научная статья по теме SYNTHESIS, CRYSTAL STRUCTURE, PROPERTIES, AND NUCLEASE ACTIVITY OF A NEW CU(II) COMPLEX [CU(L)2(PY)2(H2O)] (HL = N-(5-(4-METHYLPHENYL)-[1,3,4]-THIADIAZOLE-2-YL)TOLUENESULFONAMIDE) Химия

Текст научной статьи на тему «SYNTHESIS, CRYSTAL STRUCTURE, PROPERTIES, AND NUCLEASE ACTIVITY OF A NEW CU(II) COMPLEX [CU(L)2(PY)2(H2O)] (HL = N-(5-(4-METHYLPHENYL)-[1,3,4]-THIADIAZOLE-2-YL)TOLUENESULFONAMIDE)»

КООРДИНАЦИОННАЯ ХИМИЯ, 2015, том 41, № 6, с. 365-374

УДК 541.49

SYNTHESIS, CRYSTAL STRUCTURE, PROPERTIES, AND NUCLEASE ACTIVITY OF A NEW Cu(II) COMPLEX [Cu(L)2(Py)2(H2O)] (HL = N-(5-(4-METHYLPHENYL)-[1,3,4]-THIADIAZOLE-2-YL)TOLUENESULFONAMIDE)

© 2015 A. C. Hangan1, A. Turza2, R. L. Stan1, *, R. Stefan3, and L. S. Oprean1

1Faculty of Pharmacy, University of Medicine and Pharmacy, Cluj-Napoca, 400010 Romania 2National Institute for R&D of Isotopic and Molecular Technologies, Cluj-Napoca, 400293 Romania 3Preclinics Department, University of Agricultural Science and Veterinary Medicine, Cluj-Napoca, 400372 Romania

*E-mail: roxanaluc@yahoo.com Received October 24, 2014

A new N-sulfonamide ligand, N-(5-(4-methylphenyl)-[1,3,4]-thiadiazole-2-yl) toluenesulfonamide (HL) and its Cu(II) complex [Cu(L)2(Py)2(H2O)] (I), have been synthesized. The X-ray crystal structure of the ligand and of complex I have been determined (CIF files CCDC nos. 975153 (HL), 851790 (I)). In I, the Cu2+ ion is five-coordinated, forming a CuN4O chromophore. The ligand acts as monodentate, coordinating the metal ion through a single Nthiadiazole atom. The molecules from the reaction medium (pyridine and water) are also involved in the coordination of the Cu2+ ion. Complex I has a slightly distorted square pyramidal geometry. The complex was characterized by FT—IR, electronic, EPR spectroscopic and magnetic methods. The nuclease activity studies of the synthesized complex confirm his capacity to cleavage the DNA molecule. The ligand has two important roles in the nuclease activity of I: it influence the reactivity of the Cu2+ ion and interact with DNA molecule. The complex interacts with the DNA molecule. Immediately, the Cu2+ ion is reduced to Cu(I), and in the presence of molecular oxygen the formed Cu(I) complex produces reactive oxygen species in close proximity to the double helix.

DOI: 10.7868/S0132344X15050023

INTRODUCTION

Transition-metal complexes endowed with redox properties and DNA affinity have been developed as chemical cleavers of nucleic acids over the last two decades. Their ability to cleave DNA has several possible applications that include probing structural variations in nucleic acids, identification of binding sites of DNA ligands, design of artificial DNA cleavers and potential chemotherapeutic agents [1—3].

The synthesis of Cu(II) complexes with N-substi-tuted heterocyclic sulfonamides greatly increased in the past twenty years due to the diversity of biological activity of the resulting compounds: antimicrobial, anti-inflammatory, the mimetic superoxide dismutase (SOD) or nuclease activity. Studies have shown that Cu(II) complexes with different types of ligands can be used as potential "chemical nucleases" [4—8].

