Structure/Activity of PtII/N,N-Disubstituted-N'-acylthiourea Complexes: Anti-Tumor and Anti-Mycobacterium tuberculosis Activities

http://dx.doi.org/10.21577/0103-5053.20170222 Article J. Braz. Chem. Soc., Vol. 29, No. 6, 1256-1267, 2018 Printed in Brazil - ©2018 Sociedade Brasileira de Química Structure/Activity of PtII/N,N-Disubstituted-N’-acylthiourea Complexes: Anti‑Tumor and Anti-Mycobacterium tuberculosis Activities Ana M. Plutín,*,a Anislay Alvarez,a Raúl Mocelo,a Raúl Ramos,a Osmar C. Sánchez,a Eduardo E. Castellano,b Monize M. da Silva,c Wilmer Villarreal,c Legna Colina-Vegas,c Fernando R. Pavand and Alzir A. Batista*,c Laboratorio de Síntesis Orgánica, Facultad de Química, Universidad de La Habana, 10400 La Habana, Cuba a Instituto de Física de São Carlos, Universidade de São Paulo, 05508-090 São Carlos-SP, Brazil b Departamento de Química, Universidade Federal de São Carlos, 13565-905 São Carlos-SP, Brazil c Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista (Unesp), 14800-903 Araraquara-SP, Brazil d The syntheses, characterization, cytotoxicity against tumor cells and anti-Mycobacterium tuberculosis activity assays of PtII/PPh3/N,N-disubstituted-N’-acylthioureas complexes with general formulae [Pt(PPh3)2(L)]PF6, PPh3 = triphenylphosphine; L = N,N-disubstituted-N’-acylthiourea, are here reported. The complexes were characterized by elemental analysis, molar conductivity, infrared (IR), nuclear magnetic resonance (NMR) (1H, 13C{1H} and 31P{1H}) spectroscopy. The 31 P{1H} NMR data are consistent with the presence of two PPh3 ligands cis to each other position, and one N,N-disubstituted-N’-acylthiourea coordinated to the metal through O and S, in a chelate form. The structures of the complexes were determined by X-ray crystallography, forming distorted square-planar structures. The complexes were tested in human cell lines carcinomas and also screened with respect to their anti-Mycobacterium tuberculosis activity (H37RvATCC 27294). It was found that complexes with N,N-disubstituted-N’-acylthiourea containing open and small chains as R2 groups show higher cytotoxic and higher anti-Mycobacterium tuberculosis activity than those containing rings in this position. Keywords: platinum(II), tumor cells, Mycobacterium tuberculosis Introduction Among the most effective agents for the treatment of cancer, there are some metallodrugs based on platinum(II). However, due to the frequent development of drug resistance, they have acquired several limitations, including their side effects.1 This damage has led to the need for development of new metal-based anticancer drugs whose structure and mode of action differ from that of cisplatin and derivatives, aiming to improve their cytotoxicity and minimizing their side effects.2-9 Thus, in an attempt to overcome the drawbacks of cisplatin and derivatives (severe toxicity, drug resistance and poor oral bioavailability), the development of platinum-based drugs have progressed to the newest generation of drugs, such as satraplatin, picoplatin and the multinuclear platinum complex BBR3464 (triplatin). In this context, platinum(II) complexes of *e-mail: ; the type [Pt(L)Cl(DMSO)] (L = acylthiourea ligand, R1–C(O)NHC(S)NR2; R’ = aryl, NR2 = amine; DMSO = dimethylsulfoxide) were prepared by Sacht et al.10-12 for their biological and chemical evaluation. The acylthiourea group, after deprotonation of the amide moiety (NHCO), can act as a bidentate chelating ligand, coordinating to platinum through the oxygen and sulfur donor atoms. The facility of affording the replacement of the functional groups R1 and R2 (see below) to obtain a wide range of ligands and platinum(II) complexes with different physical and chemical properties, made the assessment of these compounds especially attractive.13-15 In previous works,16-20 some of us synthesized and determined the structures of some ligands related to those here described, and their corresponding complexes with CoII, CuII, NiII, PdII and PtII were also studied, which contain a thiourea derivative as a bidentate ligand, in different environments. In the present work, we studied the syntheses, Vol. 29, No. 6, 2018 Plutín et al. 1257 characterization, cytotoxicity and anti-Mycobacterium tuberculosis activity of new platinum(II) complexes containing PPh3 and N,N-disubstituted-N’-acylthioureas as ligands. The N,N-disubstituted-N’-acylthioureas used as ligands were synthesized by the procedure previously reported.21 Scheme 1 shows the pathway for the synthesis of the PtII complexes, which were obtained by reacting methanolic solutions of acylthioureas with the precursor, dichloro-bis(triphenylphosphine)platinum(II). The complexes were obtained by a nucleophilic substitution reaction of the two chlorido ligands from the precursor [PtCl2(PPh3)2], by the acylthiourea ligands. For the formation of the platinum(II) complexes the loss of the hydrogen atom of the acylthioureido group of the ligands occurs (see Scheme 1).16 Cytotoxic studies realized on DU-145 (human prostate tumor cells) and MDA-MB-231 (human breast tumor cells) tumor cell lines have shown that certain palladium(II) complexes with the acylthiourea ligands exhibit cytotoxicity with antiproliferative effects being dependent on the nature or the type of the substituent at the acylthiourea ligand.20 Recently there have been efforts to design non-classical platinum-acylthiourea complexes, due to their antifungal activity and inhibitory activities against viruses. Thus, here we investigate the cytotoxicity of the complexes against MDA-MB-231 and DU-145 tumor cells, and their anti-Mycobacterium tuberculosis activity, with the aim of evaluating a possible influence of R1 and R2 in the cytotoxicity and in the anti-mycobacterial activity of the complexes.8 In this work three series of N,N-disubstitutedN’-acylthioureas were synthesized where R1 = phenyl, furoyl group or thiophenyl group. unless otherwise specifically indicated. Thin layer chromatography (TLC) was performed on 0.25 mm silica gel pre-coated plastic sheets (40/80mm) (Polygram_SIL G/ UV254, Macherey& Nagel, Düren, Germany) using Caution benzene/methanol (9:1) as eluent. The infrared (IR) spectra of the compounds were recorded on a Fourier transform infrared (FTIR) BomemMichelson 102 spectrometer in the 4000-200 cm−1 region using CsI pellets. Conductivity values were obtained using 1.0 mM solutions of complexes in CH2Cl2, using a Meter Lab CDM2300 instrument. 1H, 31P{1H} and 13C{1H} nuclear magnetic resonance (NMR) were recorded on a Bruker DRX 400 MHz, internally referenced to tetramethylsilane (TMS), chemical shift (d), multiplicity (m), spin-spin coupling constant (J), integral (I). CDCl3 was used as a solvent unless mentioned. The 31P{1H} shifts are reported in relation to H3PO4, 85%. 2D heteronuclear single quantum coherence (HSQC) NMR experiments were performed in order to unequivocally assign the C=O and C=S signals of the complexes. Partial elemental analyses were carried out by the Department of Chemistry of the Federal University of São Carlos, in an instrument of CHNS st (...truncated)