Job/Unit: I20686 /KAP1 Date: 10-09-12 10:45:39 Pages: 12 FULL PAPER DOI: 10.1002/ejic.201200686 3-(2-Furyl)-2-sulfanylpropenoic Acid as a Chelating Agent for Lead(II) and Diorganonolead(IV) Compounds – Chemical Behaviour and In Vitro Protective Effect against Dimethyllead(IV) Toxicity José S. Casas,* [a] M. Victoria Castaño,* [a] Maria D. Couce, [b] Agustín Sánchez, [a] José Sordo, [a] M. D. Torres, [a] and Ezequiel M. Vázquez López [b] Keywords: Lead / S ligands / Chelates / Cytotoxicity / Organollead(IV) complexes The reaction of the title acid (H 2 fspa) with lead(II) acetate and dimethyl- or diphenyllead(IV) acetate in alcoholic me- dium gives the 1:1 complexes [Pb(fspa)] and [PbR 2 (fspa)] (R = Me, Ph). When the reaction was carried out in the presence of diisopropylamine (Q), the [HQ] 2 [Pb(fspa) 2 ] and [HQ] 2 [PbPh 2 (fspa) 2 ] derivatives formed in low yield. Ad- ditionally, the compounds Na[PbMe 2 (OAc) 3 ], [PbPh 2 (fspa)- (DMSO)] and [PbPh 2 (fspa)(DMSO)]·DMSO were also iso- lated as crystalline solids in subsequent crystallization pro- Introduction At present, the technical, economic and social relevance of lead is beyond all doubt and it is unlikely that this situa- tion will change in the near future. For example, its global usage is expected to increase by 4% in 2012 and reach 10.56 million tonnes. [1] Unfortunately, this unquestionable social usefulness is heavily shaded by the severe toxicity of all of its chemical forms. Lead compounds have deleterious ef- fects on all major body systems but particularly on the de- veloping nervous systems of infants and children. [2] In fact, after the international pooled analysis undertaken by Lan- phear et al. [3] no safe blood lead levels have been established for lead-exposed children. Lead poisoning can be motivated by two types of com- pounds: “inorganic lead” [lead(II)] or “organic lead” [or- ganolead(IV) compounds, mainly tetraalkylleads]. The lat- ter derivatives, still in use in some countries as additives in gasoline, [4] are particularly deleterious and provoke a syn- drome different from inorganic lead toxicity. [5] Chelation therapy is the clinical choice for reducing the body burden [a] Departamento de Química Inorgánica, Universidade de Santiago de Compostela, Campus Vida, 15782 Santiago de Compostela, Galicia, Spain Fax: +34-981547102 E-mail: sergio.casas@usc.es mvictoria.castano@usc.es Homepage: http://www.usc.es/ [b] Departamento de Química Inorgánica, Universidade de Vigo, 36310 Vigo, Galicia, Spain Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejic.201200686. Eur. J. Inorg. Chem. 0000, 0–0 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1 cesses. All these compounds were characterized by IR and NMR ( 1 H and 13 C) spectroscopy and, in some cases, by X- ray diffractometry and 207 Pb NMR spectroscopy. Pig renal proximal tubule LLC-PK1 culture cells were used to deter- mine in vitro the nephroprotective effect of H 2 fspa, [HQ] 2 [Zn(fspa) 2 ], vitamin B 1 and vitamin B 6 against PbMe 2 (NO 3 ) 2 toxicity. The beneficial effects of the acid, the zinc(II) complex and/or their combinations with vitamin B 1 (thiamine nitrate) are described. of inorganic lead. Some common chelating agents for the treatment of this poisoning are calcium disodium ethylene- diaminetetraacetic acid (CaNa 2 EDTA), -penicillamine (DPA), meso-2,3-dimercaptosuccinic acid (dmsa) or so- dium-2,3-dimercaptopropane-1-sulfonate (DMPS), al- though none of them fulfil the desirable characteristics of an ideal chelating agent. [6] There is no specific therapy for intoxication from organic lead compounds. [7] Experiments with rodents suggest that complementing the adminis- tration of chelators with some additional dietary nutrient such as vitamins or essential metals (e.g. zinc and calcium) enhances the efficacy of the chelating agents to reduce the body burden of inorganic lead. [6,8,9] This adjuvant effect may be related to the positive influence of some of these vitamins on the pro-oxidant/antioxidant balance of the lead burdened tissues, which is disrupted by lead(II). [10] These essential metals are possibly beneficial because they counteract their own depletion originated, as a side effect, by the chelator. [11] Also, as in the case of zinc, they can induce the biosynthesis of metallothionein, which then cap- tures the toxic metal and ameliorates its adverse effects [see, for example, ref. [12] ]. Note that, in this last case, lead(II) is not excreted from the body but remains in the target organ firmly attached and inertized. Looking for new and better chelating agents for inor- ganic and organic lead, we have explored, both from a chemical and toxicological point of view, the behaviour of the α-mercaptoacrylic acids 3-(2-thienyl)-2-sulfanylprop- enoic acid and 3-(phenyl)-2-sulfanylpropenoic acid as chela- tors for lead(II) and for dimethyl- or diphenyllead(IV) cat-