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68 RADIOCHEMISTRY, STABLE ISOTOPES, NUCLEAR ANALYTICAL METHODS, GENERAL CHEMISTRY STRUCTURAL STUDIES AND CYTOTOXICITY ASSAYS OF PLATINUM(II) CHLORIDE COMPLEXED BY (TETRAHYDROTHIOPHENE)THIOUREA Leon Fuks, Marcin Kruszewski, Nina Sadlej-Sosnowska 1/ 1/ National Institute for Public Health, Warszawa, Poland At present, chemotherapy is indispensable for the treatment of numerous kinds of cancer. Despite advances in surgery and radiotherapy, the mortality caused by cancer remained practically unchanged until the cisplatin (cis-diamminedichloroplatinum(II), CDDP) has been discovered. The introduction of platinum-based chemotherapy has significantly improved the efficiency of therapeutic regimens. Most of the platinum compounds used today are the derivatives of CDDP, with two amino groups in the cis position [1,2]. In 2000, a novel platinum complex based on sulfur as complex-forming donor atoms – bis(O-ethyldithiocarbonato)-platinum(II), named thioplatin – a tumor targeting platinum-based drug was developed by the German Cancer Research Centre and licensed by Antisoma [3]. At present, it is called the “gold standard” and forms the cornerstone of cancer treatments against a range of solid tumors resistant to cisplatin, including lung, ovarian and testicular cancers. On the basis of our previous studies [4], a question arises if the M(R 1 R 2 tu) x 2+ , where (R 1 R 2 tu) denotes various derivatives of thiourea, might exhibit the desired biological activity. The main objective of the present work was to modify the tu molecule in order to obtain other platinum(II) complexes which exhibit the antitumor activity. In details, the N-(2-methyltetrahydrothiophene)thiourea, derivative of simple thiourea containing the moiety able to link to the DNA and its platinum(II) complex were prepared and tested for antitumor properties. The biological activity was checked using the standard L1210 murine leukemia cell line. The title complex, was synthesized according to the following reaction: K 2 Pt II Cl 4 + L → Pt II LCl 2 + 2KCl by dropwise adding, at room temperature, an ethanolic solution of the ligand to the aqueous solution of K 2 PtCl 4 until the molar ratio 1:1 was achieved [4]. It is well known, that the structure of the investigated platinum(II) complexes strongly influences their biological properties. This might be of importance for their interactions with numerous biochemical targets, e.g. with DNA. However, because of the severe difficulties in obtaining crystals suitable for X-ray diffraction investigations, the registered IR spectra accompanied by quantum-chemical calculations appeared to be main source of the structural information. We have already shown that the calculations performed sufficiently well reflect the main structural features of platinum(II) complexes with the thiourea derivatives [4,5]. Structural investigations It has been already demonstrated that the MPW1PW one-parameter density-functional approach is a reliable method for predicting molecular structures and vibrational spectra of the therapeutically important platinum(II) coordination compounds: cisplatin and carboplatin. The MPW1PW/LanL2DZ method yielded the geometry and vibrational frequencies in better agreement with the experimental data, than those obtained with other functionals and using the MP2 routine [6]. It also generated the geometry and vibrational frequencies, describing complexes of the divalent platinum and palladium cations with thiourea, very similar to the experimental data [4]. Calculations for the title compound have been performed by two consecutive quantum-chemical methods: semi-empirical PM3 and MPW1PW/ LanL2DZ procedure. The LanL2DZ basis set of Hay and Wadt [7-9], takes into account relativistic effects. All calculations were performed using SPARTAN Pro 5.0 (PC version) [10] and Gaussian 98 package [11] running on the Silicon Graphics IRIS Indigo work station with the processor RISC 10000. Application of the semi-empirical PM3 method resulted in several dozens of conformers of the complex. However, during quantum-chemical calculations only one structure could be optimized. Under the assumption of the analytically found Pt:Cl mol ratio close to 3, analogously to our previous work [5], three hypothetic structures were examined. The species containing monodentately bound ligand has been chosen as the most probable structure because of its lowest energy. Two projections of the structure are shown in Fig.1. From Fig.1b, it can easily be seen that within the entire molecule two hydrogen bonds between the hydrogen and chloride atoms can be formed (2.119 and 2.795 Å). Thiophene ring of the ligand exists in the C s twisted conformation, which is characterized by the coplanarity of three adjacent ring atoms and the midpoints of the opposite bonds [12]. The computation has revealed its similarity to these of the isolated thiophene and 1-methylthiophene rings. The result obtained seems to be interesting and important for further studies, be-
