Elsevier

Polyhedron

Volume 92, 28 May 2015, Pages 7-11
Polyhedron

Hydroxypyronate, thiohydroxypyronate and hydroxypyridinonate derivatives as potential Pb2+ sequestering agents

https://doi.org/10.1016/j.poly.2015.03.006Get rights and content

Abstract

Solution equilibrium study on Pb(II) complexes of 3-hydroxy-2-methyl-4-pyrone (maltol, maltH) and its two derivatives, 3-hydroxy-2-methyl-4H-pyran-4-thione (thiomaltol, thiomalH) and 3-hydroxy-1,2-dimethyl-4-pyridinone (dhpH) have been performed by using pH-potentiometry, 1H NMR, ESI MS methods. Out of the studied ligands, the (S,O)-chelating thiomalt was found to form the most stable mono- and bis-chelated type species, [PbL]+ and [PbL2], but limited water solubility hindered the examination on this system above pH 7. The Pb(II)-binding capabilities of malt and especially dhp are still very good and the higher extent of electron delocalization in dhp compared to malt results not only in the increased stability of the 5-membered (O,O) dhp chelate, but also the possibility of some involvement of the 6s2 lone electron pair of Pb(II) in the bonding. Furthermore, dhp, compared to malt, is not just a more effective Pb(II) chelator, but also shows better selectivity toward Pb(II) against Zn(II).

Graphical abstract

Results on the title systems indicate the thiohydroxypyronate to form the most stable, but very water unsoluble Pb(II) complexes. In solution, under physiological conditions, the hydroxypyridinonate, dhp, seems to be the best Pb(II) chelator and exhibits the highest selectivity against Zn(II) what was interpreted by the most pronounced delocalization along the chelating O donors in this ligand.

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Introduction

Numerous results support the various ways of Pb(II) poisoning [1], [2], [3], what, in many cases, is in direct correlation with well-defined affinity of this metal ion toward complexation with different bioligands, for instance, proteins [3]. In some part, the toxicity of Pb(II) is attributed to the displacement of physiologically relevant metal ions (like Zn(II), Ca(II) ions) in proteins [1], [4]. Treatment of Pb(II) poisoning is frequently carried out by chelating agents [5], but very often, selectivity defects cause unwanted side-effects. With a better understanding the factors determining the interaction between a ligand and Pb(II), or by controlling the selectivity of a ligand for Pb(II) against Ca(II) and especially against Zn(II), one might be able to design more efficient molecules for the treatment of lead intoxication [6], [7], [8], [9]. To search for ligands forming discrete complex(es) with improved solubility, affinity and selectivity for Pb(II) is one of the main goals in our work nowadays [10], [11], [12], [13]. In a previous paper of ours, the high chelating ability of α-aminohydroxamates to this metal ion was found. This, however, occured only at high pH and resulted in the formation of polynuclear species [11]. In another recent work, we have done a systematic solution equilibrium study on Pb(II)-amino acid, Pb(II)-small peptide/derivative systems. The effects of the arrangement of different type of donor atoms (N, O, S) on the Pb(II)-binding ability as well as on the selectivity for Pb(II) over Zn(II) were evaluated. Significant Zn(II) preference of the investigated N-donor ligands was found, while the ability of the studied O-donor ligands for binding Zn(II) or Pb(II) was roughly the same. Out of the 25 investigated molecules, penicillamine was found to have the best Pb(II) binding ability, but compared to this ligand, a somewhat better selectivity for Pb(II) over Zn(II) was achieved with the S-containing dipeptide, alanyl-cysteine [12]. Systematic investigation on Pb(II) complexation of two hydroxamate based siderophores, desferrioxamine B and desferricoprogen, however, also showed a significant effect of the extent of the electron delocalization on the chelating function [13]. Following this line, three heterocyclic compounds have been involved into the present study.

Hydroxypyrones, thiohydroxypyrones and hydroxypyridinones have 6-membered ring scaffold and their deprotonated forms are effective metal ion chelators [14], [15], [16], [17], [18], [19]. To find some answer for the question, whether or not these compounds can be candidates as potential Pb(II) sequestering agents was the main reason, why Pb(II) complexes of 3-hydroxy-2-methyl-4-pyrone (maltol, maltH) and its two derivatives, 3-hydroxy-2-methyl-4H-pyran-4-thione (thiomaltol, thiomalH) and 3-hydroxy-1,2-dimethyl-4-pyridinone (dhpH) (see Scheme 1 for their formulae) have been included into this study. These simple heterocyclic compounds are especially interesting because there are several ways for their entering into a human body. For example, maltH is known as a non-toxic compound, its use is allowed e.g. in the baking industry as food additive [20]. Deferiprone (dhpH) is one of the best known hydroxypyridinone derivatives, appears quite frequently in many bioactive compounds as pharmaceutical drug (e.g. as iron sequestering agent in the therapy of Thalassemian patients) and its scaffold is considered as “privileged” structure in the design of new chelating drugs [14]. Because S-donor ligands are especially favoured by Pb(II) ion [6], [7], [12], thiomalH was also included into our study.

Any previous solution equilibrium results have not been found for the Pb(II) complexes of these ligands in the literature, only a single solid state work was published for the Pb(II)-dhp dinuclear bis-complex [20]. The results obtained by us and summarized in the present paper are based, first of all, on pH-potentiometric measurements, but 1H NMR and ESI-MS techniques were also used.

Section snippets

Chemicals

MaltH was commercially available (Aldrich). ThiomalH was synthesized using maltol and phosphorus-pentasulphide in abs. dioxane according to Ref. [19] while dhpH was obtained via the reaction of maltol and methylamine as previously published in Ref. [15]. Both of these ligands were characterized via 1H NMR and ESI-TOF-MS. The purity of all the ligands and the concentrations of the ligand stock solutions were checked and determined by Gran’s method [21]. The Pb(II) stock solution was prepared by

Protonation studies on the ligands

MaltH and thiomalH, each has one dissociable proton, while dhpH2+ has two of them. Because of the low solubility of PbCl2, KCl cannot be used during solution equilibrium studies on Pb(II)-containing systems. KNO3 as electrolyte is generally used and this was also the case in the present work. Consequently, also the protonation constants have been determined in the presence of 0.20 M KNO3.

For all the three ligands investigated, the protonation constants were determined by using potentiometric

Acknowledgements

The work was supported by the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of the project ENVIKUT (TÁMOP-4.2.2.A-11/1/KONV-2012-0043) and COST CM1105 program. The authors thank Mr. Attila Godó for his technical help.

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