Synthesis, crystallographic and spectroscopic characterization and magnetic properties of dimer and monomer ternary copper(II) complexes with sulfonamide derivatives and 1,10-phenanthroline. Nuclease activity by the oxidative mechanism

Article abstract of DOI:10.1016/j.poly.2009.12.030

Three dinuclear and one mononuclear copper(II)-1,10-phenanthroline ternary complexes, [Cu(L1)(phen)(OH)]₂ (1), [Cu(L2)(phen)(OH)]₂·3H₂O (2), [Cu(L3)(phen)(OH)]₂ (3) and [Cu(L4)₂(phen)(H₂O)] (4), with thiadiazole sulfonamide derivative ligands: HL1 (N-(5-ethyl-1,3,4-thiadiazol-2-yl)naphthalene-1-sulfonamide), HL2 (N-(5-ethylthio)-1,3,4-thiadiazol-2-yl)-4-methylbenzenesulfonamide), HL3 (N-(5-ethyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide) and HL4 (N-(5-ethyl-1,3,4-thiadiazol-2-yl)-4-methylbenzenesulfonamide) have been synthesized and characterized. In the four complexes each copper atom is five-coordinated. The structure of complexes 1, 2 and 3 consists of a dimeric unit with a C2 symmetry axis, where both coppers are bridged by two hydroxo anions. Magnetic measurements show that the dimer complexes are ferromagnetic according to the Cu-O-Cu angles. Cleavage experiments using pUC18 plasmid DNA in the presence of H₂O₂/ascorbic acid as an activating agent show that the title complexes are potent artificial chemical nucleases, the order of efficiency being 3 > 2 ～ 1 > 4. Control cleavage experiments indicated that the dimer complexes are stronger artificial nucleases than the [Cu(phen)₂]²⁺ complex under the same experimental conditions, while the monomer 4 has a lower nuclease activity than the [Cu(phen)₂]²⁺ complex. The inhibition of the cleavage process in the presence of reactive oxygen intermediate scavengers suggests that the hydroxyl radical and the superoxide anion are reactive species for the breakage of the DNA strands.

Full text of DOI:10.1016/j.poly.2009.12.030

Polyhedron 29 (2010) 1305–1313
Contents lists available at ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Synthesis, crystallographic and spectroscopic characterization and
magnetic properties of dimer and monomer ternary copper(II) complexes
with sulfonamide derivatives and 1,10-phenanthroline. Nuclease
activity by the oxidative mechanism
A. Hangan a, A. Bodoki a, L. Oprean a, G. Alzuet b, M. Liu-González b, J. Borrás b,
*
a Department of Inorganic Chemistry, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
b Department of Inorganic Chemistry, University of Valencia, Burjassot (Valencia), Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Three dinuclear and one mononuclear copper(II)-1,10-phenanthroline ternary complexes, [Cu(L1)(phe-
n)(OH)]2 (1), [Cu(L2)(phen)(OH)]2ꢀ3H2O (2), [Cu(L3)(phen)(OH)]2 (3) and [Cu(L4)2(phen)(H2O)] (4),
with thiadiazole sulfonamide derivative ligands: HL1 (N-(5-ethyl-1,3,4-thiadiazol-2-yl)naphthalene-1-
sulfonamide), HL2 (N-(5-ethylthio)-1,3,4-thiadiazol-2-yl)-4-methylbenzenesulfonamide), HL3 (N-(5-
ethyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide) and HL4 (N-(5-ethyl-1,3,4-thiadiazol-2-yl)-4-methyl-
benzenesulfonamide) have been synthesized and characterized. In the four complexes each copper atom
is five-coordinated. The structure of complexes 1, 2 and 3 consists of a dimeric unit with a C2 symmetry
axis, where both coppers are bridged by two hydroxo anions. Magnetic measurements show that the
dimer complexes are ferromagnetic according to the Cu–O–Cu angles. Cleavage experiments using
pUC18 plasmid DNA in the presence of H2O2/ascorbic acid as an activating agent show that the title com-
plexes are potent artificial chemical nucleases, the order of efficiency being 3 > 2 ꢁ 1 > 4. Control cleavage
experiments indicated that the dimer complexes are stronger artificial nucleases than the [Cu(phen)2]2+
complex under the same experimental conditions, while the monomer 4 has a lower nuclease activity
than the [Cu(phen)2]2+ complex. The inhibition of the cleavage process in the presence of reactive oxygen
intermediate scavengers suggests that the hydroxyl radical and the superoxide anion are reactive species
for the breakage of the DNA strands.
Received 26 June 2009
Accepted 10 December 2009
Available online 11 January 2010
Keywords:
Dimeric and monomeric copper(II)
complexes
Sulfonamide derivatives
1,10-Phenanthroline
Ferromagnetic behavior
Oxidative DNA cleavage
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
plexes with the oxidation state I or II [2]. The CuI(phen)2 complex
in the presence of hydrogen peroxide efficiently cleaves DNA by
Transition-metal complexes endowed with redox properties
and DNA affinity have been developed as chemical cleavers of nu-
cleic 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 li-
gands, design of artificial DNA cleavers and potential chemothera-
peutic agents.
1,10-Phenanthroline (phen) is a well-known motif used to pre-
pare a large range of strong chelating ligands for various metal
ions. Its complexing capability has been used to develop biomi-
metic models of metalloenzymes, to design analytical reagents
and to prepare supramolecules for molecular recognition and self
assembling systems [1]. 1,10-Phenanthroline is a versatile ligand
able to chelate copper to give mono-phen or bis-phen copper com-
oxidative attack on deoxyribose units from the DNA minor groove
[3,4]. The CuI–phen complex is less efficient [5]. DNA cleavage
products include 50- and 30-monophosphate ester termini, free
bases, 5-methylenefuranone and a small amount of 30-phosphogly-
colate [6–8]. Hydrogen peroxide can be generated closely to the
DNA by the CuII(phen)2 itself in the presence of a reductant and
molecular oxygen. [Cu(phen)2]2+ cleaves double-stranded DNA at
all nucleotides, but some preferences have been observed for par-
ticular conformations of B-DNA, lac-operon control region or TAT
triplets [9–12].
