This contribution is the result of a work of synthesis of two new bis-3-hydroxy-4-pyridinones (called DTPAPr(3,4-HP)2 and NTAPr(3,4-HP)2), derivatives of DTPA and NTA, and of the results of an investigation on their acid-base properties and binding ability towards trivalent metal cations namely Al3+ and Fe3+ in aqueous solution. Also some biological in vivo assays were carried out on mice. The 3-hydroxy-4-pyridinones (3,4-HPs) are derivatives of Deferiprone and represent a good alternative to the use of Deferoxamine in the chelating therapy for the detoxification of the human body from hard metal cations (e.g. Al3+, Fe3+), because they are effective at physiological conditions and do not involve significant undesired effects [1,2]. The 3,4-HPs can be synthesized from maltol for a reaction of protection of the –OH group with a benzyl group, followed by a double Michael-type addition. The compounds can be further derivatized with the formation of amide bonds. A deprotection of the hydroxyl group with a reaction of hydrogenation, catalyzed by 10% Pd/C concluded the synthetic procedure [3]. The synthetic work was performed during a period of research at the Centro de Química Estrutural of Instituto Superior Técnico of the Universidade de Lisboa. The study of their acid-base properties was carried out by UV-Vis spectrophotometry and spectrofluorimetry, at different experimental conditions. The protonation constants determined showed a good agreement between the two analytical techniques and with the data already reported in the literature for similar ligands [4,5]. The binding ability of DTPAPr(3,4-HP)2 and NTAPr(3,4-HP)2 towards Al3+ and Fe3+ was investigated by UV-Vis spectrophotometric and potentiometric measurements at I = 0.15 mol L-1 in NaCl(aq) and T = 298.15 K. The speciation models obtained consists of MpLqHr complexes with different stoichiometry, such as protonated, simple metal-ligand, hydrolytic mixed and polynuclear species. Furthermore, the sequestering ability of the ligands towards the metal cations was studied by the determination of an empirical parameter, the pL0.5, previously proposed by the research group [6], which represents the total concentration of ligand necessary to sequester the 50% of the metal cation present in trace in solution. Finally, in vivo assays were performed to verify the absence of toxicity of DTPAPr(3,4-HP)2 and NTAPr(3,4-HP)2 and their ability for metal sequestration, if administered to mice preloaded with the radiotracer 67Ga–citrate. Biodistribution studies indicate that these ligands have high in vivo chelating ability promoting the rapid elimination of the radiometal from the animal body.

Bis-3-hydroxy-4-pyridinones: From the synthesis to the complexation with Al3+ and Fe3+ and the biological assays

Anna IRTO
;
Rosalia Maria CIGALA;Francesco CREA;Concetta DE STEFANO;Silvio SAMMARTANO;
2017

Abstract

This contribution is the result of a work of synthesis of two new bis-3-hydroxy-4-pyridinones (called DTPAPr(3,4-HP)2 and NTAPr(3,4-HP)2), derivatives of DTPA and NTA, and of the results of an investigation on their acid-base properties and binding ability towards trivalent metal cations namely Al3+ and Fe3+ in aqueous solution. Also some biological in vivo assays were carried out on mice. The 3-hydroxy-4-pyridinones (3,4-HPs) are derivatives of Deferiprone and represent a good alternative to the use of Deferoxamine in the chelating therapy for the detoxification of the human body from hard metal cations (e.g. Al3+, Fe3+), because they are effective at physiological conditions and do not involve significant undesired effects [1,2]. The 3,4-HPs can be synthesized from maltol for a reaction of protection of the –OH group with a benzyl group, followed by a double Michael-type addition. The compounds can be further derivatized with the formation of amide bonds. A deprotection of the hydroxyl group with a reaction of hydrogenation, catalyzed by 10% Pd/C concluded the synthetic procedure [3]. The synthetic work was performed during a period of research at the Centro de Química Estrutural of Instituto Superior Técnico of the Universidade de Lisboa. The study of their acid-base properties was carried out by UV-Vis spectrophotometry and spectrofluorimetry, at different experimental conditions. The protonation constants determined showed a good agreement between the two analytical techniques and with the data already reported in the literature for similar ligands [4,5]. The binding ability of DTPAPr(3,4-HP)2 and NTAPr(3,4-HP)2 towards Al3+ and Fe3+ was investigated by UV-Vis spectrophotometric and potentiometric measurements at I = 0.15 mol L-1 in NaCl(aq) and T = 298.15 K. The speciation models obtained consists of MpLqHr complexes with different stoichiometry, such as protonated, simple metal-ligand, hydrolytic mixed and polynuclear species. Furthermore, the sequestering ability of the ligands towards the metal cations was studied by the determination of an empirical parameter, the pL0.5, previously proposed by the research group [6], which represents the total concentration of ligand necessary to sequester the 50% of the metal cation present in trace in solution. Finally, in vivo assays were performed to verify the absence of toxicity of DTPAPr(3,4-HP)2 and NTAPr(3,4-HP)2 and their ability for metal sequestration, if administered to mice preloaded with the radiotracer 67Ga–citrate. Biodistribution studies indicate that these ligands have high in vivo chelating ability promoting the rapid elimination of the radiometal from the animal body.
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11570/3129913
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact