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 ML, Banzi R, Bartolini M, Cavalli A, Tarozzi A, Andrisano V, et al. (2007). Novel Class of Quinone-Bearing Polyamines as Multi-Target-Directed Ligands To Combat Alzheimer's Disease. JOURNAL OF MEDICINAL CHEMISTRY, 50, 4882-4897 [10.1021/jm070559a].
Novel Class of Quinone-Bearing Polyamines as Multi-Target-Directed Ligands To Combat Alzheimer's Disease
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;RECANATINI, MAURIZIO;MELCHIORRE, CARLO
2007
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
