Synthesis, spectral study and cytotoxicity of platinum(II) complexes with 2,9-disubstituted-6-benzylaminopurines Michal Malon ˇ a , Zdene ˇk Tra ´vnı ´c ˇek a,b, * , Radek Marek c , Miroslav Strnad a a Laboratory of Growth Regulators, Faculty of Science, Palacky ´ University and Institute of Experimental Botany ASCR, S ˇ lechtitelu ˚ 11, CZ-783 71 Olomouc, Czech Republic b Department of Inorganic Chemistry, Faculty of Science, Palacky ´ University, Kr ˇı ´z ˇkovske ´ho 10, CZ-771 47 Olomouc, Czech Republic c Department of Organic Chemistry, Faculty of Science, Masaryk University, Kotla ´r ˇska ´ 2, CZ-611 37 Brno, Czech Republic Received 21 March 2005; received in revised form 8 July 2005; accepted 15 July 2005 Available online 6 September 2005 Abstract A series of platinum(II) complexes with 2,9-disubstituted-6-benzylaminopurines has been prepared. The complexes have the fol- lowing composition: cis-[Pt(Boh) 2 Cl 2 ](1), cis-[Pt(Oc) 2 Cl 2 ](2), cis-[Pt(Ros) 2 Cl 2 ](3), cis-[Pt(i-PrOc) 2 Cl 2 ](4), cis-[Pt(BohH + ) 2 Cl 2 ]Cl 2 (5), cis-[Pt(OcH + ) 2 Cl 2 ]Cl 2 (6), cis-[Pt(RosH + ) 2 Cl 2 ]Cl 2 (7) and cis-[Pt(i-PrOcH + ) 2 Cl 2 ]Cl 2 (8), where Boh = 2-(3-hydroxypropyla- mino)-6-benzylamino-9-isopropylpurine, Oc = 2-(2-hydroxyethylamino)-6-benzylamino-9-methylpurine, Ros = 2-(R)-(1-ethyl-2- hydroxyethylamino)-6-benzylamino-9-isopropylpurine and i-PrOc = 2-(2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine. The complexes have been characterized by elemental analyses, conductivity measurements and their infrared, ES + mass (electro- spray mass spectra in the positive ion mode) and NMR ( 1 H, 13 C, 15 N and 195 Pt) spectra. The results obtained from the physical studies, particularly from multinuclear NMR spectroscopy, show that in all the investigated complexes (1–8), two molecules of pur- ine derivative are coordinated to platinum via the N(7) atom of the imidazole ring in a cis-configuration. The prepared compounds have been screened for their in vitro cytotoxicity against G-361 (human malignant melanoma), HOS (human osteogenic sarcoma), K-562 (human chronic myelogenous leukemia) and MCF-7 (human breast adenocarcinoma) cell lines. All complexes are signifi- cantly more active than the initial 2,9-disubstituted-6-benzylaminopurine derivatives. In the case of some tumour cell lines, IC 50 val- ues for the complexes (1, 3, 4, 5, 8) are significantly lower than those obtained for cisplatin and oxaliplatin. The best cytotoxicity was achieved for the complex (3) for which IC 50 values range from 1 to 2 lM. Ó 2005 Elsevier Inc. All rights reserved. Keywords: Platinum(II) complexes; Multinuclear NMR study; CDK inhibitors; Roscovitine; In vitro cytotoxicity 1. Introduction The anticancer activity of platinum(II) complexes is well known. Cisplatin (cis-diamminedichloroplati- num(II), cis-DDP) belongs to one of the most com- monly used anticancer drugs in chemotherapy, especially against testicular, ovarian and bladder cancers [1]. Unfortunately, when using this drug, the treatment is accompanied by many undesirable side effects includ- ing nephrotoxicity, ototoxicity, neurotoxicity and nau- sea [2–5]. In addition, a natural or acquired resistance of many human tumours represents another serious problem, which causes cisplatin-based treatments to be less effective [2,6]. Thus, new platinum anticancer agents have been developed and extensively studied to over- come the above-mentioned limitations [7–13]. 2,9-Disubstituted-6-benzylaminopurine derivatives have been intensively investigated for their antitumour 0162-0134/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.jinorgbio.2005.07.009 * Corresponding author. Tel.: +420 58 563 4944; fax: +420 58 563 4954. E-mail address: trav@risc.upol.cz (Z. Tra ´vnı ´c ˇek). www.elsevier.com/locate/jinorgbio Journal of Inorganic Biochemistry 99 (2005) 2127–2138 JOURNAL OF Inorganic Biochemistry