As reported in literature, the ligands commonly used to form complexes with "nuclease activity" are quinolones, sulfonamides and flavonoides. The aromatic rings in the structure of N-substituted sulfona-mides can be intercalated between the bases of the DNA chain. This interaction, followed by reactive oxygen species (ROS) formation (due to this Cu2+ ion in the structure of the complexes) results in degradation

of the DNA molecule through an oxidative mechanism [9, 10].

For the past several years, our group has worked on the synthesis of copper-sulfonamide complexes in order to obtain novel antitumor agents. These complexes are especially attractive as anticancer agents because several substituted sulfonamides have been found to arrest the cell cycle, causing apoptosis in the M phase [11]. In this context, we have described the nuclease activity of several copper-sulfonamide complexes [12—15]. In the present paper, we report the synthesis, the crystal structure and the physico-chemical characterization of a new N-substituted heterocyclic sulfonamide: HL = = N-(5-(4-methylphenyl)-[1, 3, 4]-thiadiazole-2-yl)-tol-uenesulfonamide

Л z5 '6

H3C

7

(HL)

One complex of this ligand with Cu(II), [Cu(L)2(Py)2(H2O)] (I), was prepared and its structure was determined by X-ray diffraction. Its IR, EPR, electronic spectra and its magnetic susceptibility were investigated and discussed, along with the structural and spectral comparison with those of the analogous complexes. The study of nuclease activity shows his capacity to intercalate in the DNA molecule and the

OH' radicals and the O- ' anion radical are the species involved in the cleavage of the DNA molecule.

EXPERIMENTAL

Materials and physical measurements. Copper sulfate pentahydrate, methanol, toluenesulfonylchlo-ride, 2-amino- 5 - (4-methylphenyl) -[1,3,4] -thiadiaz-ole and pyridine were purchased from Fluka and Merck chemical companies and were used without further purification.

Elemental analyses (C, N, H, and S) were performed with Vario EL analyser. IR spectra were recorded with a Jasco FT/IR-4100 spectrophotometer using diffuse reflectance of incident radiation focused on a sample in the 4000-450 cm-1 range. All melting points were determined in open capillaries with an Electrothermal IA 9100 apparatus and were uncorrected. 1H NMR spectrum of the ligand was recorded at room temperature using DMSO- as solvent in 5 mm tubes on Bruker AM 300 NMR spectrometer equipped with a dual, 1H (multinuclear) head operating at 300 MHz for protons. Fast ion bombardment (FAB) mass spectrum of the ligand was obtained on a VG Autospec spectrometer in m-nitrobenzene as a solvent. Diffuse reflectance spectrum of the complex was carried out on a Jasco V-550 spectrophotometer. Magnetic sus-ceptibilitie was measured at room temperature with the Faraday MSB-MKI balance. Hg[Co(NCS)4] was used as susceptibility standard. Electronic paramagnetic resonance (EPR) spectrum was performed at room temperature with a Bruker ELEXSYS spectrometer operating at the X-band frequency.

Synthesis of HL. A solution containing 1 mmol of 2-amino- 5 - (4-methylphenyl) -[1,3,4] -thiadiazole and 0.9 mmol of toluenesulfonylchloride in 18 mL of pyridine was heated at reflux for 1 h, at 60°C. The mixture was added to 30 mL of cold water and stirred for several minutes. The resulting solid was recrystallized from ethanol. The yield was 87%; m.p. = 232-234°C.

For C16H15N3O2S2 (M = 345)

anal, calcd., %: C, 55.63; H, 4.38; N, 12.16; S, 18.56. Found, %: C, 55.47; H, 4.26; N, 12.25; S, 18.72.

IR (KBr; v, cm-1): 3260 (N-H), 1544 (C=Car), 1551 (thiadiazole), 1315 (S=Oaj), 1154 (S=Os); 903 (S-N). 1H NMR (DMSO-d6; 8, ppm (J, Hz)): 2.37-2.36 (6H, s., H-4, H-7), 7.38-7.34 4H, d., J = 7.8, H-5, H-2),

7.73-7.71 (4H, d., J = 7.8, H-6, H-3), 8.52 (1H, s., H-1). MS (m/z): 346 [M + H+].

