New copper-based complexes with quinoxaline N 1 ,N 4 -dioxide derivatives, potential antitumoral agents Carolina Urquiola a , Dinorah Gambino a , Mauricio Cabrera b , Marı ´a Laura Lavaggi b , Hugo Cerecetto b , Mercedes Gonza ´lez b , Adela Lo ´pez de Cerain c , Antonio Monge c , Antonio J. Costa-Filho d , Marı ´a H. Torre a, * a Ca ´ tedra de Quı ´mica Inorga ´ nica, Facultad de Quı ´mica, Universidad de la Repu ´ blica, Gral Flores 2124, C.C. 1157, 11800 Montevideo, Uruguay b Departamento de Quı ´mica Orga ´ nica, Facultad de Quı ´mica – Facultad de Ciencias, Universidad de la Repu ´ blica, Igua ´ 4225, 11400 Montevideo, Uruguay c CIFA, Universidad de Navarra, Pamplona, Spain d Instituto de Fı ´sica, Universidade de Sa ˜o Paulo, C.P. 369, 135600 Sa ˜o Carlos, Brazil Received 11 April 2007; received in revised form 12 July 2007; accepted 20 July 2007 Available online 1 August 2007 Abstract Taking into account our previous studies on cytotoxic metal compounds, new copper complexes with 3-aminoquinoxaline-2-carbo- nitrile N 1 ,N 4 -dioxide derivatives as ligands were synthesized and characterized by different spectroscopic methods. The hypoxic selective cytotoxicity towards V79 cells and the superoxide dismutase-like activity of the complexes were determined and related to physicochem- ical properties of the compounds. In particular, the copper(II) complex with 3-amino-6-chloro-7-fluoroquinoxaline-2-carbonitrile N 1 ,N 4 - dioxide showed cytotoxic selectivity in hypoxia being the most lipophilic compound of the series. On the contrary, the complex with 3-aminoquinoxaline-2-carbonitrile N 1 ,N 4 -dioxide was cytotoxic but not selective and that with 3-amino-7-chloro-6-methoxy-quinoxa- line-2-carbonitrile N 1 ,N 4 -dioxide was not cytotoxic towards V79 cells neither in oxia nor in hypoxia in the assayed conditions. The r m Hammett substituent electronic descriptor was related to the effect in hypoxic conditions and the SOD-like activity was correlated to the effect in normoxia. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Copper complexes; Quinoxaline N 1 ,N 4 -dioxides; Hypoxia selective cytotoxins; Antitumor agents 1. Introduction One general strategy for the research on new anticancer agents has been the therapeutic use of metal containing compounds [1,2]. Specially, in the search of less toxic metal-based antineoplastic drugs, essential metal com- plexes such as copper-based drugs have been developed [3]. The cytotoxicity of these complexes can be explained by different mechanisms of action. In particular, the report by Oberley and Buettner showed that cancer cells have a less than normal superoxide dismutase (SOD) activity and the treatment with bovine native Cu-SOD decreased the growth of several solid tumors [4]. As a consequence a variety of copper complexes presenting SOD-like activity were exam- ined for anticancer activity [3]. For instance, [Cu(II)(3,5- diisopropyl salicylate) 2 ] shows important SOD-like activity and can be used for the differentiation of cultured cancer cells from normal cells at concentrations that do not cause cell death [5,6]. Besides, it has been reported that complexes with SOD-mimetic action activate H 2 O 2 to give reactive radical species such as hydroxyl radical (OH Æ ) that present high biocidal potency [7,8]. On the other hand, copper(II) complexes with amino acids [9], casiopeines [10], oligopeptides [11,12], mono- and bis-thiosemicarbazones [5,13], among others, have 0162-0134/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.jinorgbio.2007.07.028 * Corresponding author. Tel.: +598 2 9249739; fax: +598 2 9241906. E-mail address: mtorre@fq.edu.uy (M.H. Torre). www.elsevier.com/locate/jinorgbio Available online at www.sciencedirect.com Journal of Inorganic Biochemistry 102 (2008) 119–126 JOURNAL OF Inorganic Biochemistry