Redox-active copper complexes of 1,10-phenanthroline deriva-
tives, which are able to catalyze the single strand cleavage of nu-
cleic acids in the presence of dioxygen and a reductant, have
been used as footprinting agents and conformational probes, or
as more specific DNA cleavers when attached to intercalators, pro-
teins, nucleic acids or minor groove binders [13–18]. In fact, the
design of artificial nucleases is a growing research area because
* Corresponding author. Fax: +34 963544960.
E-mail address: Joaquin.Borras@uv.es (J. Borrás).
0277-5387/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2009.12.030

1306
A. Hangan et al. / Polyhedron 29 (2010) 1305–1313
2
2
2
3
2
3
3
N-(5-ethyl-1,3,4-thiadiazol-2-yl)naphthalene-1-sulfonamide (HL1)
N-(5-(ethylthio)-1,3,4-thiadiazol-2-yl)-4-methylbenzenesulfonamide (HL2)
2
2
2
2
3
3
3
N-(5-ethyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide (HL3)
N-(5-ethyl-1,3,4-thiadiazol-2-yl)-4-methylbenzenesulfonamide (HL4)
Scheme 1.
major advancements in this field might have possible important
applications as tools in molecular biology and as potential chemo-
therapeutic agents [15,19,20].
Meunier and co-workers [21] even developed the Clip-phen ser-
ies containing two phen moieties linked through tethers in order to
favor the stoichiometry of two phen units per copper. These
authors showed that the DNA cleavage activity of copper Clip-phen
complexes increased dramatically in relation to that of the phen
parent compound. They then went on to determine the cytostatic
activity of these complexes [22].
were taken at the X-band frequency at room temperature with a
Bruker ELEXSYS spectrometer. The variable temperature magnetic
susceptibility measurements on microcrystalline samples were
taken with a Quantum Design MPMS2 SQUID susceptometer
equipped with a 55 kG magnet, operating at 10 kG in the range 1.8–
400 K. The susceptometer was calibrated with (NH4)2Mn(SO4)2ꢀ
12H2O. Corrections for the diamagnetism were estimated from
Pascal constants.
2.2. Synthesis
Our group has previously reported several copper ternary com-
plexes of N-substituted sulfonamides and phen with the ability to
damage DNA in the presence of various reducing agents [23,24].
Another aspect that must be taken into account in the design
and synthesis and characterization of artificial chemical nucleases
is the formation of mononuclear or polynuclear copper complexes.
Karlin and co-workers [25] showed that di or trinuclear complexes
present a synergistic effect as chemical nucleases with respect to
the mononuclear complexes. In a previous paper we also observed
this synergism [26].
In the present work we describe the synthesis of three dinuclear
copper(II) complexes with two hydroxo as bridging ligands and
one mononuclear copper(II) compound with four N-substituted
sulfonamides derived from the 1,3,4-thiadiazole ring (Scheme 1).
A detailed study of the physico-chemical properties of the com-
plexes is performed. Furthermore, research into the ability of the
four complexes to damage DNA in the presence of activators is pre-
sented. Previously the synthesis, crystal structures and spectro-
scopic properties of ternary copper(II) complexes of L3ꢂ and L4ꢂ
with pyridine have been reported [27].
2.2.1. Synthesis of the ligands
2.2.1.1. N-(5-Ethyl-1,3,4-thiadiazol-2-yl)naphthalene-1-sulfonamide
(HL1) and N-(5-ethylthio)-1,3,4-thiadiazol-2-yl)-4-methylbenzene-
sulfonamide (HL2). A solution containing 1 mmol of 2-amino-5-
ethyl-[1,3,4]-thiadiazole or 1 mmol of 2-amino-5-thioethyl-
[1,3,4]-thiadiazole and 0.9 mmol of naphthalenesulfonylchloride
or 0.9 mmol of toluenesulfonylchloride for HL1 or HL2, respec-
tively in 6 mL of pyridine was heated at reflux at 60 °C for 1 h.
The mixture was added to 10 mL of cold water and stirred for sev-
eral minutes. The resulting solid was recrystallized from ethanol at
60 °C. Anal. Calc. for C14H13N3S2O2 (319.4) (HL1): C, 52.64; H, 4.10;
N, 13.16; S, 20.08. Found: C, 52.77; H, 3.97; N, 13.15; S, 20.07%.
Yield: 87%. IR (KBr) (
(SO2); 917
FAB: m/z+ 320 [HL1+H+].
m
max, cmꢂ1): 1545 (thiadiazole); 1308, 1147
*
m(S–N). Solid UV–Vis (kmax, nm): 314, 325 (p–p ).
m
Anal. Calc. for C11H13N3S3O2 (315.4) (HL2): C, 41.88; H, 4.15; N,
13.72; S, 30.49. Found: C, 42.38; H, 4.15; N, 12.80; S, 30.38%. Yield
72%. IR (KBr) (
920
316 [HL2+H+].
m
max, cmꢂ1): 1555 (thiadiazole); 1314, 1157
*
m(SO2);
+
m
(S–N). Solid UV–Vis (kmax, nm): 314, 327 (p–p ). FAB: m/z
2. Experimental
2.2.1.2.
N-(5-Ethyl-[1,3,4]-thiadiazole-2-yl)-benzenesulfonamide
(HL3) and N-(5-ethyl-[1,3,4] thiadiazole-2-yl)-toluenesulfonamide
(HL4). These ligands were obtained and characterized as previ-
ously reported [22].
2.1. Materials and physical methods
Reagents and solvents were commercially available and were
used without further purification. Elemental analyses (C, N, H, S)
were performed on a Carlo Erba AAS instrument. IR spectra (KBr
disks) were taken using a Mattson Satellite FT-IR in the range
4000–400 cmꢂ1. Diffuse reflectance spectra (Nujol mulls) of the
complexes were carried out on a Shimadzu UV-2101 PC spectro-
photometer. Electronic Paramagnetic Resonance (EPR) spectra
2.2.2. Synthesis of [Cu2(L1)2(phen)2(OH)2] (1),
[Cu2(L2)2(phen)2(OH)2]ꢀ3H2O (2), [Cu2(L3)2(phen)2(OH)2] (3) and
[Cu(L4)2(phen)(H2O)] (4)
1 mmol of ligand (HL1, HL2, HL3 or HL4) was dissolved in
40 mL of methanol which contained 2 mL of a 1 M NaOH solution.

