Identification of the Spiro(oxindole-3,3′-thiazolidine)-Based Derivatives as Potential p53 Activity Modulators
Identification of the Spiro(oxindole-3,3′-thiazolidine)-Based Derivatives as Potential p53 Activity Modulators
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DOI：
10.1021/jm100838z
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发表时间：
2010-12-09
影响因子：
7.3
通讯作者：
Novellino, Ettore
中科院分区：
文献类型：
--
作者：
Gomez-Monterrey, Isabel;Bertamino, Alessia;Novellino, Ettore
在这里，我们报告的设计新的类似物的spirooxoindolepyrrolidine核作为调制器的p53活性。化合物（3R，7aR）-6（4-氯苄基）-1H-螺[咪唑并[1，5-c]噻唑-3，3 '-二氢吲哚]-2'，5，7（6 H，7aH）-三酮（9 c）和（3R，7aR）-5 '-甲基-6-（三氟甲基）苯并咪唑并[1，5-c]噻唑-3，3'-二氢吲哚（3，4，5-三甲氧基苄基）-1H-螺[咪唑并[1，5-c]噻唑-3，3 ′-二氢吲哚]-2 ′，5，7（6 H，7aH）-三酮（10 d）是该系列中最有效的化合物，分别在亚微摩尔和微摩尔浓度下抑制不同人肿瘤细胞的细胞生长。化合物9 c在24小时诱导人黑色素瘤细胞系M14的细胞凋亡，而在相同条件下，处理10天显示出明显的G2/M期阻滞，诱导细胞周期进程延迟。这些活性可能是由于抑制p53-MDM 2相互作用和随后的p53释放和激活。
Here, we report the design of new analogues of spirooxoindolepyrrolidine nucleus as modulators of p53 activity. Compounds (3R,7aR)-6(4-chlorobenzyl)-1H-spiro[imidazo[1,5-c]thiazole-3,3'-indoline]-2',5,7(6H,7aH)-trione (9c) and (3R,7aR)-5'-methyl-6-(3,4, 5-trimethoxybenzyl)-1H-spiro[imidazo[1,5-c]thiazole-3,3'-indoline]-2',5,7(6H,7aH)-trione (10d) are the most potent compounds of this series, inhibiting cell growth of different human tumor cells at submicromolar and micromolar concentrations, respectively. Compound 9c induces apoptotic cell death in human melanoma cell line M14 at 24 h, while in the same condition, treatment with 10d showes a clear arrest at G2/M phase inducing delay of cell cycle progression. Possibly, these activities may be due to inhibition of p53-MDM2 interaction and subsequent p53 release and activation.