title: Evaluation of 2-methyl-3-hydroxy-4-pyridinecarboxylic acid as a possible chelating agent for iron and aluminium.
abstract: In view of a possible application to Fe and Al chelation therapy, 2-methyl-3-hydroxy-4-pyridinecarboxylic acid (DT2) was synthesised, and its complex formation, electrochemical and cytotoxic properties were studied. The complexing properties of DT2 towards Fe(III) and Al(III) were investigated in aqueous 0.6 m (Na)Cl at 25 degrees C by means of potentiometric titrations, UV-vis spectrophotometry, and 1H NMR spectroscopy. DT2 is a triprotic acid (H3L+) having pKa1 = 0.47, pKa2 = 5.64 and pKa3 = 11.18. The metal-ligand complexes observed in solution and their corresponding stability constants (log beta values) are the following: FeLH (19.38), FeL (16.01), FeLH(-1) (12.28), FeL2H2 (37.29), FeL3H3 (53.41), FeL3H2 (47.99), FeL3H (41.21) and FeL3 (34.1); AlLH (17.43), AlL2H2 (33.74), AlL2H (27.6), AlL3H3 (48.72), AlL3H2 (42.67), AlL3H (35.8) and AlL3 (27.92). The complex formation between DT2 and Fe(II) was studied by UV-vis: the weak complex FeLH (log beta = 15.8) was detected. DT2 shows a lower complexation efficiency with Fe(III) and Al(III) than that of other available chelators, but higher than that of its non-methylated analogue 3-hydroxy-4-pyridinecarboxylic acid (DT0). The electrochemical behaviour of DT2 was investigated by means of cyclic voltammetry, indicating that the oxidation of the ligand proceeds through a two electron process with a CECE mechanism. Voltammetric curves suggest that the oxidation or the reduction of DT2 in vivo is unlikely. According to the thermodynamic data, also the Fe(III)-DT2 complexes do not undergo redox cycling at physiological pH. Amperometric titrations of solutions containing Fe(III) and DT2 at pH = 5 indicated the same Fe(III) : ligand stoichiometric ratio as calculated from potentiometric data. The toxicity of DT2 and of other simple hydroxypyridinecarboxylic acids was investigated in vitro and no cytotoxic activity was observed (IC50 > 0.1 mM) on cancer cell lines and also on primary human cells, following a three day exposure.
authors: Dipartimento di Scienze Chimiche, Università di Padova, via Marzolo 1, 35131, Padova, Italy.
authors: Annalisa
authors: A
authors: Dean
authors: Maria Grazia
authors: MG
authors: Ferlin
authors: Paola
authors: P
authors: Brun
authors: Ignazio
authors: I
authors: Castagliuolo
authors: Denis
authors: D
authors: Badocco
authors: Paolo
authors: P
authors: Pastore
authors: Alfonso
authors: A
authors: Venzo
authors: G Giorgio
authors: GG
authors: Bombi
authors: Valerio B
authors: VB
authors: Di Marco
mesh_terms: D000535:Aluminum / Q000737:chemistry*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry* / Q000494:pharmacology; D004563:Electrochemistry; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D007502:Iron Chelating Agents / Q000737:chemistry* / Q000494:pharmacology; D007539:Isonicotinic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013056:Spectrophotometry, Ultraviolet; D013816:Thermodynamics; D018675:Toxicity Tests
chemical_list: C529743:2-methyl-3-hydroxy-4-pyridinecarboxylic acid; D002614:Chelating Agents; D007502:Iron Chelating Agents; D007539:Isonicotinic Acids; D000535:Aluminum