A. Hangan et al. / Polyhedron 29 (2010) 1305–1313
1307
Separately, another mixture was prepared by dissolving 0.5 mmol
CuSO4?5H2O and 0.5 mmol of phenanthroline (phen) in 25 mL of
methanol. By adding the ligand solution into the Cu(II)–phenan-
throline mixture, the color turned green. After stirring at 30 °C
for an hour, the reaction mixture was filtered in order to remove
the precipitate (a complex of copper with phenanthroline). The fil-
trate was left to stand at room temperature and, after a few days,
green crystals suitable for X-ray diffraction analysis were formed.
Anal. Calc. C52H42Cu2N10S4O6 (1158.3) (1): C, 53.91; H, 3.65; N,
12.09; S, 11.07. Found: C, 53.75; H, 3.70; N, 12.00; S, 10.98%. Yield:
and 25 mm (4) and a total of 417 (1), 139 (2), 156 (3) and 295 (4)
images were collected by means of the oscillation method, with a
scan angle per frame of 2° (1, 2, 3 and 4) oscillation and 85 s (1),
10 s (2), 5 s (3) and 275 s (4) exposure time per image.
The data collection strategy was calculated with the program
Collect [28]. For data reduction and cell refinement we used HKL
Denzo and Scalepack [29]. The unit cells were determined from
3381 (1), 3928 (2), 2682 (3) and 5494 (4) reflections between
h = 0.998° and 22.722° (1), 0.998° and 27.485° (2), 0.999° and
27.490° (3), and 0.998° and 24.407° (4). The final mosaicity was
0.50 (1), 0.85 (2), 0.76 (3) and 0.54 (4).
72%. IR (KBr) (cmꢂ1): 1460 (thiadiazole); 1285, 1144
(S–N). Solid UV–Vis (kmax, nm): 642 (d–d).
Anal. Calc. for C46H48Cu2N10S6O9 (1204.4) (2): C, 45.87; H, 4.01;
m(SO2); 932
m
Crystal structures were solved by direct methods using the pro-
gram SIR-97 [30]. Structural refinement was achieved using the
least squares refinement method using the program SHELXL-97
[31]. All non-hydrogen atoms were anisotropically refined. Hydro-
gen atoms were located in a difference Fourier map and located
geometrically, except for compound 3 where all hydrogen atoms
were located geometrically. For complex 1 the final cycle of full-
matrix least squares refinement based on 3488 reflections and
N, 11.63; S, 15.97. Found: C, 46.02; H, 3.67; N, 11.80; S, 16.34%.
Yield: 68%. IR (KBr) (cmꢂ1): 1451 (thiadiazole); 1279, 1133
m
(SO2); 929
m(S–N). Solid UV–Vis (kmax, nm): 630 (d–d).
Anal. Calc. for C44H38Cu2N10S4O6 (1058.2) (3): C, 49.94; H, 3.62;
N, 13.23; S, 12.12. Found: C, 49.87; H, 3.70; N, 13.18; S, 12.21%.
Yield 58%. IR (KBr) (cmꢂ1): 1434 (thiadiazole); 1274, 1138
m
(SO2); 948
Anal. Calc. for C34H34CuN8S4O5 (826.5) (4): C, 49.41; H, 4.14; N,
13.56; S, 15.52. Found: C, 49.27; H, 4.03; N, 13.40; S, 15.40%. Yield
44%. IR (KBr) (cmꢂ1): 1460 (thiadiazole); 1284, 1123
(SO2); 938
(S–N). Solid UV–Vis (kmax, nm): 662 (d–d).
m
(S–N). Solid UV–Vis (kmax, nm): 636 (d–d).
380 parameters converged to a final value of R1 (F2 > 2
r
F2)) =
0.082, wR2 (F2 > 2 F2)) = 0.219, R1 (F2) = 0.154, wR2 (F2) = 0.271.
r
For complex 2, the final cycle of full-matrix least squares refine-
m
ment based on 5936 reflections and 391 parameters converged
m
to a final value of R1 (F2 > 2 F2)) = 0.052, wR2 (F2 > 2 F2)) =
r r
0.147, R1 (F2) = 0.079, wR2 (F2) = 0.180. For complex 3, the final
cycle of full-matrix least squares refinement based on 5151 reflec-
tions and 311 parameters converged to a final value of R1
2.3. Crystal structure determination
(F2 > 2 F2)) = 0.067, wR2 (F2 > 2 F2)) = 0.180, R1 (F2) = 0.118, wR2
r r
A dark green crystal measuring 0.18 ꢃ 0.2 ꢃ 0.2 mm (1), an
emerald green crystal measuring 0.16 ꢃ 0.18 ꢃ 0.22 mm (2), a
green crystal measuring 0.08 ꢃ 0.1 ꢃ 0.15 mm (3) and a green crys-
tal measuring 0.6 ꢃ 0.04 ꢃ 0.08 mm (4), and either a monoclinic
(F2) = 0.238. For complex 4, the final cycle of full-matrix least
squares refinement based on 6154 reflections and 469 parameters
converged to
a r
final value of R1 (F2 > 2 F2)) = 0.066, wR2
(F2 > 2 F2)) = 0.162, R1 (F2) = 0.123, wR2 (F2) = 0.206.
r
ꢀ
space group P21/n (1) or a triclinic space group P1 (2, 3 and 4) (as
The C1 atom in complex 1 shows disorder with an occupancy of
53% at the A position (C1A). In 2, two water molecules are affected
by a considerable disorder degree with the O2W and O3W atoms
showing an occupancy of 30% and 25%, respectively.
determined from the systematic absences) were used. Data collec-
tion was performed at 293 K on a Nonius Kappa-CCD single crystal
diffractometer, using Mo Ka radiation (k=0.71073 Å). The crystal-
detector distance was fixed at 40 mm (1), 30 mm (2), 35 mm (3)
Table 1
Crystal data and structure refinement for 1, 2, 3 and 4.
