Abstract
BACE1 inhibitory conjugates derived from two natural products, luteolin (1) and p-hydroxy-cinnamic acid (2), were subjected to systematic structure modifications, including various positions in luteolin segment for conjugation, different linkers (length, bond variation), as well as various substitutions in cinnamic acid segment (various substituents on benzene, and replacement of benzene by heteroaromatics and cycloalkane). Optimal conjugates such as 7c and 7k were chosen on the basis of a series of bioassay data for further investigation.
Highlights
Alzheimer’s disease (AD) is an age-dependent chronic neurodegenerative disease that is characterized by the presence of extracellular senile plaques and neurofibrillary tangles, as well as synaptic dysfunction and neuronal cell death
According to the World Health Organization (WHO), about 35.6 million people were diagnosed with dementia in 2010, and the number is projected to double every 20 years
A peptide consisting of 37–43 amino acids, is proposed as aggregating into soluble oligomers and fibrils, which are toxic to neurons, causing neuronal death
Summary
Alzheimer’s disease (AD) is an age-dependent chronic neurodegenerative disease that is characterized by the presence of extracellular senile plaques and neurofibrillary tangles, as well as synaptic dysfunction and neuronal cell death. A peptide consisting of 37–43 amino acids, is proposed as aggregating into soluble oligomers and fibrils, which are toxic to neurons, causing neuronal death. Another protein, tau, can be a causative factor independently, presumably acting downstream of Aβ aggregation [2,3,4]. Have finished the phase III clinical trial due to diverse side effects and/or lack of effectiveness [7]. (1) and and p-hydroxy-cinnamic p-hydroxy-cinnamic acid were found found to to simultaneously bind different parts of BACE1 protein by STD-NMR experiment [14]. We designed the simultaneously bind different parts of BACE1 protein by STD-NMR experiment [14].
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