Synthesis of complex I. A solution of CuSO4 • 5H2O (4 mmol) in 20 mL of pyridine-H2O (V : V = 1 : 1) was added dropwise under continuous stirring to a solution of HL ligand (1 mmol) dissolved in 25 mL pyridine-H2O (V: V = 2 : 3). The resulting solution was stirred at room temperature for 2 h and left to stand at room temperature. After two months by the slow evaporation of the solvent, green-blue crystals suitable for X-ray diffraction were obtained. The yield was ~58%.

For C42H40N8O5S4Cu (M = 928.61)

anal, calcd., %: C, 54.31; H, 4.31; N, 12.06; S, 13.79.

Found, %: C, 54.20; H, 4.22; N, 12.21; S, 13.85.

IR (KBr; v, cm-1): 1488 (thiadiazole); 1296 (S=Oas), 1125 (S=Os), 927 (S-N). UV-Vis (solid; ^max , nm): 314 (n ^ n*), 401(LMCT), 583 (d-d).

X-ray crystallography. A white crystal of the ligand (HL), size 0.25 x 0.21 x 0.15 mm was mounted on a glass fiber and used for data collection. Crystal data were collected at 293(2) K using a dual microsourse Supervova Diffractometer and Mo^a radiation (^ = = 0.71073 A). A blue crystal of I was mounted on a glass fiber and used for data collection. Crystal data were collected at 293(2) K using a dual microsourse Supervova Diffractometer and Cu^a radiation (^ = = 1.54184 A).

The data were processed with CrysAlisPro [16] and corrected for absorbtion using ABSPACK [17]. The structure was solved by direct methods using the program SHELXS-97 [18] and refined by full-matrix least-squares techniques against F2 using SHELXL-97 [19]. Both SHELXS-97 and SHELXL-97 are incorporated in Olex2 [20] software package. Positional and aniso-tropic atomic displacement parameters were refined for all nonhydrogen atoms. Hydrogen atoms were located in difference maps and included as fixed contributions riding on attached atoms with isotropic thermal parameters. Atomic scattering factors were from International Tables for Crystallography [21]. Molecular graphics were from PLATON [22] and SCHAKAL [23]. A summary of the crystal data, experimental details and refinement results is listed in Table 1.

Supplementary material has been deposited with the Cambridge Crystallographic Data Centre (nos. 975153 (HL), 851790 (I); deposit@ ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk).

DNA cleavage. Reactions were performed by mixing 7 |L of cacodylate buffer 0.1 M, pH 6 (cacodylic acid/sodium cacodylate), 6 |L of complex solution (final concentrations: 3, 6, 9, 12 and 15 |M), 1 |L of pUC18 DNA solution (0.25 |ig/|L, 750 |M in base pairs), and 6 |L of activating agent solution (H2O2-ascorbic acid) in a threefold molar excess relative to

Table 1. Crystal data, experimental details and refinement results for HL and complex I

Parameter Value

Formula weight 345.44 928.61

Temperature, K 293(2) 293(2)

Crystal system Triclinic Monoclinic

Space group P1 P/n2

a, A 6.5667(4) 15.0977(3)

b, A 10.6561(10) 21.7903(4)

c, A 13.5350(16) 13.1399(2)

a, deg 67.598(10) 90

P, deg 88.551(8) 103.3750(17)

Y, deg 72.139(7) 90

Volume, A3 828.91(13) 4205.56(8)

Z 2 4

Pcalcd mg/m3 1.432 1.468

Absorption coefficient, mm-1 0.336 3.049

/(000) 372 1928

Crystal size, mm 0.25 x 0.21 x 0.15 0.37 x 0.14 x 0.07

9 Range for data collection, deg 6.28-58.14 3.46-74.78

Limiting indices -8 < h < 8, -14 < k < 14, -17 < l < 18 -14 < h < 18, -26 < k< 22, -16 < l< 11

Collected reflections 6166 8243

In

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