Crystal Structure and Antitumor Activity of the Novel Zwitterionic Complex of tri- ? -Butyltin(IV) with 2-Thiobarbituric Acid

Hindawi Publishing Corporation Bioinorganic Chemistry and Applications Volume 2008, Article ID 654137, 5 pages doi:10.1155/2008/654137 Research Article Crystal Structure and Antitumor Activity of the Novel Zwitterionic Complex of tri-n-Butyltin(IV) with 2-Thiobarbituric Acid Vasilios I. Balas,1 Sotiris K. Hadjikakou,1 Nick Hadjiliadis,1 Nikolaos Kourkoumelis,1 Mark E. Light,2 Mike Hursthouse,2 Apostolos K. Metsios,3 and Spyros Karkabounas3 1 Section of Inorganic and Analytical Chemistry, Department of Chemistry, University of Ioannina, Ioannina 45110, Greece 2 Department of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK 3 Department of Experimental Physiology, Medical School, University of Ioannina, Ioannina 45110, Greece Correspondence should be addressed to Sotiris K. Hadjikakou, Received 2 October 2007; Accepted 8 January 2008 Recommended by Virtudes Moreno A novel tri-n-butyl(IV) derivative of 2-thiobarbituric acid (HTBA) of formula [(n-Bu)3 Sn(TBA)·H2 O] (1) has been synthesized and characterized by elemental analysis and 119 Sn-NMR and FT-IR spectroscopic techniques. The crystal structure of complex 1 has been determined by single crystal X-ray diffraction analysis at 120(2) K. The geometry around Sn(IV) is trigonal bipyramidal. Three n-butyl groups and one oxygen atom from a deprotonated 2-thiobarbituric ligand are bonded to the metal center. The geometry is completed with one oxygen from a water molecule. Compound 1 exhibits potent, in vitro, cytotoxicity against sarcoma cancer cells (mesenchymal tissue) from the Wistar rat, polycyclic aromatic hydrocarbons (PAH, benzo[a]pyrene) carcinogenesis. In addition, the inhibition caused by 1, in the rate of lipoxygenase (LOX) catalyzed oxidation reaction of linoleic acid to hyperoxolinoleic acid, has been also kinetically and theoretically studied. The results are compared to that of cisplatin. Copyright © 2008 VasiliosI. Balas et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The increasing interest in the bioinorganic chemistry of organotin(IV) compounds has led to extended studies on their interactions with different types of biomolecules such as carbohydrates, nucleic acid derivatives, amino acids and peptides [1, 2]. The organotin(IV) compounds are exhibiting significant antitumor activity [1–8]. More particularly, organotin(IV) complexes with ligands containing phenolic –OH groups and a heterocyclic nitrogen {N} donor atom comprise an interesting class of such complexes because they contain an amide group [9, 10]. Surprisingly, only few organotin(IV) complexes of this type have been structurally characterized up to now [10]. Recently, the inhibition caused by organotin(IV) complexes of thioamide ligands towards lipoxygenase (LOX) catalyzed oxidation reaction of linoleic acid to hyperoxolinoleic acid in relation with the antitumor activity caused by these complexes was studied [3–8] and a mechanism of free radicals was proposed. 2-Thiobarbituric acid, on the other hand, is a reagent in use for the detection of lipid hydroperoxides and lipid oxidation [11, 12]. In order to investigate further the mechanism of cytotoxic activity of organotin(IV)-thioamide complexes, we re- port here the synthesis of a new complex with formula [(nBu)3 Sn(TBA)·H2 O] (1) (HTBA is the 2-thiobarbituric acid) (Scheme 1). The complex has been characterized by elemental analysis and 119 Sn-NMR and FT-IR spectroscopic techniques. The structure of the complex was also determined by X-ray crystallography at 120(2) K. The tri-n-butlyltin derivative was chosen, since it is known to possess antiparasitic properties [1, 2]. 2-Thiobarbituric acid, a well-known reagent in use for the determination of the lipid peroxidation in biological systems, is chosen in order to possibly increase the LOX inhibition activity of organotin moiety [3–8, 11, 12]. The anticancer cell screening results of the compound tested are also reported. The inhibition caused by 1, in the rate of lipoxygenase (LOX) catalyzed oxidation reaction of linoleic acid to hyperoxolinoleic acid has also been kinetically and theoretically studied. Complex 1 was synthesized by reacting a methanolic solution of tri-n-butlyltin(IV) chloride (n-Bu)3 SnCl with an aqueous solution of 2-thiobarbituric acid (HTBA) which contains an equimolar amount of potassium hydroxide. The structure was solved by direct methods SHELXS97 [13] and 2 Bioinorganic Chemistry and Applications O NH HO NH S Scheme 1 successive difference Fourier syntheses. Refinement applied full-matrix least-squares methods SHELXL97 [14]. Atomic scattering factors for neutral atoms and real and imaginary dispersion terms were taken from International Tables for X-ray Crystallography [15]. Intensity data for the colorless crystals were collected on a Nonius Kappa CCD diffractometer with graphite-monochromated MoKα radiation at 120(2) K. C16 H32 N2 O3 SSn, MW = 451.19, monoclinic in P21 /n, a = 11.0956(2), b = 17.3425(4), c = 11.1879(2) Å, β = 95.3080(10)◦ , V = 2143.60(7) Å3 , Z = 4, D = 1.398 Mg/m3 , μ = 1.303 mm−1 , final R = 0.0247 for 4906 unique observed [F2 > 2 σ (F2 )] diffractometer data. Measurements of in vitro cells toxicity have been carried out in preliminary repetitions according to the method described in literature [3–8]. The ir spectrum of complex 1 shows distinct absorption at 2959 cm−1 due to the C–H bond vibrations of nbutyl groups, at 1546 and 1398 cm−1 , which are assigned to ν(CN) vibrations (thioamide I and II bands) and at 1194 and 906 cm−1 , which are attributed to the ν(CS) vibrations (thioamide III and IV bands). The corresponding thioamide I and II bands in crystalline HTBA appear at 1527 and 1350 cm−1 while thioamide bands III and IV are observed at 1154 and 801 cm−1 [16]. 119 Sn-NMR spectrum of complex 1, in DMSO-d solu6 tion, shows a resonance signal at 5.7 ppm indicating a four coordinated Sn atom [17]. Since the corresponding value for the (n-Bu)3 SnCl in DMSO-d6 is found to be at 2.7 ppm [18], this is indicative of a partial positive charged Sn atom in 1 (see crystal structure). Chemical shifts δ are given in ppm referenced to119 Sn-Me4 Sn. The stability of 1 in DMSO-d6 solution was verified by recording its 1 H-NMR spectrum, as a function of time. Free HTBA ligand shows a resonance signal at 12.1 ppm (s, H(N)), 4.9 ppm (s, H(C)), and 3.5 ppm (s, H(C)) (Scheme 1) [16] which are shifted at 10.9 ppm (s, H(N)) and at 4.2 ppm (s, H(C)) in case of 1 . The signal at 3.5 ppm (s, H(C)) could not be observed in the 1 H-NMR of the complex since enol-keton tautomerims can not be established in case of coordinated HTBA. Resonance signals at 1.55 ppm (t), 1.28 ppm (m), 1.09 ppm (m), and at 0.87 ppm (t) were assigned to the H(C) of the n-butyl group. A diagram of 1 as well as selected bond lengths and angles (...truncated)