期刊
ACS CHEMICAL NEUROSCIENCE
卷 5, 期 5, 页码 390-399出版社
AMER CHEMICAL SOC
DOI: 10.1021/cn4002208
关键词
p53; Alzheimer's disease; pifithrin-beta; non-beta-amyloid component (NAC); virtual screening; database searching
资金
- Italian Ministry of Education, University and Research (MIUR, Italy) [PRIN 2009]
- University of Pisa
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.
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