p53 Functional Inhibitors Behaving Like Pifithrin-β Counteract the Alzheimer Peptide Non-β-amyloid Component Effects in Human SH-SY5Y Cells
p53 Functional Inhibitors Behaving Like Pifithrin-β Counteract the Alzheimer Peptide Non-β-amyloid Component Effects in Human SH-SY5Y Cells
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DOI：
10.1021/cn4002208
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发表时间：
2014-05-01
影响因子：
5
通讯作者：
Greco, Giovanni
中科院分区：
文献类型：
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作者：
Da Pozzo, Eleonora;La Pietra, Valeria;Greco, Giovanni
阿尔茨海默病 (AD) 是由复杂的遗传和生化改变引起的，其中包括大脑中 p53 水平的升高。在此，在人神经母细胞瘤 SH-SYSY 细胞中证明了 AD 的纤维状非 fl-淀粉样蛋白成分 (NAC) 对 p53 的强烈和特异性激活。首次证实了 NAC 可以提高 p53 靶基因转录水平、细胞周期停滞和细胞凋亡诱导。这些影响被 Pifithrin-fl（一种干扰 p53 功能的小分子）所抵消。使用pifithrin-fl类似物的结构作为参考，对ZINC数据库进行基于药效团的虚拟筛选。在所得结果中，选择了 20 种药物样杂环化合物，并在人类 SH-SYSY 细胞模型中评估了它们对纤维状 NAC 的神经保护活性。三种化合物表现出神经保护作用。特别是，2-(4-甲氧基苯基1)-7-甲基-7H-吡唑并[4,3-e][1,2,4]三唑并[1,5-c]嘧啶成为一种有前途的先导化合物，可用于进一步开发神经保护方面的抗AD药物，通过更有效地功能性抑制p53靶基因转录，降低NAC诱导的细胞死亡率，其活性高于pifithrin-fl。
Alzheimer's disease (AD) develops from a complex setting of genetic and biochemical alterations, including an increased level of p53 in the brain. Here, the robust and specific activation of p53 by the fibrillar non-fl-amyloid component (NAC) of AD was demonstrated in human neuroblastoma SH-SYSY cells. For the first time, the increase in the level of p53 target gene transcription, the cell cycle arrest, and the induction of apoptosis elicited by NAC were evidenced. These effects were counterbalanced by pifithrin-fl, a small molecule interfering with the p53 functions. Using the structure of a pifithrin-fl analogue as a reference, a pharmacophore-based virtual screening of the ZINC database was performed. Among the resulting hits, 20 druglike heterocyclic compounds were selected and evaluated for their neuroprotective activity against fibrillar NAC in the human SH-SYSY cellular model. Three compounds exhibited neuroprotective effects. In particular, 2-(4-methoxypheny1)-7-methyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine resulted in a promising lead compound for further development of anti-AD agents in terms of neuroprotection, reducing the rate of NAC-induced cell death with an activity higher than that of pifithrin-fl, as a result of a more effective functional inhibition of p53 target gene transcription.