FULL PAPER Structural Trends in Divalent Benzil Bis(thiosemicarbazone) Complexes David G. Calatayud, [a] Elena López-Torres, [a] M. Antonia Mendiola,* [a] César J. Pastor, [b] and Jesús R. Procopio [c] Keywords: Copper / N ligands / S ligands / Thiosemicarbazone complexes / Zinc Redox-related changes in the biological properties of copper bis(thiosemicarbazones) are induced by the backbone of the ligand. To get information about how these changes depend on the structural parameters, three X-ray structures of com- plexes with different behaviour of the benzil bis(thiosemicar- bazone) ligand have been determined. These include two al- most planar copper(II) complexes with different grades of de- protonation in the ligand and a Zn II complex in which the ligand acts as a monoanion and a nitrate group is bonded to Introduction The increasing interest in thiosemicarbazones (TSCs) that has arisen in the last decades is related to their wide range of biological properties, for example as antiviral, anti- bacterial and anticancer agents. [1–4] These biological activi- ties are often attributed to their chelating ability with metal ions. Copper complexes of bis(thiosemicarbazones) have been investigated for use as anti-cancer chemotherapeutic agents [5,6] and as superoxide dismutase-like radical scaven- gers. [7] It is, however, their use as delivery agents for radio- active copper in new copper-based radiopharmaceuticals and the hypoxic selectivity of certain copper bis(thiosem- icarbazonate) complexes that has created much recent inter- est. [8–20] The biological characteristics of copper bis(thiose- micarbazonate) complexes derived from 1,2-diones are de- pendent on the nature of the “backbone” substituents in the ligand. The most detailed studies of these structure– activity relationship have been carried out in connection with hypoxia imaging. [14,15,21] These studies correlated hyp- oxic cell selectivity with the reduction potential, electronic structure and chemical behaviour and found that all of these properties are extraordinarily sensitive to the alkyl groups attached to the diimine backbone of the ligand. The trapping in a hypoxic cell is believed to occur by reduction of the copper() complex by intracellular reducing agents [a] Departamento de Química Inorgánica, Universidad Autónoma, 28049 Madrid, Spain E-mail: antonia.mendiola@uam.es [b] Servicio Interdepartamental de Investigación, Universidad Aut- ónoma, 28049 Madrid, Spain [c] Departamento de Química Analítica y Análisis Instrumental, Universidad Autónoma, 28049 Madrid, Spain Eur. J. Inorg. Chem. 2005, 4401–4409 DOI: 10.1002/ejic.200500363 © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4401 the metal ion in a square-based pyramid. The changes in the backbone bond lengths agree with the variation in the ionic radius and with the grade of electronic charge delocalisation in the chelate rings; these have consequences for the coordi- nation sphere, allowing the metal to fit slightly better into the ligand cavity, which in turn may affect the complex sta- bility and the redox potential. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005) to give stable protonated Cu I species, which are trapped in- side the cell. [22] The structure–activity relationships of cop- per bis(thiosemicarbazone) radiopharmaceuticals derived from 1,2-diones show a correlation between the reduction potential for the Cu II /Cu I couple and the hypoxic cell selec- tivity. [14,23] The hypoxia-selective radiopharmaceutical [Cu- (ATSM)] [ATSM = biacetyl bis(4-methylthiosemicarba- zone)], for example, undergoes a reversible reduction at E 1/2 = –0.620 V in DMF at a glassy carbon working elec- trode. On the other hand, some zinc thiosemicarbazone complexes that have been shown to be active as anti-tumour agents are as cytotoxic as cisplatin and are also effective against cisplatin-resistant cell lines. [24] Recently, fluores- cence studies and the cellular distribution of zinc bis(thiose- micarbazone) complexes have been reported. [25] Since relatively superficial modifications induce remark- able changes in redox and biological properties, it is natural to enquire whether they might also significantly affect the core structural parameters of the complexes and, if so, whether this might be related to their biological behaviour. The aim of this work is to get information about the impor- tance of the changes induced by the modification of the backbone of benzil bis(thiosemicarbazone) (LH 6 ) in some complexes. In particular, for copper() complexes these changes affect the redox properties and therefore their po- tential activity as hypoxia-selective radiopharmaceuticals. We report the X-ray structures of two copper complexes derived from LH 6 (Figure 1) whose reduction potential val- ues are –0.550 and –0.520 V, [26] close to those of [Cu- (ATSM)], a related zinc complex, as well as the structure of a nickel complex for comparison. [27] We also discuss struc- tural variations as a function of the ligand behaviour and/ or the metal ion.