title: Novel class of quinone-bearing polyamines as multi-target-directed ligands to combat Alzheimer's disease.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, Italy. marialaura.bolognesi@unibo.it
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Bolognesi
authors.forename: Rita
authors.initials: R
authors.lastname: Banzi
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.forename: Andrea
authors.initials: A
authors.lastname: Tarozzi
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.forename: Anna
authors.initials: A
authors.lastname: Minarini
authors.forename: Michela
authors.initials: M
authors.lastname: Rosini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tumiatti
authors.forename: Christian
authors.initials: C
authors.lastname: Bergamini
authors.forename: Romana
authors.initials: R
authors.lastname: Fato
authors.forename: Giorgio
authors.initials: G
authors.lastname: Lenaz
authors.forename: Patrizia
authors.initials: P
authors.lastname: Hrelia
authors.forename: Antonino
authors.initials: A
authors.lastname: Cattaneo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Recanatini
authors.forename: Carlo
authors.initials: C
authors.lastname: Melchiorre
mesh_terms: 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
chemical_list: 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