Synthesis and biological evaluation of imidazolo[2,1-b]benzothiazole derivatives, as potential p53 inhibitors
Synthesis and biological evaluation of imidazolo[2,1-b]benzothiazole derivatives, as potential p53 inhibitors
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DOI：
10.1016/j.bmc.2011.01.039
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发表时间：
2011-03-01
影响因子：
3.5
通讯作者：
Zunino, Franco
中科院分区：
文献类型：
--
作者：
Christodoulou, Michael S.;Colombo, Francesco;Zunino, Franco
由于在细胞毒性应激反应中p53的激活可能具有促凋亡或保护作用，这取决于损伤的性质，p53的抑制剂可能作为化疗毒性或疗效的调节剂具有治疗意义。为了鉴定新的p53抑制剂，我们设计并合成了一系列与聚氟乙烯- β结构相关的化合物，作为p53的潜在抑制剂。生物化学和生物学评价支持四氢苯并噻唑系列化合物是p53转录活性的抑制剂，并有效增强紫杉醇诱导的细胞凋亡。相比之下，尽管细胞毒性增强，但苯并噻唑系列的选定化合物不能调节p53的转录活性，这表明p21表达缺乏变化。前系列化合物与紫杉烷结合的治疗兴趣在人类肿瘤异种移植模型中得到证实。(C) 2011 Elsevier Ltd.版权所有。
Since activation of p53 in response to cytotoxic stress may have proapoptotic or protective effects depending on the nature of the injury, inhibitors of p53 may have therapeutic interest as modulators of chemotherapy toxicity or efficacy. In an attempt to identify novel p53 inhibitors, a quality collection of compounds structurally related to pifithrin-beta were designed and synthesized as potential inhibitors of p53. The biochemical and biological evaluations supported that compounds of the tetrahydrobenzothiazole series were inhibitors of the p53 transcriptional activity and were effective in enhancing paclitaxel-induced apoptosis. In contrast, in spite of the increased cytotoxic potency, selected compounds of the benzothiazole series were not able to modulate the transcriptional activity of p53, as indicated by lack of change of p21 expression. The therapeutic interest of the compounds of the former series in combination with taxanes was confirmed in a human tumor xenograft model. (C) 2011 Elsevier Ltd. All rights reserved.