4-Hydroxy-3,5-pyridinedicarboxylic Acids: Synthesis, Complexation Properties Towards Fe(III), Al(III), Cu(II), Zn(II), Human Serum Albumin, and Cellular Toxicity

Abstract

4-hydroxy-3,5-pyridinedicarboxylic acid (DQ58) and 4-hydroxy-1-methyl-3,5pyridinedicarboxylic acid (DQ71508) have been synthesized, and their Fe(III), Al(III), Cu(II), and Zn(II) coordination properties have been studied by potentiometry, UV/Vis (in the case of Fe(III), Al(III), Cu(II)), 1 H-NMR (for Al(III)), and EPR (for Cu(II)). Thermodynamic results were used to model the extent of the toxic metal ions decorporation (Fe(III) or Al(III)) in the presence of the essential metal ion (Cu(II) or Zn(II)). DQ58 and DQ71508 were demonstrated to interact with human serum albumin (HSA), which is assumed to be the main serum transporter of the chelators, and binding constants have been obtained by ultrafiltration. IC50 values of 5.185 mM and 1.033 mM were collected after 24 and 48 h of treatment with DQ71508 towards human embryonic kidney HEK-293 cells, demonstrating the relatively low cytotoxicity of this compound. According to these results, both DQ58 and DQ71508 seem to be potential candidates for Fe chelation therapy, and DQ58 is a better Fe(III) chelator than DQ71508.

Gradual Changes in the Aromaticity in a Series of Hydroxypyridine-Carboxylic Acid Derivatives and Their Effect on Tautomerism and Crystal Packing

“…The compounds were synthesized as described previously. ,− The compounds were used without further purification. In the previous papers, , compounds…”

“…Their favorable properties include low toxicity, no redox activity, and high complex stability. 4,5 The effect of aromaticity on the proton dissociation process is important because this proton is replaced by the metal ion during chelation therapy. In our previous studies, we investigated the complexation properties of selected 3HPC and 4HPC derivates with copper(II) 6 and with zinc(II).…”

“…6,8−10 The compounds were used without further purification. In the previous papers, 4,5 compounds A1−A3 were named 3H4P (or DT0), DT21, and DT1, whereas compounds B1−B8 were named 4H3P (or DQ0), DQ6, DQ1, DQ715, DQ716, DQ7176, DQ7165, and DQ58, respectively. Single crystals suitable for X-ray diffraction analysis were obtained by slow evaporation from different solvents or solvent mixtures according to their different solubility properties.…”

“…HPC derivates have been proposed recently as potential chelating agents for Fe­(III) and Al­(III) to overcome the side effects of deferiprone (3-hidroxy-1,2-dimetilpiridin-4­(1 H )-on), a widely used chelator. Their favorable properties include low toxicity, no redox activity, and high complex stability. , The effect of aromaticity on the proton dissociation process is important because this proton is replaced by the metal ion during chelation therapy. In our previous studies, we investigated the complexation properties of selected 3HPC and 4HPC derivates with copper­(II) and with zinc­(II) .…”

Crystal structures of zinc(II) complexes with β-hydroxypyridinecarboxylate ligands: examples of structure-directing effects used in inorganic crystal engineering

“…Hydroxypyridinecarboxylic acid (HPC) derivatives have been considered (Di Marco et al, 2002;Crisponi et al, 2013;Sija et al, 2014;Dean et al, 2018) as potential chelating agents for the treatment of iron-overloading conditions. The design of these compounds was based on deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one), which is a globally used iron-chelating drug.…”