In vitro studies of 3-hydroxy-4-pyridinones and their glycosylated derivatives as potential agents for Alzheimer's disease

Abstract

Glycosides of 3-hydroxy-4-pyridinones were synthesized and characterized by mass spectrometry, elemental analysis, (1)H and (13)C NMR spectroscopy, and in one case by X-ray crystallography. The Cu(2+) complex of a novel 3-hydroxy-4-pyridinone was synthesized and characterized by IR and X-ray crystallography, showing the ability of these compounds to chelate potentially toxic metal ions. An MTT cytotoxicity assay of a selected glycosylated compound showed a relatively low toxicity of IC(50) = 570 +/- 90 microM in a human breast cancer cell line. The pyridinone glycosides could be cleaved by a broad specificity beta-glycosidase, Agrobacterium sp.beta-glucosidase, and for one compound k(cat) and K(m) were determined to be 19.8 s(-1) and 1.52 mM, respectively. Trolox Equivalent Antioxidant Capacity (TEAC) values were determined for the free pyridinones, indicating the good antioxidant properties of these compounds. Metal-Abeta(1-40) aggregates with zinc and copper were resolubilized by the non-glycosylated pyridinone ligands.

A new water-soluble Cu(II) chelator that retrieves Cu from Cu(amyloid-β) species, stops associated ROS production and prevents Cu(II)‐induced Aβ aggregation

“…Recently several groups have conceived such new molecules (see Refs. [9][10][11][12][13][14][15][16] and for recent reviews, Refs. [17][18][19]).…”

A potent antioxidant small molecule aimed at targeting metal-based oxidative stress in neurodegenerative disorders

“…5, 12, 14, 17 Given this success we set-out to enhance the antioxidant activity of 1 , without affecting the metal ion chelation capability. 18, 19 The conversion from a pyridine to a pyridol, ( 2 ) was pursued as pyridols are known to react with hydroxyl radicals via addition at the C3 or C5 position of the pyridol ring with the products being reminiscent of tannins, well known for their antioxidant power. 3, 18, 20, 21 Methods used to 2 are detailed in Schemes S1-S3.…”

Prochelator strategies for site-selective activation of metal chelators

“…[21][22][23][24][25] The molecules in this form require the cleavage of the carbohydrate moiety to exert their activity once inside the brain. As a proof, it has been demonstrated that Agrobacterium faecalis glucosidase converts these glucoconjugates in their chelating versions.…”

“…β-glucosidases and glucose transporters) and the high levels of Cu 2+ . The rationale behind the development of HQ glucoconjugates(19)(20)(21)(22)(23) resides on glucose avidity of cancer cells (PMT approach) whereas galactoconjugates(24)(25)(26)(27)(28)(29)(30) could exploit ADEPT strategy. Specific β-glucosidases or β-galactosidases can activate HQ glycoconjugates releasing the active aglycone in target cells.…”