Compound
1
2
3
4
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system, space group
Unit cell dimensions
a (Å)
C26H21CuN5O3S2
579.20
293(2)
0.71073
monoclinic, P21/n
C23H24CuN5O4.5S3
602.15
293(2)
C22H19CuN5O3S2
529.10
293(2)
C34H34CuN8O5S4
826.47
293(2)
0.71073
triclinic, P1
0.71073
triclinic, P1
0.71073
triclinic, P1
ꢀ
ꢀ
ꢀ
11.1818(6)
21.8504(11)
11.8358(7)
90
114.907 (14)
90
2622.8(2)
4
1.508
1.035
9.9810 (2)
11.2230(3)
13.5490(4)
105.8050 (10)
100.1590(10)
108.8381(14)
1322.61(6)
15.9070(4)
15.6950(4)
17.4540(5)
92.1090 (17)
111.9930 (17)
106.781 (3)
1136.73(7)
2
9.8200(5)
b (Å)
c (Å)
12.9820(7)
15.8830(7)
76.314 (2)
74.172(3)
87.799 (2)
1892.00(16)
2
1.451
0.850
854
a
(°)
b (°)
c
(°)
Volume (Å3)
Z
2
Calculated density (Mg/m3)
Absorption coefficient (mmꢂ1
F(0 0 0)
1.517
1.104
623
1.541
1.179
539
)
1222
Crystal size (mm)
h Range for data collection (°)
Limiting indices
0.18 ꢃ 0.20 ꢃ 0.20
1.86–22.78
ꢂ12 ꢄ h ꢄ 12,
ꢂ23 ꢄ k ꢄ 23,
ꢂ12 ꢄ l ꢄ 12
6610/3488 (0.0712)
98.3%
0.16 ꢃ 0.18 ꢃ 0.22
1.63–27.41
ꢂ12 ꢄ h ꢄ 12,
ꢂ14 ꢄ k ꢄ 14,
ꢂ16 ꢄ l ꢄ 17
9028/5936 (0.0214)
98.6%
0.15 ꢃ 0.10 ꢃ 0.08
1.82–27.51
ꢂ12 ꢄ h ꢄ 11,
ꢂ14 ꢄ k ꢄ 14,
0 ꢄ l ꢄ 15
0.60 ꢃ 0.04 ꢃ 0.08
2.16–24.43
ꢂ11 ꢄ h ꢄ 11,
ꢂ15 ꢄ k ꢄ 15,
ꢂ18 ꢄ l ꢄ 18
10 224/6154 (0.0658)
98.6%
Reflections collected/unique (Rint
Completeness to h = 22.76
Data/restraints/parameters
Goodness-of-fit on F2
)
7349/5151 (0.0000)
98.5%
3488/0/380
1.248
5936/2/391
1.121
5151/0/311
1.062
6154/0/469
1.054
Final R indices [I > 2
r
(I)]
R1 = 0.0819, wR2 = 0.2190
R1 = 0.1538, wR2 = 0.2713
0.625 and ꢂ0.564
R1 = 0.0524, wR2 = 0.1468
R1 = 0.0795, wR2 = 0.1803
1.040 and ꢂ0.886
R1 = 0.0667, wR2 = 0.1796
R1 = 0.1183, wR2 = 0.2381
0.752 and ꢂ1.021
R1 = 0.0661, wR2 = 0.1622
R1 = 0.1235, wR2 = 0.2058
0.678 and ꢂ0.563
R indices (all data)
Largest difference in peak and hole (e Åꢂ3
)

1308
A. Hangan et al. / Polyhedron 29 (2010) 1305–1313
Geometrical calculations were made with PARST [32,33], and
The structure of the complexes 1, 2 and 3 consists of a dimeric
unit with a C2 symmetry axis, where both coppers are bridged by
two hydroxo anions. Each copper atom of the dinuclear entity is
the crystallographic plots were made with ORTEP [34].
A summary of the crystal data, experimental details and refine-
ment results for the four complexes are listed in Table 1.
five-coordinated. The distortion factor
of pentacoordinated complexes (
s
is calculated in the case
s
= (b ꢂ
a)/60°), where b and
a
are the main opposite angles of the equatorial plane. In the case
2.4. DNA cleavage
of a square-pyramidal geometry or of a perfect trigonal bipyrami-
dal geometry, the values of
s are 0 and 1, respectively. The s values
Reactions were performed by mixing 7
0.1 M, pH 6 (cacodylic acid/sodium cacodylate), 6
solution (final concentrations: 3, 6, 9, 12 and 15
pUC18 DNA solution (0.25 g/ L, 750 M in base pairs), and 6 lL
of activating agent solution (H2O2/ascorbic acid) in a threefold mo-
lar excess relative to the concentration of the complex. The result-
ing solutions were incubated for 1 h at 37 °C, after which a quench
l
L of cacodylate buffer
L of complex
M), 1 L of
of 0.175 (complex 1), 0.094 (complex 2) and 0.108 (complex 3)
indicate a slightly distorted square-pyramidal geometry. In the
three complexes, the copper(II) ions are linked to two N atoms of
a phenanthroline molecule, to the O3 atom of one hydroxo ligand
and to the O(3)#1 atom of a second hydroxo ligand. These N and O
atoms form the equatorial plane; the copper(II) ion deviates from
this plane by ꢂ0.3303(1) (1), ꢂ0.1893(5) (2) and ꢂ0.1601(6) Å
(3). The Cu–N–phen bond distances are in the range 2.005(8)–
2.048(4) Å and are similar to those found in previously reported
copper-phenanthroline complexes [35]. The Cu–O bond distances
are in the range 1.938(6)–1.967(7) Å. The apical position is occu-
pied by one nitrogen atom of the thiadiazole ring of the L1ꢂ ligand
[Cu–N(2) = 2.255(9) Å] or L2ꢂ [Cu–N(2) = 2.269(4) Å] or L3ꢂ [Cu–
N(2) = 2.249(4) Å]. The changes in bond length are described by
tetragonality (T5), the tetragonality value of 0.88 for 1, 2 and 3 fit
into the range expected for square-pyramidal complexes with
mixed nitrogen–oxygen ligands [36].
