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 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 Abeta 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.
Bolognesi
Maria Laura
ML
Department of Pharmaceutical Sciences, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, Italy. marialaura.bolognesi@unibo.it
Banzi
Rita
R
Bartolini
Manuela
M
Cavalli
Andrea
A
Tarozzi
Andrea
A
Andrisano
Vincenza
V
Minarini
Anna
A
Rosini
Michela
M
Tumiatti
Vincenzo
V
Bergamini
Christian
C
Fato
Romana
R
Lenaz
Giorgio
G
Hrelia
Patrizia
P
Cattaneo
Antonino
A
Recanatini
Maurizio
M
Melchiorre
Carlo
C
D000110:Acetylcholinesterase / Q000737:chemistry; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000737:chemistry; D018384:Oxidative Stress / Q000187:drug effects; D011073:Polyamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011809:Quinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002800:Cholinesterase Inhibitors; D008024:Ligands; D011073:Polyamines; D011809:Quinones; D017382:Reactive Oxygen Species; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase