Novel Class of Quinone-Bearing Polyamines as Multi-Target-Directed Ligands To Combat Alzheimer's Disease

One of the characteristics of Alzheimer's disease (AD) that hinders the discovery of effective disease-modifying therapies is the multifactorial nature of its etiopathology. To circumvent this drawback, the use of multi-target-directed ligands (MTDLs) has recently been proposed as a means of si...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-10, Vol.50 (20), p.4882-4897
Main Authors: Bolognesi, Maria Laura, Banzi, Rita, Bartolini, Manuela, Cavalli, Andrea, Tarozzi, Andrea, Andrisano, Vincenza, Minarini, Anna, Rosini, Michela, Tumiatti, Vincenzo, Bergamini, Christian, Fato, Romana, Lenaz, Giorgio, Hrelia, Patrizia, Cattaneo, Antonino, Recanatini, Maurizio, Melchiorre, Carlo
Format: Article
Language:English
Subjects:
Acetylcholinesterase - chemistry
Alzheimer Disease - drug therapy
Amyloid beta-Peptides - chemistry
Antioxidants - chemical synthesis
Antioxidants - chemistry
Antioxidants - pharmacology
Binding Sites
Biological and medical sciences
Butyrylcholinesterase - chemistry
Cell Line
Cholinesterase Inhibitors - chemical synthesis
Cholinesterase Inhibitors - chemistry
Cholinesterase Inhibitors - pharmacology
Humans
Ligands
Medical sciences
Models, Molecular
NAD(P)H Dehydrogenase (Quinone) - chemistry
Neuropharmacology
Neuroprotective agent
Oxidative Stress - drug effects
Pharmacology. Drug treatments
Polyamines - chemical synthesis
Polyamines - chemistry
Polyamines - pharmacology
Protein Binding
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Quinones - chemical synthesis
Quinones - chemistry
Quinones - pharmacology
Reactive Oxygen Species - metabolism
Structure-Activity Relationship
Substrate Specificity
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Summary:One of the characteristics of Alzheimer's disease (AD) that hinders the discovery of effective disease-modifying therapies is the multifactorial nature of its etiopathology. To circumvent this drawback, the use of multi-target-directed ligands (MTDLs) has recently been proposed as a means of simultaneously hitting several targets involved in the development of the AD syndrome. In this paper, a new class of MTDLs based on a polyamine−quinone skeleton, whose lead (memoquin, 2) showed promising properties in preclinical investigations (Cavalli et al. Angew. Chem., Int. Ed. 2007, 46, 3689−3692), is described. 3 − 29 were tested in vitro against a number of isolated AD-related targets, namely, AChE and BChE, and Aβ aggregation (both AChE-mediated and self-induced). Furthermore, the ability of the compounds to counteract the oxidative stress in a human neuronal-like cellular system (SH-SY5Y cells) was assayed, in both the presence and absence of NQO1, an enzyme able to generate and maintain the reduced form of quinone.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm070559a