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

• 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm070559a

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.