Department of Pharmaceutical and Toxicological Chemistry, University of Naples "Federico II", Italy.
J Med Chem. 2010 Dec 9;53(23):8319-29. doi: 10.1021/jm100838z. Epub 2010 Nov 8.
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.
在这里，我们报告了作为 p53 活性调节剂的螺噁吲哚吡咯烷核的新类似物的设计。化合物 (3R,7aR)-6-(4-氯苄基)-1H-螺[咪唑并[1,5-c]噻唑-3,3'-吲哚]-2',5,7(6H,7aH)-三酮 (9c) 和 (3R,7aR)-5'-甲基-6-(3,4,5-三甲氧基苄基)-1H-螺[咪唑并[1,5-c]噻唑-3,3'-吲哚]-2',5,7(6H,7aH)-三酮 (10d) 是该系列中最有效的化合物，分别以亚微摩尔和微摩尔浓度抑制不同人肿瘤细胞的细胞生长。化合物 9c 在 24 小时内诱导人黑色素瘤细胞系 M14 的细胞凋亡死亡，而在相同条件下，用 10d 处理显示出 G2/M 期的明显阻滞，导致细胞周期进程的延迟。可能，这些活性可能是由于抑制 p53-MDM2 相互作用以及随后的 p53 释放和激活。
