Possible chelating agents for iron and aluminium - 4-hydroxy-5-methyl- and 4-hydroxy-1,5-dimethyl-3-pyridinecarboxylic acid

Annalisa Dean, Éva Sija, Éva Zsigõ, Maria Grazia Ferlin, Daniele Marton, Valentina Gandin, Cristina Marzano, Denis Badocco, Paolo Pastore, Alfonso Venzo, Roberta Bertani, T. Kiss, Valerio Di Marco

Research output: Contribution to journalArticle

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Abstract

4-Hydroxy-5-methyl-3-pyridinecarboxylic acid (DQ5) and 4-hydroxy-1,5- dimethyl-3-pyridinecarboxylic acid (DQ715) were synthesized and evaluated for possible application in iron and aluminium chelation therapy. Metal ion/ligand solution chemistry, electrochemistry, cytotoxicity and chelation efficiency in vitro were studied. The solution chemistry of each ligand with FeIII or AlIII was investigated in aqueous NaCl solution (0.6 m) at 25°C by means of potentiometric titrations, UV/Vis spectrophotometry, ESI-MS and (in the case of AlIII) by 1H NMR measurements. Accordingly, the effects of the 5-methyl substitution of 4-hydroxy-3- pyridinecarboxylic acid on the stability of Fe and Al complexes were rationalized. Electrochemical measurements allowed to obtain the standard reduction potentials of some FeIII/DQ715 complexes and their kinetic constants. These results indicate that FeIII/DQ715 complexes do not redox cycle in vivo and complex formation is not kinetically limited. The lack of cytotoxicity of DQ715 was demonstrated on human embryonic kidney cells (HEK-293): the IC50 values calculated from the dose-survival curves were 1.4 (after 24 h treatment) and 0.8 mmol/L (after 48 h treatment). The treatment of cells with DQ715 in the presence of FeIII sensibly reduced antiproliferative activity promoted by the metal ion, which suggests an FeIII chelate effect induced by DQ715. According to our results, DQ715 is a chelator for both metal ions, whereas DQ5 is more suitable as a selective Al chelator.

Original languageEnglish
Pages (from-to)1310-1319
Number of pages10
JournalEuropean Journal of Inorganic Chemistry
Issue number8
DOIs
Publication statusPublished - Mar 2013

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Iron Chelating Agents
Niacin
Aluminum
Metal ions
Cytotoxicity
Chelating Agents
Chelation
Ligands
Spectrophotometry
Electrochemistry
Titration
Substitution reactions
Iron
Cells
Nuclear magnetic resonance
Kinetics

Keywords

  • Aluminum
  • Chelation therapy
  • Cytotoxicity
  • Iron
  • Medicinal chemistry
  • Potentiometry

ASJC Scopus subject areas

  • Inorganic Chemistry

Cite this

Possible chelating agents for iron and aluminium - 4-hydroxy-5-methyl- and 4-hydroxy-1,5-dimethyl-3-pyridinecarboxylic acid. / Dean, Annalisa; Sija, Éva; Zsigõ, Éva; Ferlin, Maria Grazia; Marton, Daniele; Gandin, Valentina; Marzano, Cristina; Badocco, Denis; Pastore, Paolo; Venzo, Alfonso; Bertani, Roberta; Kiss, T.; Di Marco, Valerio.

In: European Journal of Inorganic Chemistry, No. 8, 03.2013, p. 1310-1319.

Research output: Contribution to journalArticle

Dean, A, Sija, É, Zsigõ, É, Ferlin, MG, Marton, D, Gandin, V, Marzano, C, Badocco, D, Pastore, P, Venzo, A, Bertani, R, Kiss, T & Di Marco, V 2013, 'Possible chelating agents for iron and aluminium - 4-hydroxy-5-methyl- and 4-hydroxy-1,5-dimethyl-3-pyridinecarboxylic acid', European Journal of Inorganic Chemistry, no. 8, pp. 1310-1319. https://doi.org/10.1002/ejic.201201040
Dean, Annalisa ; Sija, Éva ; Zsigõ, Éva ; Ferlin, Maria Grazia ; Marton, Daniele ; Gandin, Valentina ; Marzano, Cristina ; Badocco, Denis ; Pastore, Paolo ; Venzo, Alfonso ; Bertani, Roberta ; Kiss, T. ; Di Marco, Valerio. / Possible chelating agents for iron and aluminium - 4-hydroxy-5-methyl- and 4-hydroxy-1,5-dimethyl-3-pyridinecarboxylic acid. In: European Journal of Inorganic Chemistry. 2013 ; No. 8. pp. 1310-1319.
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AU - Dean, Annalisa

