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

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Abstract

4-hydroxy-3,5-pyridinedicarboxylic acid (DQ58) and 4-hydroxy-1-methyl-3,5-pyridinedicarboxylic 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 spectroscopy (in the case of Fe(III), Al(III), Cu(II)), 1H-NMR (for Al(III)) and EPR (for Cu(II)). The 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 ions (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 × 10−3 and 1.033 × 10−3 mol·L−1 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.

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References

  1. Nurchi, V.M., Crisponi, G., Lachowicz, J.I., Medici, S., Pean, M., Zoroddu, M.A.: Chemical features of in use and in progress chelators for iron overload. J. Trace Elem. Med. Biol. 38, 10–18 (2016)

    Article  CAS  Google Scholar 

  2. Toso, L., Crisponi, G., Nurchi, V.M., Crespo-Alonso, M., Lachowicz, J.I., Mansoori, D., Arca, M., Santos, M.A., Marques, S.M., Gano, L., Niclos-Gutierrez, J., Gonzalez-Perez, J.M., Dominguez-Martin, A., Choquesillo-Lazarte, D., Szewczuk, Z.: Searching for new aluminium chelating agents: A family of hydroxypyrone ligands. J. Inorg. Biochem. 130, 112–121 (2014)

    Article  CAS  Google Scholar 

  3. Hider, R.C., Kong, X.: Iron: effect of overload and deficiency. In: Sigel, A., Sigel, H., Sigel, R.K.O.: Interrelations Between Essential Metal Ions and Human Diseases (Metal Ions in Life Sciences, volume 13), pp. 229–294. Springer, Heidelberg (2013)

  4. Crisponi, G., Dean, A., Di Marco, V., Lachowicz, J.I., Nurchi, V.M., Remelli, M., Tapparo, A.: Different approaches in the study of chelating agents for iron and aluminium overload pathologies. Anal. Bioanal. Chem. 405, 585–601 (2013)

    Article  CAS  Google Scholar 

  5. Liu, Z.D., Hider, R.C.: Design of clinically useful iron(III)-selective chelators. Med. Res. Rev. 22, 26–64 (2002)

    Article  CAS  Google Scholar 

  6. Dean, A., Ferlin, M.G., Cvijovic, M., Djurdjevic, P., Dotto, F., Badocco, D., Pastore, P., Venzo, A., Di Marco, V.B.: Evaluation of 1,2-dimethyl-3-hydroxy-4-pyridinecarboxylic acid and of other 3-hydroxy-4-pyridinecarboxylic acid derivatives for possible application in iron and aluminium chelation therapy. Polyhedron 67, 520–528 (2014)

    Article  CAS  Google Scholar 

  7. Balogh, M., Hermecz, I., Mészaros, Z., Simon, K., Pusztay, L., Horváth, G., Dvortsak, P.: Studies on chemotherapeutics I. Synthesis of 5-substituted-4-oxo-1,4-dihydro-3-pyridinecarboxylic acid derivatives. J. Heter. Chem. 17, 359–368 (1980)

  8. Dean, A., Sija, É., Zsigó, É., Ferlin, M.G., Marton, D., Gandin, V., Marzano, C., Badocco, D., Pastore, P., Venzo, A., Bertani, R., Kiss, T., Di Marco, V.: Possible chelating agents for iron and aluminium: 4-hydroxy-5-methyl-3-pyridinecarboxylic acid and 1,5-dimethyl-4-hydroxy-3-pyridinecarboxylic acid. Eur. J. Inorg. Chem. 1310–1319 (2013)

  9. Di Marco, V.B., Tapparo, A., Bombi, G.G.: Complex formation between aluminium(III) and two hydroxyaromatic ligands: 2-hydroxyphenylethanone and 2-hydroxybenzeneacetic acid. Ann. Chim. (Rome) 89, 397–407 (1999)

    Google Scholar 

  10. Di Marco, V.B., Tapparo, A., Bombi, G.G.: New possible chelating agents of clinical interest for iron(III): 2-hydroxynicotinic acid and 3-hydroxypicolinic acid. A thermodynamic study. Ann. Chim. (Rome) 91, 595–603 (2001)

    Google Scholar 

  11. Irving, H.M., Miles, M.G., Pettit, L.D.: A study of some problems in determining the stoichiometric proton dissociation constants of complexes by potentiometric titrations using a glass electrode. Anal. Chim. Acta 38, 475–481 (1967)

    Article  CAS  Google Scholar 

  12. Di Marco, V.B., Tapparo, A., Bombi, G.G.: Complex formation between aluminium(III) and two pyridine derivatives: 2-hydroxynicotinic and 3-hydroxypicolinic acid. Ann. Chim. (Rome) 89, 535–546 (1999)

    Google Scholar 

  13. Di Marco, V.B.: Ph. D. Thesis, University of Padova (1998)

  14. Zékány, L., Nagypál, I., Peintler, G.: PSEQUAD for Chemical Equilibria. Technical Software Distribution, Baltimore (1991)

    Google Scholar 

  15. Rossotti, F.J.C., Rossotti, H.: The determination of stability constants and other equilibrium constants in solution. Mc Graw–Hill Book Company Inc., New York (1961)

    Google Scholar 

  16. Öhman, L.O., Sjöberg, S.: The experimental determination of thermodynamic properties for aqueous aluminum complexes. Coord. Chem. Rev. 149, 33–57 (1996)