The Cuꢀ ꢀ ꢀCu distances are 2.895(2) (1), 2.893(1) (2) and
2.8751(11) Å (3). The N–Cu–N angles range from 80.7(1)° to
104.7(1)°, the smaller angle being formed by the copper ion and
two N phenanthroline atoms is common in copper–phenanthroline
complexes [37–39]. The Cu(1)–O(3)–Cu(1)# angles are 95.70(3)°
(1), 95.68(11)° (2) and 95.46(16)° (3), which are comparable to
those of other dinuclear complexes with the same geometry de-
scribed in the literature [40–44].
l
l
l
l
l
l
buffer solution (3 lL) consisting of bromophenol blue (0.25%), xy-
lene cyanole (0.25%) and glycerol (30%) was added. The solution
was then subjected to electrophoresis on 0.8% agarose gel in
0.5ꢃ TBE buffer (0.045 M Tris, 0.045 M boric acid, and 1 mM EDTA)
containing 5lL/100 mL of a solution of ethidium bromide (10 mg/
mL) at 100 V for 2 h. The bands were photographed on a capturing
system (Gelprinter Plus TDI).
To test for the presence of reactive oxygen species (ROS) gener-
ated during strand scission and for possible complex-DNA interac-
tion sites, various reactive oxygen intermediate scavengers and
groove binders were added to the reaction mixtures. The scaveng-
ers used were 2,2,6,6-tetramethyl-4-piperidone (0.5 M), t-butyl
alcohol (10.5 M), sodium azide (NaN3) (400 mM), superoxide dis-
mutase (SOD) (15 units). In addition, a chelating agent of copper(I),
neocuproine (36
lM), along with the groove binder distamycin
(80 M) were also assayed. Samples were treated as described
l
above.
3. Results and discussion
Complex 1 is stabilized by a moderate hydrogen bond between
a N-thiadiazole and an O-water [O2 Wꢀ ꢀ ꢀN(1) 3.005 Å; O2 W–
H2 Wꢀ ꢀ ꢀN(1) 137.88°]. The structure of 2 is stabilized by moderate
hydrogen bonds between an O-water and an O-sulfonamidato
[O2Wꢀ ꢀ ꢀO2 2.957 Å; O(2W)–H(W)ꢀ ꢀ ꢀO2 153.27°] and between a
N-thiadiazole and an O-water [O1Wꢀ ꢀ ꢀN(1) 3.087 Å; O1W–H1W–
N(1) 111.07°]. Complex 3 is stabilized by moderate and weak
3.1. Crystal structures of complexes 1, 2 and 3
The ORTEP drawings of the complexes 1, 2 and 3 with the atom-
ic numbering scheme are shown in Figs. 1–3, respectively. The rel-
evant structural parameters for these compounds are listed in
Table 2.
Fig. 1. ORTEP drawing of the complex [Cu(L1)(phen)(OH)]2 (1).

A. Hangan et al. / Polyhedron 29 (2010) 1305–1313
1309
Fig. 2. ORTEP drawing of the complex [Cu(L2)(phen)(OH)]2 (2).
Fig. 3. ORTEP drawing of the complex [Cu(L3)(phen)(OH)]2ꢀ3H2O (3).
hydrogen bonds formed by the O(3) atom of the hydroxo group
and two nitrogen atoms, N(2) and N(3), of the sulfonamidato li-
gand [O3ꢀ ꢀ ꢀN3, 2.898(6) Å, O3–H3ꢀ ꢀ ꢀN3, 159.04(2.7)°; O3ꢀ ꢀ ꢀN2,
3.194(5) Å, O3–H3ꢀ ꢀ ꢀN2, 113.22(2.4)° [45].
basal atoms are quasi coplanar and the copper ion is displaced
0.1098(8) Å above the plane. The apical site is occupied by the oxy-
gen atom of the coordinated water molecule. The Cu–N–phen bond
distances, 2.025(5) and 2.041(5) Å, are very similar to those found
in other previously reported copper(II)–phen complexes and to the
complexes described above. The Cu–N-thiadiazole and the Cu–O–
water bond distances are 1.986(5), 2.041(5) and 2.240(5) Å, respec-
tively. A small angle of 81.5(2)° is formed by the copper ion and
two N phenanthroline atoms, as is common in copper–phenan-
throline complexes.
3.2. Crystal structure of complex 4
Fig. 4 shows an ORTEP view of the molecule with the atomic
numbering scheme. Selected bond distances and angles are listed
in Table 2. The coordination sphere of copper(II) is best described
The structure is stabilized through weak hydrogen bonds be-
tween the N-thiadiazole and the O-water atoms [O1Wꢀ ꢀ ꢀN(1A)
2.967(6) Å; O1W–H1Wꢀ ꢀ ꢀN(1A) 108.0°].
as a square based pyramid, as can be deduced from the
s value
of 0.06. The T5 parameter is a measure of the tetragonal distortion
of the geometry of the molecule. It is calculated as the ratio be-
tween the arithmetic mean of the distances between the atoms
on the equatorial plane and the atoms on the axial plane. The T5 va-
lue of 0.90 is similar to that of other elongated distorted square-
pyramid copper complexes [40]. The basal positions are occupied
by the two nitrogen atoms from the phenanthroline ligand and
two nitrogen atoms from the thiadiazole of two deprotonated sul-
fonamide molecules which act as monodentate ligands. The four
3.3. Spectroscopic properties
3.3.1. Infrared and electronic spectra
The IR spectra of the four complexes present a similar pattern.
With respect to the IR spectra of the ligands the following modifi-
cations are found: (i) the band corresponding to the stretching

1310
A. Hangan et al. / Polyhedron 29 (2010) 1305–1313
Table 2
Selected bond distances (Å) and angles (°) for compounds 1, 2, 3 and 4.