AU - Sija, Éva

AU - Zsigõ, Éva

AU - Ferlin, Maria Grazia

AU - Marton, Daniele

AU - Gandin, Valentina

AU - Marzano, Cristina

AU - Badocco, Denis

AU - Pastore, Paolo

AU - Venzo, Alfonso

AU - Bertani, Roberta

AU - Kiss, T.

AU - Di Marco, Valerio

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N2 - 4-Hydroxy-5-methyl-3-pyridinecarboxylic acid (DQ5) and 4-hydroxy-1,5- dimethyl-3-pyridinecarboxylic acid (DQ715) were synthesized and evaluated for possible application in iron and aluminium chelation therapy. Metal ion/ligand solution chemistry, electrochemistry, cytotoxicity and chelation efficiency in vitro were studied. The solution chemistry of each ligand with FeIII or AlIII was investigated in aqueous NaCl solution (0.6 m) at 25°C by means of potentiometric titrations, UV/Vis spectrophotometry, ESI-MS and (in the case of AlIII) by 1H NMR measurements. Accordingly, the effects of the 5-methyl substitution of 4-hydroxy-3- pyridinecarboxylic acid on the stability of Fe and Al complexes were rationalized. Electrochemical measurements allowed to obtain the standard reduction potentials of some FeIII/DQ715 complexes and their kinetic constants. These results indicate that FeIII/DQ715 complexes do not redox cycle in vivo and complex formation is not kinetically limited. The lack of cytotoxicity of DQ715 was demonstrated on human embryonic kidney cells (HEK-293): the IC50 values calculated from the dose-survival curves were 1.4 (after 24 h treatment) and 0.8 mmol/L (after 48 h treatment). The treatment of cells with DQ715 in the presence of FeIII sensibly reduced antiproliferative activity promoted by the metal ion, which suggests an FeIII chelate effect induced by DQ715. According to our results, DQ715 is a chelator for both metal ions, whereas DQ5 is more suitable as a selective Al chelator.

AB - 4-Hydroxy-5-methyl-3-pyridinecarboxylic acid (DQ5) and 4-hydroxy-1,5- dimethyl-3-pyridinecarboxylic acid (DQ715) were synthesized and evaluated for possible application in iron and aluminium chelation therapy. Metal ion/ligand solution chemistry, electrochemistry, cytotoxicity and chelation efficiency in vitro were studied. The solution chemistry of each ligand with FeIII or AlIII was investigated in aqueous NaCl solution (0.6 m) at 25°C by means of potentiometric titrations, UV/Vis spectrophotometry, ESI-MS and (in the case of AlIII) by 1H NMR measurements. Accordingly, the effects of the 5-methyl substitution of 4-hydroxy-3- pyridinecarboxylic acid on the stability of Fe and Al complexes were rationalized. Electrochemical measurements allowed to obtain the standard reduction potentials of some FeIII/DQ715 complexes and their kinetic constants. These results indicate that FeIII/DQ715 complexes do not redox cycle in vivo and complex formation is not kinetically limited. The lack of cytotoxicity of DQ715 was demonstrated on human embryonic kidney cells (HEK-293): the IC50 values calculated from the dose-survival curves were 1.4 (after 24 h treatment) and 0.8 mmol/L (after 48 h treatment). The treatment of cells with DQ715 in the presence of FeIII sensibly reduced antiproliferative activity promoted by the metal ion, which suggests an FeIII chelate effect induced by DQ715. According to our results, DQ715 is a chelator for both metal ions, whereas DQ5 is more suitable as a selective Al chelator.

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KW - Cytotoxicity

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KW - Medicinal chemistry

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