Multifunctional diamine AGE/ALE inhibitors with potential therapeutical properties against Alzheimer's disease

Abstract

An important part of pathogenesis of Alzheimer's disease (AD) is attributed to the contribution of AGE (Advanced Glycation Endproducts) and ALE (Advanced Lipid peroxidation Endproducts). In order to attenuate the progression of AD, we designed a new type of molecules that consist of two trapping parts for reactive carbonyl species (RCS) and reactive oxygen species (ROS), precursors of AGE and ALE, respectively. These molecules also chelate transition metals, the promoters of ROS formation. In this paper, synthesis of the new AGE/ALE inhibitors and evaluation of their physicochemical and biological properties (carbonyl trapping capacity, antioxidant activity, Cu(2+)-chelating capacity, cytotoxicity and protective effect against in vitro MGO-induced apoptosis in the model AD cell-line PC12) are described. It is found that compounds 40b and 51e possess promising therapeutic potentials for treating AD.

Keywords: AGE (Advanced Glycation Endproducts); ALE (Advanced Lipid peroxidation Endproducts); Alzheimer's disease; Biometal dyshomeostasis; Carbonyl stress; Diamine building blocks; Hydroxypyridinone (HOPO) ligands; Oxidative stress; Phenolic acids.