    Article  Google Scholar 

  17. Flynn Jr., C.M.: Hydrolysis of inorganic iron(III) salts. Chem. Rev. 84, 31–41 (1984)

    Article  CAS  Google Scholar 

  18. Öhman, L.O.: Stable and metastable complexes in the system H+–Al3+citric acid. Inorg. Chem. 27, 2565–2570 (1988)

    Article  Google Scholar 

  19. Covington, A.K., Paabo, M., Robinson, R.A., Bates, R.G.: Use of the glass electrode in deuterium oxide and the relation between the standardized pD (paD) scale and the operational pH in heavy water. Anal. Chem. 40, 700–706 (1968)

    Article  CAS  Google Scholar 

  20. Enyedi, É.A., Farkas, E., Dömötör, O., Santos, M.A.: Interaction of folic acid and some MMP inhibitor folate-γ-hydroxamate derivatives with Zn(II) and human serum albumin. J. Inorg. Biochem. 105, 326–335 (2011)

    Google Scholar 

  21. Alley, M.C., Scudiero, D.A., Monks, A., Hursey, M.L., Czerwinski, M.J., Fine, D.L., Abbott, B.J., Mayo, J.G., Shoemaker, R.H., Boyd, M.R.: Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res. 48, 589–601 (1988)

    CAS  Google Scholar 

  22. Di Marco, V.B., Dean, A., Ferlin, M.G., Yokel, R.A., Li, H., Venzo, A., Bombi, G.G.: Methyl-hydroxypyridinecarboxylic acids as possible bidentate chelating agents for aluminium(III): synthesis and metal–ligand solution chemistry. Eur. J. Inorg. Chem. 1284–1293 (2006)

  23. Di Marco, V.B., Yokel, R.A., Ferlin, M.G., Tapparo, A., Bombi, G.G.: Evaluation of 3,4-hydroxypyridinecarboxylic acids as possible bidentate chelating agents for aluminium(III): synthesis and metal–ligand solution chemistry. Eur. J. Inorg. Chem. 2648–2655 (2002)

  24. Kiss, T., Farkas, E.: The bioinorganic chemistry of aluminium. Perspec. Bioinorg. Chem. 3, 199–250 (1996)

    CAS  Google Scholar 

  25. Sija, É., Dean, A., Jakusch, T., Di Marco, V.B., Venzo, A., Kiss, T.: Interactions of pyridinecarboxylic acid chelators with brain metal ions: Cu(II), Zn(II), and Al(III). Monatsh. Chem. 142, 399–410 (2011)

    Article  CAS  Google Scholar 

  26. Wu, Y., Mu, Y., Bai, L., Guo, S., Zhao, J., Li, D.: Synthesis, crystal structures, and magnetic properties of two Cu(II)-complexes based on in situ generated 5-NO2-2-hydroxyisophthalic acid. J. Coord. Chem. 67, 1629–1638 (2014)

    Article  CAS  Google Scholar 

  27. Li, S., Liu, J., Guo, J., Ji, L., Song, W., Ma, D.: Construction of two novel 2D coordination frameworks with the ligand H3nbtc: synthesis, crystal structures, and luminescence. Z. Anorg. Allgem. Chem. 638, 832–837 (2012)

    Article  CAS  Google Scholar 

  28. Zhu, X., Wang, N., Li, B., Zhang, H., Luo, Y., Pang, Y., Tian, D.: Syntheses, crystal structures, and magnetic properties of four novel Cu(I/II) complexes. Inorg. Chim. Acta 383, 235–243 (2012)

    Article  CAS  Google Scholar 

  29. Crisponi, G., Remelli, M.: Iron chelating agents for the treatment of iron overload. Coord. Chem. Rev. 252, 1225–1240 (2008)

    Article  CAS  Google Scholar 

  30. Di Marco, V.B., Tapparo, A., Dolmella, A., Bombi, G.G.: Complexation of 2-hydroxynicotinic and 3-hydroxypicolinic acid with zinc(II). Solution state study and crystal structure of trans-diaqua-bis-(3-hydroxypicolinato)zinc(II). Inorg. Chim. Acta 357, 135–142 (2004)

    Article  Google Scholar 

  31. Reinhold, J.G.: Trace elements - a selective survey. Clin. Chem. 21, 476–500 (1975)

    CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by University of Padova, ‘‘Progetto Ateneo 2008, CPDA083904/08, 54000 €’’. We thank Nicola Bianchetto, Annamaria Cassini, Maristella Feltracco, Maria Zulpo (University of Padova), and Nelli Suba (University of Szeged), for their excellent work. The research was supported by the National Research, Development and Innovation Office-NKFIH through project GINOP-2.3.2-15-2016-00038.

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Authors and Affiliations

  1. Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131, Padua, Italy

    Annalisa Dean, Daniele Marton & Valerio B. Di Marco

  2. Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131, Padua, Italy

    Maria Grazia Ferlin, Davide Carta, Fernanda Fabiola Faccioli & Sofia Parrasia

  3. Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm Tér 7, 6701, Szeged, Hungary

    Tamas Jakusch & Tamas Kiss

  4. CNR-IENI, Institute of Energetic and Interphases, Via Marzolo 1, 35131, Padua, Italy

    Alfonso Venzo

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  1. Annalisa Dean
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Correspondence to Valerio B. Di Marco.

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Dean, A., Ferlin, M.G., Carta, D. et al. 4-Hydroxy-3,5-pyridinedicarboxylic Acids: Synthesis, Complexation Properties Towards Fe(III), Al(III), Cu(II), Zn(II), Human Serum Albumin, and Cellular Toxicity. J Solution Chem 47, 92–106 (2018). https://doi.org/10.1007/s10953-018-0709-0

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