Platinum(II) and palladium(II) complexes with (N,N′) and (C,N,N′) - ligands derived from pyrazole as anticancer and antimalarial agents: Synthesis, characterization and in vitro activities Josefina Quirante a , Daniel Ruiz a , Asensio Gonzalez a , Concepción López b, ⁎, Marta Cascante c , Roldán Cortés c , Ramon Messeguer d , Carme Calvis d , Laura Baldomà e , Aurélie Pascual f , Yann Guérardel g, h , Bruno Pradines f , Mercè Font-Bardía i , Teresa Calvet j , Christophe Biot g, h, ⁎⁎ a Laboratori de Química Orgànica, Facultat de Farmàcia, Institut de Biomedicina, (IBUB), Universitat de Barcelona, Av. Joan XXIII, s/n, 08028 Barcelona, Spain b Departament de Química Inorgànica, Facultat de Química, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain c Department of Biochemistry and Molecular Biology, Faculty of Biology, Institute of Biomedicine of University of Barcelona (IBUB) and IDIBAPS, Unit Associated with CSIC, Diagonal 645, 08028 Barcelona, Spain d Leitat Tecnological Center, Parc Cientific de Barcelona, Edifici Hèlix, C/Baldiri Reixach, 15-21, 08028 Barcelona, Spain e Departament de Bioquímica i Biologia Molecular, Facultat de Farmàcia, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Av. Joan XXIII s/n, 08028 Barcelona, Spain f Institut de Recherche Biomédicale des Armées, Antenne de Marseille, Unité de Parasitologie, URMITE-UMR 6236, Allée du Médecin Colonel Jamot, Parc le Pharo, BP 60109, 13262 Marseille Cedex 07, France g Université Lille Nord de France, Université Lille 1, Unité de Glycobiologie Structurale et Fonctionnelle, 59650 Villeneuve d'Ascq, France h UMR CNRS 8576, France i Unitat de Difracció de Raig-X, Centre Científici Tecnològic de La Universitat de Barcelona, Solé I Sabarís 1-5, 08028 Barcelona, Spain j Departament de Cristal.lografia, Mineralogia I Dipòsits Minerals, Facultat de Geologia, Universitat de Barcelona, Martí i Franquès s/n. 08028 Barcelona, Spain abstract article info Article history: Received 31 May 2011 Received in revised form 12 September 2011 Accepted 14 September 2011 Available online xxxx Keywords: Cancer Malaria Palladium Platinum The study of the reactivity of three 1-(2-dimethylaminoethyl)-1H-pyrazole derivatives of general formula [1-(CH 2 ) 2 NMe 2 }-3,5-R 2 -pzol] {where pzol represents pyrazole and R_H(1a), Me (1b) or Ph (1c)} with [MCl 2 (DMSO) 2 ] (M_Pt or Pd) under different experimental conditions allowed us to isolate and character- ize cis-[M{κ 2 -N,N′-{[1-(CH 2 ) 2 NMe 2 }-3,5-R 2 -pzol])}Cl 2 ] {MM_PtPt (2a–2c) or Pd (3a–3c)} and two cyclo- metallated complexes [M{κ 3 -C,N,N′-{[1-(CH 2 ) 2 NMe 2 }-3-(C 5 H 4 )-5-Ph-pzol])}Cl] {M_Pt(II) (4c) or Pd(II) (5c)}. Compounds 4c and 5c arise from the orthometallation of the 3-phenyl ring of ligand 1c. Complex 2a has been further characterized by X-ray crystallography. Ligands and complexes were evaluated for their in vitro antimalarial against Plasmodium falciparum and cytotoxic activities against lung (A549) and breast (MDA MB231 and MCF7) cancer cellular lines. Complexes 2a–2c and 5c exhibited only moderate an- timalarial activities against two P. falciparum strains (3D7 and W2). Interestingly, cytotoxicity assays revealed that the platinacycle 4c exhibits a higher toxicity than cisplatin in the three human cell lines and that the complex 2a presents a remarkable cytotoxicity and selectivity in lung (IC 50 =3 μM) versus breast cancer cell lines (IC 50 N 20 μM). Thus, complexes 2c and 4c appear to be promising leads, creating a novel family of anticancer agents. Electrophoretic DNA migration studies in presence of the synthesized compounds have been performed, in order to get further insights into their mechanism of action. © 2011 Elsevier Inc. All rights reserved. 1. Introduction Platinum drugs have played a key role among the metal-based anti- cancer agents [1]. The discovery of the antitumor properties of cis-[PtCl 2 (NH 3 ) 2 ] cisplatin [2] (Fig. 1) in 1965 was rapidly followed by clinical trials and finally in 1978, FDA granted approval. Platinum(II) complexes such as cisplatin and carboplatin (Fig. 1) are widely used to treat cancers such as testicular, ovarian, urinary bladder, melanoma, etc. The cytotoxicity of Pt- based drugs is mainly attributed to their ability to bind DNA and to induce DNA damage leading then to apoptosis [3–5]. Unfortunately, the use of cisplatin is restricted due to dose-limiting toxicity, including nephrotoxicity, neurotoxicity and ototoxicity [6,7]. Additional side effects such as blood pressure increase, severe nausea, vomiting and diarrhea have also been reported. Moreover, the biochem- ical resistance mode limits the clinical utility of the Pt-based drugs in cur- rent use [1]. Journal of Inorganic Biochemistry xxx (2011) xxx–xxx ⁎ Corresponding author. Tel.: + 34 934039134; fax: + 34 934907725. ⁎⁎ Correspondence to: C. Biot, Université Lille Nord de France, Université Lille 1, Unité de Glycobiologie Structurale et Fonctionnelle, 59650 Villeneuve d'Ascq, France. Tel.: +33 3 20436941; fax: +33 3 20436555. E-mail addresses: conchi.lopez@qi.ub.es (C. López), christophe.biot@univ-lille1.fr (C. Biot). JIB-08919; No of Pages 9 0162-0134/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.jinorgbio.2011.09.021 Contents lists available at SciVerse ScienceDirect Journal of Inorganic Biochemistry journal homepage: www.elsevier.com/locate/jinorgbio Please cite this article as: J. Quirante, et al., Platinum(II) and palladium(II) complexes with (N,N′) and (C,N,N′)- ligands derived from pyr- azole as anticancer and antimalarial ag..., J. Inorg. Biochem. (2011), doi:10.1016/j.jinorgbio.2011.09.021