Novel multifunctional iron chelators of the aroyl nicotinoyl hydrazone class that markedly enhance cellular NAD+ /NADH ratios.

Autor:	Wu, Zhixuan, Palanimuthu, Duraippandi, Braidy, Nady, Salikin, Nor Hawani, Egan, Suhelen, Huang, Michael L.H., Richardson, Des R.
Předmět:	NAD (Coenzyme) IRON chelates STRUCTURE-activity relationships CAENORHABDITIS elegans ALZHEIMER'S disease ADP-ribosyltransferases RESEARCH RESEARCH methodology ORGANIC compounds PROTEOLYTIC enzymes CHELATING agents MEDICAL cooperation EVALUATION research COENZYMES COMPARATIVE studies RESEARCH funding PEPTIDES
Zdroj:	British Journal of Pharmacology; May2020, Vol. 177 Issue 9, p1967-1987, 21p, 1 Diagram, 3 Charts, 6 Graphs
Abstrakt:	Background and Purpose: Alzheimer's disease (AD) is a multifactorial condition leading to cognitive decline and represents a major global health challenge in ageing populations. The lack of effective AD therapeutics led us to develop multifunctional nicotinoyl hydrazones to target several pathological characteristics of AD.Experimental Approach: We synthesised 20 novel multifunctional agents based on the nicotinoyl hydrazone scaffold, which acts as a metal chelator and a lipophilic delivery vehicle, donating a NAD+ precursor to cells, to target metal dyshomeostasis, oxidative stress, β-amyloid (Aβ) aggregation, and a decrease in the NAD+ /NADH ratio.Key Results: The most promising compound, 6-methoxysalicylaldehyde nicotinoyl hydrazone (SNH6), demonstrated low cytotoxicity, potent iron (Fe)-chelation efficacy, significant inhibition of copper-mediated Aβ aggregation, oxidative stress alleviation, effective donation of NAD+ to NAD-dependent metabolic processes (PARP and sirtuin activity) and enhanced cellular NAD+ /NADH ratios, as well as significantly increased median Caenorhabditis elegans lifespan (to 1.46-fold of the control); partly decreased BACE1 expression, resulting in significantly lower soluble amyloid precursor protein-β (sAPPβ) and Aβ1-40 levels; and favourable blood-brain barrier-permeation properties. Structure-activity relationships demonstrated that the ability of these nicotinoyl hydrazones to increase NAD+ was dependent on the electron-withdrawing or electron-donating substituents on the aldehyde- or ketone-derived moiety. Aldehyde-derived hydrazones containing the ONO donor set and electron-donating groups were required for NAD+ donation and low cytotoxicity.Conclusions and Implications: The nicotinoyl hydrazones, particularly SNH6, have the potential to act as multifunctional therapeutic agents and delivery vehicles for NAD+ precursors for AD treatment. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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