Inhibition of β-amyloid-induced neurotoxicity by imidazopyridoindoles derived from a synthetic combinatorial library
Article
Reixach, N, Crooks, E, Ostresh, JM et al. (2000). Inhibition of β-amyloid-induced neurotoxicity by imidazopyridoindoles derived from a synthetic combinatorial library
. JOURNAL OF STRUCTURAL BIOLOGY, 130(2-3), 247-258. 10.1006/jsbi.2000.4245
Reixach, N, Crooks, E, Ostresh, JM et al. (2000). Inhibition of β-amyloid-induced neurotoxicity by imidazopyridoindoles derived from a synthetic combinatorial library
. JOURNAL OF STRUCTURAL BIOLOGY, 130(2-3), 247-258. 10.1006/jsbi.2000.4245
Alzheimer's disease is a progressive neurodegenerative disorder characterized by the deposit of amyloid fibrils in the brain that result from the self-aggregative polymerization of the β-amyloid peptide (Aβ). Evidence of a direct correlation between the ability of Aβ to form stable aggregates in aqueous solution and its neurotoxicity has been reported. The cytotoxic effects of Aβ have been attributed to the aggregation properties of a domain corresponding to the peptide fragment Aβ25-35. In an effort to generate novel inhibitors of Aβ neurotoxicity and/or aggregation, a mixture-based synthetic combinatorial library composed of 23 375 imidazopyridoindoles was generated and screened for inhibition of Aβ25-35 neurotoxicity toward the rat pheochromocytoma PC-12 cell line. The effect of the identified lead compounds on Aβ25-35 aggregation was then evaluated by means of circular dichroism (CD) and thioflavin-T fluorescence spectroscopy. Their activity against Aβ1-42 neurotoxicity toward the PC-12 cell line was also determined. The most active imidazopyridoindoles inhibited both Aβ25-35 and Aβ1-42 neurotoxicity in the low- to mid-micromolar range. Furthermore, inhibition of the random coil to β-sheet transition and self-aggregation of Aβ25-35 was observed by CD and fluorescence spectroscopy, supporting the relationship between inhibition of the Aβ aggregation process and neurotoxicity. (C) 2000 Academic Press.
