Novel Ru(III) Complexes with Some Benzothiazole Derivatives: Synthesis, Physicochemical and Pharmacological Investigations

A. Nikolova; G. Momekov; A. Bakalova; K. Nikolova; D. Ivanov

doi:10.1055/s-0034-1382052

Drug Research, Table of Contents

Drug Res (Stuttg) 2015; 65(06): 317-322
DOI: 10.1055/s-0034-1382052

Original Article

Novel Ru(III) Complexes with Some Benzothiazole Derivatives: Synthesis, Physicochemical and Pharmacological Investigations

A. Nikolova

¹Department of Chemistry, Faculty of Pharmacy, Medical University – Sofia, Sofia, Bulgaria

,

G. Momekov

²Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University – Sofia, Sofia, Bulgaria

,

A. Bakalova

¹Department of Chemistry, Faculty of Pharmacy, Medical University – Sofia, Sofia, Bulgaria

,

K. Nikolova

¹Department of Chemistry, Faculty of Pharmacy, Medical University – Sofia, Sofia, Bulgaria

,

D. Ivanov

¹Department of Chemistry, Faculty of Pharmacy, Medical University – Sofia, Sofia, Bulgaria

› Author Affiliations

Abstract

In this work we present 3 new complexes of Ruthenium (III) with a general formula HL[Ru(L)₂Cl₄], where L=benzothiazole, 2-methylbenzothiazole and 2-mercaptobenzothiazole. The syntheses were carried out in polar medium under argon. The compounds obtained were characterised by IR-, ¹H-NMR- ¹³C-NMR-, UV-VIS-spectroscopy and conductivity measurements. The ligands behaved as monodentate, bounding Ru(III) through the nitrogen atoms from the heterocycle. The cytotoxicity of the new complexes was tested against 2 human leukemic cell lines (K-562 and KE-37), using the MTT-dye reduction assay. The Ru(III) coordination compound with 2-methylbenzothiazole displayed superior activity compared to the other novel complexes. Its IC50 values were comparable to that of the reference cytotoxic drug cisplatin. In general, the ligands displayed only marginal inhibitory effects on the human leukemic cell lines. Moreover, the ability of the complexes to trigger apoptosis was evaluated using a commercially available DNA-fragmentation ELISA kit and the obtained data indicated that their proapoptotic effects well correlate to the MTT-bioassay data.

