772131]
- Science & Technology Department of Sichuan Province [2017JZYD0001, 2017JQ0002, 2017JY0323, 2019YFSY0004]
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 (R) 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. (C) 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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