Multifunctional Diamine AGE/ALE Inhibitors with Promising Properties for Treating Alzheimer's Disease

Reactive carbonyl species (RCS) such as methylglyoxal (MGO) or malondialdehyde (MDA) are endogenously formed during the sugar glycoxidation and lipid peroxidation of polyunsaturated fatty acids induced by oxidative stress exacerbation. Their condensation with amino groups of tissue proteins gives AGE (Advanced Glycation Endproducts) and ALE (Advanced Lipid peroxidation Endproducts). In Alzheimer's disease (AD), extensive AGE/ALE accumulation has been reported in extracellular amyloid β (Aβ) plaques and intracellular tau-associated neurofibrillary tangles. Indeed, a critical imbalance between cerebral reactive oxygen species (ROS) production and endogenous antioxidant capacities associated with biometal dyshomeostasis has been suggested to be a driving force for AD onset and progression. Aβ-oligomers induce oxidative stress whereas transition metals (Zn²⁺, Cu²⁺ and Fe³⁺) stimulate Aβ aggregation and APP (amyloid precursor protein) processing. Consequently, RCS accumulation takes part in the vicious downward redox amyloid spiral leading to neurodegeneration.^1,2 AGE/ALE are now considered to play an important role at the late stages of AD pathogenesis through three main mechanisms.³ First, glycated Aβ cross-linking promotion accelerates its deposition and its protease resistance. Secondly, AGE/ALE formation not only accelerates tau hyperphosphorylation, disturbs the neuronal membrane depolarization process and the glucose transport but also exacerbates glutamate-mediated excitotoxicity. Thirdly, AGE promote via their receptors RAGE oxidative stress and inflammation as well as cell apoptosis.

Taking into account the multifactorial pathogenesis of AD, we designed new multifunctional drugs that are simultaneously able to trap RCS (primary vicinal diamine function) as well as ROS and biometals (phenolic acid or hydroxypyridinone moiety).⁴ In the presentation, synthesis of these new promising hybrid AGE/ALE inhibitors and evaluation of their physicochemical and biological properties (carbonyl trapping capacity, antioxidant activity, Cu²⁺-chelating capacity, cytotoxicity and protective effect against in vitro MGO-induced apoptosis in the model AD cell-line PC12) are reported.

References

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