Key words

cytotoxicity - ruthenium(III) complexes - benzothiazole - synthesis

Full Text

References

References
1 Rosenberg B, VanCamp L, Trosko JE et al. Platinum compounds: a new class of potent antitumor agents. Nature 1969; 222: 385-386
2 Jakupec MA, Galanski M, Arion VB et al Antitumour metal compounds: more than theme and variations. Dalton Trans 2008; 2: 183-194
3 Clarke MJ. Ruthenium metallopharmaceuticals. Coord Chem Rev 2002; 232: 69-93
4 Gianferrara T, Bratsos I, Alessio E. A categorization of metal anticancer compounds based on their mode of action. Dalton Trans 2009; 37: 7588-7598
5 Domotor O, Hartinger CG, Bytzek AK et al. Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies. J Biol Inorg Chem 2013; 18: 9-17
6 Bergamo A, Gaiddon C, Schellens JHM et al. Approaching tumour therapy beyond platinum drugs: Status of the art and perspectives of ruthenium drug candidates. J Inorg Biochem 2012; 106: 90-99
7 Mura P, Camalli M, Messori L et al. Synthesis, Structural Characterisation, Solution Chemistry And Preliminary Studies Of The Biological Activity Of Tzh]Trans-Rucl4(Tz)2 And Tzh]Trans-RuCl4(DMSO) (Tz)].(DMSO), The Thiazole Analogues Of The Antitumor Ruthenium(III) Complexes ICR And NAMI. Inorg Chem 2004; 43: 3863-3870
8 Chen JC, Chen LM, Liao SY et al. A DFT study on the hydrolysis mechanism of the potential antitumor Ru(III) complex TzNAMI. J Mol Struct: Theochem 2009; 901: 137-144
9 Chen JC, Chen LM, Liao SY et al. A theoretical study on the hydrolysis process of two Keppler-type antitumor complexes TzH]trans-RuCl4(Tz)(2) and 2-NH(2)TzH]trans-RuCl4(2-NH(2)Tz)(2)]. Phys Chem Chem Phys 2009; 11: 3401-3410
10 Huang ST, Hsei IJ, Chen C. Synthesis and anticancer evaluation of bis(benzimidazoles), bis(benzoxazoles), and benzothiazoles. Bioorg Med Chem 2006; 14: 6106-6119
11 Lion CJ, Matthews CS, Wells G et al. Antitumour properties of fluorinated benzothiazole-substituted hydroxycyclohexa-2, 5-dienones (‘quinols’). Bioorg Med Chem Lett 2006; 16: 5005-5008
12 Turan-Zitouni G, Demirayak S, Ozdemir A et al. Synthesis of some 2-(benzazole-2-yl)thioacetylamino]thiazole derivatives and their antimicrobial activity and toxicity. Eur J Med Chem 2004; 39: 267-272
13 Magdolen P, Zahradnik P, Foltinova P. Synthesis and Antimicrobial Activity of New 2-Phenyletinylbenzothiazoles and Related Salts. Arzneim.-Forsch./Drug Res 2000; 50: 1023-1027
14 Venkatesh P, Pandeya SN. Synthesis, characterisation and anti-inflammatory activity of some 2-amino benzothiazole derivatives. Int J Chem Tech Res 2009; 1: 1354-1358
15 Naik BD, Desai KR. Synthesis of some heterocyclic Schiff base and azetidinone compounds and their antibacterial activity. Asian J Chem 2004; 16: 1749-1752
16 Tellez F, Flores-Parra A, Barba-Behrens N et al. Cobalt(II) and zinc(II) compounds with unsaturated ligands derived from 2-aminobenzothiazole. Polyhedron 2004; 23: 2481- 2489
17 Grevy JM, Tellez F, Bernes S et al. Coordination compounds of thiabendazole with main group and transition metal ions. Inorg Chim Acta 2002; 339: 532-542
18 Ayres H, Young F. Spectrofotometric study of the Ruthenium-Thiourea complex. Anal Chem 1950; 22: 1277-1280
19 Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55-63
20 Konstantinov S., Eibl H, Berger MR. BCR-ABL influences the antileukemic efficacy of Alkylphosphocholines. Br J Haematol. 1999 107. 365-374
21 Keppler BK, Rupp W, Juhl UM et al. Synthesis, molecular structure, and tumor-inhibiting properties of imidazolium trans-bis(imidazole)tetrachlororuthenate(III) and its methyl-substituted derivatives. Inorg Chem 1987; 26: 4366-4370
22 Hasegawa K, Ono T, Noguchi T. Vibrational spectra and Ab initio DFT calculations of 4-methylimidazole and its different protonation forms: infrared and Raman markers of the protonation state of a histidine side chain. J Phys Chem B 2000; 104: 4253- 4265