1
2
3
4
Cu(1)–O(3)#1
Cu(1)–O(3)
Cu(1)–N(4)
Cu(1)–N(5)
Cu(1)–N(2)
Cu(1)–Cu(1)#1
1.938(6)
1.967(7)
2.005(8)
2.029(9)
2.255(9)
2.895(2)
84.3(3)
Cu(1)–O(3)
Cu(1)–O(3)#1
Cu(1)–N(5)
Cu(1)–N(4)
Cu(1)–N(2)
Cu(1)–Cu(1)#1
1.944(2)
1.959(2)
2.024(3)
2.032(3)
2.269(3)
2.893(8)
84.32(11)
96.51(13)
163.34(13)
168.99(12)
94.86(12)
81.14(14)
95.49(12)
95.78(12)
100.69(13)
95.52(13)
42.35(7)
Cu(1)–O(3)#1
Cu(1)–O(3)
Cu(1)–N(5)
Cu(1)–N(4)
Cu(1)–N(2)
Cu(1)–Cu(1)#1
1.941(3)
1.944(4)
2.036(5)
2.048(4)
Cu(1)–N(2A)
Cu(1)–N(2B)
Cu(1)–N(1)
Cu(1)–N(2)
1.986(5)
2.005(5)
2.025(5)
2.041(5)
2.240(5)
93.4(2)
172.5(2)
93.4(2)
91.2(2)
2.249(4)
Cu(1)–O(1W)
2.875(11)
84.54(16)
97.07(17)
170.09(15)
163.59(16)
95.01(16)
80.66(18)
102.05(16)
98.97(16)
90.28(17)
94.23(17)
42.30(11)
42.24(10)
138.52(13)
134.98(13)
104.26(12)
N(2A)–Cu(1)–N(2B)
N(2A)–Cu(1)–N(1)
N(2B)–Cu(1)–N(1)
N(2A)–Cu(1)–N(2)
N(4)–Cu(1)–N(2)
N(2B)–Cu(1)–N(2)
N(1)–Cu(1)–N(2)
N(2A)–Cu(1)–O(1W)
N(2B)–Cu(1)–O(1W)
N(1)–Cu(1)–O(1W)
N(2)–Cu(1)–O(1W)
O(3)#1–Cu(1)–O(3)
O(3)#1–Cu(1)–N(4)
O(3)–Cu(1)–N(4)
O(3)#1–Cu(1)–N(5)
O(3)–Cu(1)–N(5)
N(4)–Cu(1)–N(5)
O(3)#1–Cu(1)–N(2)
O(3)–Cu(1)–N(2)
N(4)–Cu(1)–N(2)
N(5)–Cu(1)–N(2)
O(3)#1–Cu(1)–Cu(1)#1
O(3)–Cu(1)–Cu(1)#1
N(4)–Cu(1)–Cu(1)#1
N(5)–Cu(1)–Cu(1)#1
N(2)–Cu(1)–Cu(1)#1
O(3)–Cu(1)– O(3)#1
O(3)–Cu(1)–N(5)
O(3)#1–Cu(1)–N(5)
O(3)–Cu(1)–N(4)
O(3)#1 –Cu(1)–N(4)
N(5)–Cu(1)–N(4)
O(3)–Cu(1)–N(2)
O(3)#1 –Cu(1)–N(2)
N(5)–Cu(1)–N(2)
N(4)–Cu(1)–N(2)
O(3)–Cu(1)–Cu(1)#1
O(3)#1–Cu(1)–Cu(1)#1
N(5)–Cu(1)–Cu(1)#1
N(4)–Cu(1)–Cu(1)#1
N(2)–Cu(1)–Cu(1)#1
O(3)#1–Cu(1)–O(3)
O(3)#1–Cu(1)–N(5)
O(3)–Cu(1)–N(5)
O(3)#1–Cu(1)–N(4)
O(3)–Cu(1)–N(4)
N(5)–Cu(1)–N(4)
O(3)#1–Cu(1)–N(2)
O(3)–Cu(1)–N(2)
N(5)–Cu(1)–N(2)
N(4)–Cu(1)–N(2)
O(3)#1–Cu(1)–Cu(1)#1
O(3)–Cu(1)–Cu(1)#1
N(5)–Cu(1)–Cu(1)#1
N(4)–Cu(1)–Cu(1)#1
N(2)–Cu(1)–Cu(1)#1
95.3(3)
160.8(3)
171.3(3)
96.4(3)
81.1(4)
97.1(3)
94.2(3)
104.8(3)
91.6(3)
42.53(19)
41.77(18)
134.8(3)
137.5(3)
97.6(2)
94.23(17)
168.7(2)
81.5(2)
93.7(2)
101.8(2)
87.90(19)
88.11(19)
41.97(7)
136.46(10)
135.80(10)
97.62(8)
Symmetry transformations used to generate equivalent atoms: (1): #1 ꢂx, ꢂy, ꢂz + 2; (2, 3, 4): #1 ꢂx + 1, ꢂy, ꢂz + 1.
The bands corresponding to phenanthroline appear, according
to literature, at 3337, 1434, 1274, 1138, 1090, 851 and 756 cmꢂ1
[48,49]. The spectra of the complexes present bands at 1125,
1087 and 730 cmꢂ1, which are attributed to the coordinated phe-
nanthroline molecule [50].
C11a
C8a
C9a
The RD spectra of the complexes 1, 2, 3 and 4 show a band at
642, 630, 636 and 662 nm, respectively, corresponding to d–d tran-
sitions. This band is in the 600–850 nm range, as stated in the lit-
erature for Cu(II) complexes with square-pyramidal geometries
and that have a CuN3O2 chromophore [51,52].
