Synthesis, Physicochemical Characterization, and Biological Evaluation of 2-(1‘-Hydroxyalkyl)-3-hydroxypyridin-4-ones:  Novel Iron Chelators with Enhanced pFe³⁺ Values

Abstract

The synthesis of a range of 2-(1'-hydroxyalkyl)-3-hydroxypyridin-4-ones as bidentate iron(III) chelators with potential for oral administration is described. The pK(a) values of the ligands and the stability constants of their iron(III) complexes have been determined. Results indicate that the introduction of a 1'-hydroxyalkyl group at the 2-position leads to a significant improvement in the pFe(3+) values. Such an effect was found to be greater with the hydroxyethyl substituent than with the hydroxymethyl substituent, particularly in the cases of 1-ethyl-2-(1'-hydroxyethyl)-3-hydroxypyridin-4-one (pFe(3+) = 21.4) and 1,6-dimethyl-2-(1'-hydroxyethyl)-3-hydroxypyridin-4-one (pFe(3+) = 21.5) where an enhancement on pFe(3+) values in the region of two orders of magnitude is observed, as compared with Deferiprone (1, 2-dimethyl-3-hydroxypyridin-4-one) (pFe(3+) = 19.4). The ability of these novel 3-hydroxypyridin-4-ones to facilitate the iron excretion in bile was investigated using a [(59)Fe]ferritin-loaded rat model. Chelators and prodrug chelators possessing high pFe(3+) values show great promise in their ability to remove iron under in vivo conditions.

Maltol‐Derived Ruthenium–Cymene Complexes with Tumor Inhibiting Properties: The Impact of Ligand–Metal Bond Stability on Anticancer Activity In Vitro

“…[37] Ligand 1 e was obtained by conversion of 1 b with formaldehyde under alkaline conditions (70 %). [37] The thiopyrones 1 g and 1 h were prepared by reaction of P 4 S 10 with the corresponding pyrones 1 b and 1 d (40-60 %).…”

“…[37] Ligand 1 e was obtained by conversion of 1 b with formaldehyde under alkaline conditions (70 %). [37] The thiopyrones 1 g and 1 h were prepared by reaction of P 4 S 10 with the corresponding pyrones 1 b and 1 d (40-60 %). [38] Ligands 1 a-h were converted with bis[dichlorido(h 6 -p-cyA C H T U N G T R E N N U N G mene)ruthenium(II)] under alkaline conditions into the corresponding Ru II complexes 2 a-h in good yields (61-85 %) (Scheme 1).…”

“…[37,38] Melting points were determined with a Büchi B-540 apparatus and are uncorrected. Elemental analyses were carried out with a Perkin-Elmer 2400 CHN Elemental Analyzer at the Microanalytical Laboratory of the University of Vienna.…”

Comparative solution equilibrium studies of anticancer gallium(III) complexes of 8-hydroxyquinoline and hydroxy(thio)pyrone ligands

“…Allomaltol, thiomaltol and thioallomaltol were prepared according to literature procedures [12,13]. The purity and stability of the ligands were checked and the exact concentrations of the stock solutions were determined by the Gran method [14].…”

Amido‐3‐hydroxypyridin‐4‐ones as Iron(III) Ligands

“…[9] To increase the iron-chelating ability further, we have established that introduction of a 1'-hydroxyalkyl group at the 2 position of HPOs leads to an appreciable enhancement of pFe 3 + values. [10] Chelators with high pFe 3 + values are predicted not only to be able to scavenge iron efficiently at a lower ligand concentration, but also to dissociate less readily and, therefore, are less likely to redistribute iron to other parts of the body. With 3-hydroxypyridin-4-ones, the increase of the pFe 3 + value can result from a de-…”