RADIOCHEMISTRY, STABLE ISOTOPES, NUCLEAR ANALYTICAL METHODS, GENERAL CHEMISTRY a b 69 Fig.1. Linear (a) and seven-membered (b) structures of the platinum(II) complex; possible hydrogen bonds are shown. cause the most stable conformation of its oxygen analog – tetrahydrofuran – appeared to be different. The results published already of ab initio calculations [13] suggest that the equilibrium conformation of tetrahydrofuran is an envelope C s structure. On the contrary, the calculations performed in our group for the 1-methyltetrahydrofuran ring suggest that the lowest-energy is associated to even the most low (C 1 ) symmetry of the ring. Biological investigations Cytotoxicity of the studied complex was estimated in vitro by means of the relative growth test with 1 hour exposure to the drug, as described elsewhere [14]. Studies were performed with the mouse lymphoma cell line L1210. The 50% inhibition dose (ID 50 ) was determined by extrapolation of the steep part of survival curves obtained. Concentration range of the investigated species was 0.01-0.150 mg·cm –3 . Precision of the calculated ID 50 value was estimated using the propagation of measuring uncertainty technique, and the error limits of the estimates for the slope and intercept of survival curves. If the toxicity of the reference CDDP was found to be ID 50 =5 µM [15], the ID 50 of the species investigated in the presented work appeared to be about 313.8±10.8 and 10.63±1.31 µM for the ligand and complex, respectively (Fig.2). The latter value, being comparable to that for CDDP, suggests the necessity of determining the therapeutic Fig.2. Cytotoxicity of the studied ligand and platinum(II) complex. index of the complex (TI=LD 50 /ID 90 ; TI of the CDDP being 8.1 [16]) as well as of checking its toxicity against other tumor lines. We thank Prof. Adam Krówczyński (Department of Chemistry, Warsaw University) for synthesizing the ligand. References [1]. Hollis L.S.: In: Platinum and other metal coordination compounds in cancer chemotherapy. Ed. S.B. Howell. Plenum Press, New York 1991. [2]. Lebwohl D., Canetta R.: Eur. J. Cancer, 34, 1522-1534 (1998). [3]. Amtmann E., Zöller M., Wesch H., Schilling G.: Cancer Chemother. Pharmacol., 47, 461-466 (2001). [4]. Fuks L., Sadlej-Sosnowska N., Samochocka K., Starosta W.: J. Mol. Struct., 740, 229-235 (2005). [5]. Fuks L., Kruszewski M., Sadlej-Sosnowska N., Samochocka K.: Characterization studies and cytotoxicity assays of Pt(II) chloride complexed by N-(2-methyltetrahydrofuryl)thiourea. In: INCT Annual Report 2004. Institute of Nuclear Chemistry and Technology, Warszawa 2005, pp.63-67. [6]. Wysokiński R., Michalska D.: J. Comput. Chem., 22, 901-912 (2002). [7]. Hay P.J., Wadt W.R.: J. Chem. Phys., 82, 270-283 (1985). [8]. Wadt W.R., Hay P.J.: J. Chem. Phys., 82, 284-298 (1985). [9]. Hay P.J., Wadt W.R.: J. Chem. Phys., 82, 299-310 (1985). [10]. PC Spartan Pro Ver. 1. Wavefunction, Inc., Irvine 1999. [11]. Frisch M.J. et al.: Gaussian 98-A.7 Revision. Gaussian, Inc., Pittsburgh 1998. [12]. Meyer R., López J.C., Alonso J.L., Melandri S., Favero P.G., Caminati W.: J. Chem. Phys., 111, 7871-7880 (1999). [13]. Rayón V.M., Sordo J.A.: J. Chem. Phys., 122, 204303-204310 (2005). [14]. Samochocka K., Kruszewski M., Szumiel I.: Chem. Biol. Interact., 105, 145-155 (1997). [15]. Fuks L., Samochocka K., Anulewicz-Ostrowska R., Kruszewski M., Priebe W., Lewandowski W.: Eur. J. Med. Chem., 38, 775-780 (2003). [16]. Bertini I., Gray H., Lippert S.J., Valentine J.S.: Bioinorganic chemistry. University Science Books, Mill Valey 1994, p.526.
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ANNUAL REPORT 2005 50 years in the
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CONTENTS GENERAL INFORMATION 9 MANA
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DETERMINATION OF CADMIUM, LEAD, COP
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NUCLEONIC CONTROL SYSTEMS AND ACCEL
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GENERAL INFORMATION 9 GENERAL INFOR
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MANAGEMENT OF THE INSTITUTE 11 MANA
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MANAGEMENT OF THE INSTITUTE 13 •
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NUCLEAR TECHNOLOGIES AND METHODS 12
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THE INCT PUBLICATIONS IN 2005 163 V
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NUKLEONIKA 169 NUKLEONIKA THE INTER
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NUKLEONIKA 171 7. Influence of time
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INTERVIEWS IN 2005 173 INTERVIEWS I
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CONFERENCES ORGANIZED AND CO-ORGANI
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EDUCATION 209 EDUCATION Ph.D. PROGR
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RESEARCH PROJECTS AND CONTRACTS 211
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RESEARCH PROJECTS AND CONTRACTS IAE
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LIST OF VISITORS TO THE INCT IN 200
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LECTURES AND SEMINARS DELIVERED OUT
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LECTURES AND SEMINARS DELIVERED OUT
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AWARDS IN 2005 221 AWARDS IN 2005 1
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INSTRUMENTAL LABORATORIES AND TECHN
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INDEX OF THE AUTHORS 235 Lisowska H
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