C7a
C10a
C6a
C2a
C5a
C1a
3.3.2. Magnetic properties and EPR spectra
O1a
S1a
C3a
C4a
Magnetic susceptibility measurements of compounds 1 and 2
were performed on ground crystals in the temperature range 2–
300 K. The magnetic properties of 1 are depicted in Fig. 5 in the
S2a
O2a
N1a
N2a
N3a
form of vMT versus T for two copper(II) ions (where vM is the mag-
Cu1
netic susceptibility per two copper(II) ions). At room temperature
O1w
N2
N1
C1
C10
1.15
C12
C2
C9
C11
C7
1.1
1.05
1
C8
C3
C4
C5
Fig. 4. ORTEP drawing of the complex [Cu(L4)2(phen)(H2O)] (4).
C6
vibration of the thiadiazole ring is markedly shifted by ca. 130–
90 cmꢂ1 to lower frequencies with respect to the uncoordinated li-
0.95
0.9
gands, (ii) the
m(SO2)as and m(SO2)s bands in the complexes are
shifted to lower frequencies (by ca. 30 and 20 cmꢂ1, respectively),
and (iii) the characteristic band corresponding to m(S–N) appears
0
50
100
150
200
250
300
350
near 920 cmꢂ1, changed by ca. 9–22 cmꢂ1 to higher frequencies.
In general, the IR spectra are similar to those for other copper N-
sulfonamide compounds [46,47]. The changes of the IR character-
istic bands are mainly due to the sulfonamide deprotonation.
T / K
Fig. 5. Temperature dependence of
represents the fitted function.
vMT for [Cu(L1)(phen)(OH)]2 (1). The solid line

A. Hangan et al. / Polyhedron 29 (2010) 1305–1313
1311
v
MT is equal to 0.97 cm3 molꢂ1 K, a value which is higher than that
constant (2J) and the Cu–O–Cu angle (h). An antiferromagnetic
character was found for complexes with h larger than 97.5°, while
ferromagnetism was observed for smaller values of h. A similar cor-
relation was deduced by Ruiz et al. [55] using density functional
calculations. These authors indicate that the structural require-
ments for an hydroxo-bridged Cu(II) binuclear compound with a
strong ferromagnetic coupling are: small Cu–O–Cu angles, short
Cu–O distances, large out-of-plane shifts of the hydrogen atoms
on the bridge and hinge-distorted Cu2O2 rings.
From the Cu–O–Cu angles of complexes 1 and 2 (95.70° and
95.68°, respectively) we could predict that the magnetic behavior
of these complexes would be strongly ferromagnetic, for instance
[Cu(bipy)OH]2(NO3)2 has a h value of 95.5° and its exchange cou-
pling constant J is +172 cmꢂ1 [56]. The J values for complexes 1
and 2 are significantly lower than that reported for the above men-
tioned complex with bipyridine, probably due to the planar Cu2O2
rings of complexes 1 and 2. For complex 3, taking into account the
similar value of h (95.46°), a similar ferromagnetism to the other
two dimers is proposed.
expected for
a
magnetically isolated spin doublet (0.75 cm3
molꢂ1 K). The value increases until 40 K (1.11 cm3 molꢂ1 K) and
then decreases sharply at very low temperatures, reaching a value
of 0.92 cm3 molꢂ1 K at 1.86 K. This behavior is typical of a ferro-
magnetic interaction between the copper(II) ions. The data were
fitted to the Bleaney–Bowers equation [53], which has been
modified considering the fraction of monomeric impurity (
and with a corrective term for interdimer interactions (h). The fit
was accomplished by minimization of R = mTcalc
mTobs)2/
q), TIP
R
(v
ꢂ
v
(v
mTobs)2 by a least-squares procedure. The fitting results for com-
plex
1
were J = 85 cmꢂ1
,
g = 2.10, TIP = 130 ꢃ 10ꢂ6
, q = 0.02,
h = ꢂ0.74 K and R = 1.4 ꢃ 10ꢂ3. For complex 2, the values were
J = 85 cmꢂ1, g = 2.13, TIP = 125 ꢃ 10ꢂ6
,
q
= 0.01, h = ꢂ0.44 K and
R = 8.8 ꢃ 10ꢂ4
.
Hydroxo-bridged Cu(II) binuclear complexes are one of the
most extensively studied families from a experimental point of
view since they provide examples of the simplest case of magnetic
interaction involving only two unpaired electrons. Complexes of
this type exhibit ferromagnetic or antiferromagnetic character,
depending on their geometry. Hatfield and Hodgson [54] found a
linear correlation between the experimental exchange coupling
The X-band EPR spectra of ground crystals of compounds 1, 2
and 3 show a very weak signal with a g value at about 2.07.
The EPR spectrum of compound 4 is axial. The EPR parameters,
(a) Complex 3
1
2
3
4
5
6
7
8
9
10 11 12 13
Form II
Form III
Form I
(b) Complex1
1
2
3
4
5
6
7
8
9
10 11 12 13
Form II
Form III
Form I
(c) Complex 2
1
2
3
4
5
6
7
8
9
10 11 12 13
Form II
Form III
Form I
(d) Complex 4
1
2
3
4
5
6
7
8
9
10 11 12 13
Form II
Form III
Form I
Fig. 6. Agarose gel of pUC18 plasmid treated with the complexes. (a) Complex 3, (b) complex 1, (c) complex 2: (1) pUC18 plasmid; (2) pUC18 plasmid with reducing agents;
M; (8) complex 3 M; (9) complex 6 M; (10) complex
M, (d) complex 4: (1) pUC18 plasmid; (2) pUC18 plasmid with reducing agents; (3) CuSO4ꢀ5H2O
M; (6) CuSO4ꢀ5H2O 15 M; (7) CuSO4ꢀ5H2O 18 M; (8) complex 6 M; (9) complex 9 M; (10) complex 12 M; (11)
M; (13) [Cu(phen)2]2+ 12
M.
(3) CuSO4ꢀ5H2O 3
l
M; (4) CuSO4ꢀ5H2O 6
M; (11) complex 12 M; (12) complex 15
M; (4) CuSO4ꢀ5H2O 9 M; (5) CuSO4ꢀ5H2O 12
M; (12) complex 18
l
M; (5) CuSO4ꢀ5H2O 9
l
M; (6) CuSO4ꢀ5H2O 12
l
M; (7) CuSO4ꢀ5H2O 15
l
l
l
9
6
l
l
l
l
l
M; (13) [Cu(phen)2]2+
9 l
l
l
l
l
l
l
complex 15
l
l
l

1312
A. Hangan et al. / Polyhedron 29 (2010) 1305–1313
obtained by simulation [57], are gk ¼ 2:245 and g? ¼ 2:054, which
are in agreement with the coordination polyhedron deduced from
the crystallographic data.
