Novel p53 inactivators with neuroprotective action: syntheses and pharmacological evaluation of 2-imino-2,3,4,5,6,7-hexahydrobenzothiazole and 2-imino-2,3,4,5,6,7-hexahydrobenzoxazole derivatives.
Novel p53 inactivators with neuroprotective action: syntheses and pharmacological evaluation of 2-imino-2,3,4,5,6,7-hexahydrobenzothiazole and 2-imino-2,3,4,5,6,7-hexahydrobenzoxazole derivatives.
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DOI：
10.1021/jm020044d
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发表时间：
2002-10
影响因子：
7.3
通讯作者：
XiaoXiang Zhu;Qian-sheng Yu;R. Cutler;C. Culmsee;H. Holloway;D. Lahiri;M. Mattson;N. Greig
中科院分区：
文献类型：
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作者：
XiaoXiang Zhu;Qian-sheng Yu;R. Cutler;C. Culmsee;H. Holloway;D. Lahiri;M. Mattson;N. Greig
肿瘤抑制蛋白p53是一种细胞内蛋白，在通过细胞凋亡导致细胞死亡的生化级联反应中起关键作用。最近的研究发现，四氢苯并噻唑类似物氟虫腈- α(2)是一种p53抑制剂，可有效保护神经元细胞免受各种致命损伤，并减少抗癌药物的副作用。由于p53的上调已被描述为包括阿尔茨海默病在内的几种神经退行性疾病的共同特征，2和新型类似物（3-16）被合成来(i)评估四氢苯并噻唑类似物作为神经保护剂的价值，（ii）确定p53失活的结构要求。化合物2不仅在组织培养和体内中风模型中都表现出神经保护活性，而且化合物6、7、10、13、15和16被证明对PC12细胞具有高度有效的保护作用，化合物3、4和6在保护原代海马细胞免受dna损伤剂喜树碱诱导的死亡方面也具有高度有效的保护作用。
Tumor suppressor protein, p53, is an intracellular protein that is critical within the biochemical cascade that leads to cell death via apoptosis. Recent studies identified the tetrahydrobenzothiazole analogue, pifithrin-alpha (2), as a p53 inhibitor that was effective in protecting neuronal cells against a variety of lethal insults and reducing the side effects of anticancer drugs. As up-regulation of p53 has been described as a common feature of several neurodegenerative disorders, including Alzheimer's disease, 2 and novel analogues (3-16) were synthesized to (i) assess the value of tetrahydrobenzothiazole analogues as neuroprotective agents and (ii) define the structural requirements for p53 inactivation. Not only did 2 exhibit neuroprotective activity in both tissue culture and in vivo stroke models but also compounds 6, 7, 10, 13, 15, and 16 proved to be highly potent in protecting PC12 cells and compounds 3, 4, and 6 were highly potent in protecting primary hippocampal cells against death induced by the DNA-damaging agent, camptothecin.