23 Collado JA, Tunon I, Silla E et al. Vibrational dynamics of histamine monocation in solution: an experimental (FT-IR, FT-Raman) and theoretical (SCRF-DFT) study. J Phys Chem A 2000; 104: 2120-2131
24 Mishra L, Vilaplana R, Singh VK et al. Nitrate/nitrite reductase activity of sulfido/selenido bridged dinuclear ruthenium(III) complexes. J Inorg Biochem 2001; 86: 581-585
25 He X-F, Vogels CM, Decken A et al. Pyridyl benzimidazole, benzoxazole, and benzothiazole platinum complexes. Polyhedron 2004; 23: 155-160
26 Singh N, Sinha RK. Preparation, characterization and electrical conductivity of heterometallic complexes derived from 2-sulfanylbenzothiazolate. Inorg Chem Comm 2001; 4: 454-458
27 Li X-H, Tang Z-X, Zhang X-Z. Molecular structure, IR spectra of 2-mercaptobenzothiazole and 2-mercaptobenzoxazole by density functional theory and ab initio Hartree-Fock calculations. Spectrochim Acta Part A 2009; 74: 168-173
28 Pereira GA, Massabni AC, Castellano EE et al. A broad study of two new promising antimycobacterial drugs: Ag(I) and Au(I) complexes with 2-(2-thienyl)benzothiazole. Polyhedron 2012; 38: 291-296
29 Keppler BK, Balzer W, Seifried V. Synthesis and antitumor activity of triazolium-bis(triazole)tetrachlororuthenate(III) and bistriazolium-triazolepenta-chlororuthenate(III). Two representatives of a new class of inorganic antitumor agents, Arzneim Forsch/Drug Res 1987; 37: 770-771
30 Cetinkaya B, Ozdemir I, Bruneau C et al. Benzimidazole, Benzothiazole and Benzoxazole Ruthenium(II) Complexes; Catalytic Synthesis of 2,3-Dimethylfuran. Eur J Inorg Chem 2000; 1: 29-32
31 Richardson C, Keene FR, Steel PJ. Ruthenium(II) Complexes of Chelating Ligands Containing Benzoxazole and Benzothiazole Subunits: Synthesis, X-Ray Crystallography, Spectroscopy and Electrochemistry. Aust J Chem 2008; 61: 183-188
32 Marchesi E, Marchi A, Marvelli L et al. Rhenium(III) and technetium(III) complexes with 2-mercapto-1,3-azole ligands and X-ray crystal structures. Inorg Chim Acta 2005; 358: 352-362
33 Yousif E, Farina Y, Kasar K et al. Complexes of 2-thioacetic acid benzothiazole with some metal ions. Am J Applied Sci 2009; 6: 582-585
34 Marjani K, Mousavi M, Hughes DL. Synthesis and crystal structure determination of copper(II) and iron(III) complexes of 2-(2-pyridyl)benzothiazole. Trans Met Chem 2009; 34: 85-89
35 Cesar ML, Cox O, Muir MM et al. Cytotoxic anionic tribromo platinum(II) complexes containing benzothiazole and benzoxazole donors: synthesis, characterization, and structure-activity correlation. Inorg Chim Acta 1998; 271: 137-144
36 Racane L, Mihalic Z, Ceric H et al. Synthesis, structure and tautomerism of two benzothiazolyl azo derivatives of 2-naphthol: A crystallographic, NMR and computational study. Dye Pigment 2013; 96: 672-678
37 Machura B, Wolff M, Benoist E et al. Tricarbonyl rhenium(I) complex of benzothiazole – Synthesis, spectroscopic characterization, X-ray crystal structure and DFT calculations. J Organomet Chem 2013; 724: 82-87
38 Etaiw SE, Farag RS, El-Atrash AM et al. Spectrophotometric studies of some thiazole and benzothiazole derivatives. Spectrochim Acta A 1992; 48: 025-1026
39 Ibrahim AMA, Etaiw SEH. Paramagnetic charge transfer complexes: new molecular composites via intercalation of thiazole and benzothiazole derivatives within the cavities of the 3D host polymers (Me3E)3Fe(CN)6]∞; E – Sn or Pb. Polyhedron 1997; 16: 1585-1594
40 Neelakantan MA, Marriappan SS, Dharmaraja J et al. Spectral, XRD, SEM and biological activities of transition metal complexes of polydentate ligands containing thiazole moiety. Spectrochim Acta A 2008; 71: 628-635
41 Geary WJ. The use of conductivity measurements in organic solvents for the characterisation of coordination compounds. Coord Chem Rev 1971; 7: 81-122