Isoindolinone-based inhibitors of the MDM2-p53 protein-protein interaction

被引:96
作者
Hardcastle, IR
Ahmed, SU
Atkins, H
Calvert, AH
Curtin, NJ
Farnie, G
Golding, BT
Griffin, RJ
Guyenne, S
Hutton, C
Källbad, P
Kemp, SJ
Kitching, MS
Newell, DR
Norbedo, S
Northen, JS
Reid, RJ
Saravanan, K
Willems, HMG
Lunec, J
机构
[1] Univ Newcastle Upon Tyne, Sch Nat Sci Chem, No Inst Canc Res, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England
[2] Univ Newcastle Upon Tyne, Sch Med, No Inst Canc Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England
[3] De Novo Pharmaceut, Cambridge CB4 9ZR, England
基金
英国工程与自然科学研究理事会; 英国生物技术与生命科学研究理事会;
关键词
cancer; MDM2; p53; protein-protein interactions;
D O I
10.1016/j.bmcl.2004.12.061
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of 2-N-alkyl-3-aryl-3-alkoxyisoindolinones has been synthesised and evaluated as inhibitors of the MDM2-p53 interaction. The most potent compound, 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (NU8231), exhibited an IC50 of 5.3 +/- 0.9 mu M in an ELISA assay, and induced p53-dependent gene transcription in a dose-dependent manner, in the SJSA human sarcoma cell line. (c) 2005 Elsevier Ltd. All rights reserved.
引用
收藏
页码:1515 / 1520
页数:6
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