Novel class of quinone-bearing polyamines as multi-target-directed ligands to combat Alzheimer's disease

J Med Chem. 2007 Oct 4;50(20):4882-97. doi: 10.1021/jm070559a. Epub 2007 Sep 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Alzheimer Disease / drug therapy*
  • Amyloid beta-Peptides / chemistry
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology
  • Binding Sites
  • Butyrylcholinesterase / chemistry
  • Cell Line
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Humans
  • Ligands
  • Models, Molecular
  • NAD(P)H Dehydrogenase (Quinone) / chemistry
  • Oxidative Stress / drug effects
  • Polyamines / chemical synthesis*
  • Polyamines / chemistry
  • Polyamines / pharmacology
  • Protein Binding
  • Quinones / chemical synthesis*
  • Quinones / chemistry
  • Quinones / pharmacology
  • Reactive Oxygen Species / metabolism
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • Amyloid beta-Peptides
  • Antioxidants
  • Cholinesterase Inhibitors
  • Ligands
  • Polyamines
  • Quinones
  • Reactive Oxygen Species
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • Acetylcholinesterase
  • Butyrylcholinesterase