Ionophoric polyphenols selectively bind Cu(2+), display potent antioxidant and anti-amyloidogenic properties, and are non-toxic toward Tetrahymena thermophila.
Alzheimer's disease (AD) is the most common form of dementia affecting more than 28million people in the world. Only symptomatic treatments are currently available. Anticipated tri-fold increase of AD incidence in the next 50years has established the need to explore new possible treatments. Accumulation of extracellular amyloid-β (Aβ) plaques, intracellular tangles in the brain, and formation of reactive oxygen species (ROS) are the major hallmarks of the disease. The active role of some metal ions, especially Cu(2+), in promoting both Aβ aggregation and reactive oxygen species formation has rendered ionophoric drugs as a promising treatment strategy. In this work, a series of 5 disease-modifying and multi-target ionophoric polyphenols (1-5), inspired on the structure of natural resveratrol, have been synthesized and characterized. All compounds bind Cu(2+) selectively over other biologically relevant metal ions. They form 2:1 (compound/Cu(2+)) complexes with association constants logKa 12-14 depending on the molecular design. Our results indicate that compounds 1-5 possess excellent antioxidant properties: they inhibit the Cu(2+)-catalyzed reactive oxygen species production between 47% and 100%, and they scavenge DPPH (1,1-diphenyl-2-picryl-hydrazyl) and AAPH (2,2'-azobis(2-amindino-propane)dihydrochloride) free radicals in general better than clioquinol, resveratrol and ascorbic acid. In addition, compounds 1-5 interact with Aβ peptides and inhibit both the Cu(2+)-catalyzed aggregation and the self-assembly of Aβ(1-40) up to a ∼92% extent. Interestingly, 1-5 are also able to disaggregate up to ∼91% of pre-formed Aβ(1-40) aggregates. Furthermore, cytotoxic studies show remarkably low toxicity of 1-5 toward Tetrahymena thermophila with LD50 values higher than 150μM, comparable to non-toxic natural resveratrol.
Department of Chemistry, New York City College of Technology, The City University of New York (CUNY), Brooklyn, NY 11201, USA. Electronic address: amartinez@citytech.cuny.edu.
Alberto
A
Martínez
Department of Biology, New York City College of Technology, The City University of New York (CUNY), Brooklyn, NY 11201, USA.
Ralph
R
Alcendor
Department of Chemistry, New York City College of Technology, The City University of New York (CUNY), Brooklyn, NY 11201, USA.
Tanzeen
T
Rahman
Department of Chemistry, New York City College of Technology, The City University of New York (CUNY), Brooklyn, NY 11201, USA.
Magdalena
M
Podgorny
Department of Chemistry, New York City College of Technology, The City University of New York (CUNY), Brooklyn, NY 11201, USA.
Ismaila
I
Sanogo
Department of Chemistry, New York City College of Technology, The City University of New York (CUNY), Brooklyn, NY 11201, USA.
Rebecca
R
McCurdy
D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D000975:Antioxidants / Q000494:pharmacology*; D001812:Blood-Brain Barrier; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D003300:Copper / Q000378:metabolism*; D059808:Polyphenols / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D016808:Tetrahymena thermophila / Q000187:drug effects*
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D059808:Polyphenols; D003300:Copper
Alzheimer’s disease; Amyloid-beta aggregation; Antioxidant; Ionophoric compound; Multi-target compound; Polyphenol; Reactive oxygen species; Tetrahymena