1
2
3
4
5
6
7
8
9
10
3.4. DNA cleavage
It is known that the DNA cleavage is controlled by relaxation of
the supercoiled circular conformation of pUC18 DNA to the nicked
circular and/or linear conformations. When electrophoresis is ap-
plied to plasmid DNA, the fastest migration will be observed for
DNA of the closed circular conformation (Form I), if one strand is
cleaved, the supercoiled conformation will relax to produce a
slower-moving nicked conformation (Form II). If both strands are
cleaved, a linear conformation (Form III) will be generated that mi-
grates in between.
The ability of the complexes to cleave DNA was assayed with
the aid of gel electrophoresis on supercoiled pUC18 DNA in DMF:
cacodylate buffer (0.1 M, pH 6.0) [1:9] for complexes 1 and 3,
and [1:4] for complexes 2 and 4 in the presence of H2O2/ascorbic
acid, 3.0-fold excess relative to the complex concentration. Control
experiments with CuSO4 and the bis(o-phenanthroline)-copper
complex were also carried out under the same experimental
conditions.
Fig. 7. Agarose gel electrophoresis of pUC18 plasmid treated with complex 3 in the
presence of potential inhibitors. (1) pUC18 plasmid; (2) pUC18 plasmid with
reducing agents; (3) complex 12
12 M + DMSO; (5) complex 12 M + t-butyl alcohol; (6) complex 12
(7) complex 12 M + piperidone; (8) complex 12 M + distamycin; (9) complex
12 M + SOD; (10) complex 12 M + neocuproine.
lM
without inhibitors; (4) complex
l
l
l
M + NaN3;
l
l
l
l
lator (neocuproine) and the minor groove binder distamycin
were also used. The assays were performed with H2O2/ascorbic
acid (in a 3.0-fold molar excess relative to the complex concentra-
tion) as an activating agent. The results for complex 3 are shown in
Fig. 7. The hydroxyl radical scavengers DMSO (lane 4) and tert-bu-
tyl alcohol (lane 5) diminished the DNA breakdown of complex 3,
which indicates that the hydroxyl radical participates in the oxida-
tive cleavage. Sodium azide and 2,2,6,6-tetramethylpiperidone
(lanes 6 and 7) had no significant effect on the DNA cleavage. This
fact rules out the involvement of the participation of 1O2 or singlet
oxygen-like entities in the reaction. No apparent inhibition of DNA
damage was observed in the presence of the minor groove binder
distamycin (lane 8), suggesting the lack of interaction of complex
3 through the DNA minor groove. The significant reduction in the
ability of complex 3 to cleave DNA in the presence of the superox-
ide-dismutase enzyme (lane 9) suggests that Oꢂ2 is one of the reac-
tive species that actually breaks the DNA.
Fig. 6 shows the electrophoretic results of complexes 1, 2, 3 and
4. In Fig. 6a we can appreciate that the DNA cleavage starts at
6.0
Form II (lane 9). Then, at 9
appear (lane 10). At higher concentrations (lanes 11 and 12)
smearing is observed. CuSO4 at the highest concentration, 15 M,
lM of complex 3, giving an appreciable amount of plasmid
lM the nicked circular and linear forms
l
does not present any DNA cleavage activity. Finally, we found that
the activity of 3, is higher than that of the bis(o-phenanthro-
line)copper complex (compare lane 10 with lane 13). As a conse-
quence, complex 3 can be defined as a strong nuclease agent in
the presence of H2O2/ascorbic acid. Figs. 6b and 6c show the results
for complexes 1 and 2. Both complexes are also strong nuclease
agents in the presence of H2O2/ascorbic acid, even stronger than
the bis(o-phenanthroline)copper complex (compare lane 10 of
Figs. 6b and 6c with lane 13). However, both complexes present
lower DNA cleavage than complex 3 (compare lanes 11 and 12 of
Figs. 6a with 6b and 6c). Fig. 6d shows the electrophoretic results
The addition of neocuproine also diminished the degradation of
DNA (lane 10). This attenuation of the cleavage activity can be ex-
plained by taking into consideration the reduction of Cu(II) in the
ROS production process. From these results we can conclude that
a Cu(I) species, superoxide Oꢂ2 and the hydroxyl radical OH are
Å
the active species involved in the DNA cleavage. Similar results
have been obtained for the complexes 1, 2 and 4 (data not shown).
Hydroxyl radicals are generated by a variety of chemical and
in the presence of complex 4. At 12 and 15
lM, a mixture of Form
II and Form III is observed, and at 18 M Form II, Form III and
l
smearing are appreciated. This fact is clearly indicative of the abil-
ity of complex 4 to act as an artificial nuclease. From the compar-
ison between lane 10 and lane 13, we can deduce that 4 presents
similar activity to that of the bis(o-phenanthroline)copper complex
and as a consequence is much less active than complexes 1, 2 and
3. The higher ability to cleave DNA of complexes 1, 2 and 3 with to
respect complex 4 can be attributed to the dimeric nature of these
compounds. The direct influence of the nuclearity of the copper(II)
complexes on their nuclease activity has previously been showed
by Karlin et al. [58,25,59,60]. Moreover, the effect of the nuclearity
of the compounds on the nuclease efficiency has been described by
us for related sulfonamide compounds [26].
Another aspect to be considered is why complex 3 is more ac-
tive than complexes 1 and 2. The crystal structures of 1, 2 and 3
are very similar, the main difference being the presence of the ben-
zene ring in complex 3, while complexes 1 and 2 contain a toluene
or a naphthalene ring, respectively. Steric effects could be the rea-
son why complexes 1 and 2 have lower nuclease activity than com-
plex 3.
Å
physical processes. Transition-metal mediated OH production is
known to occur by a number of routes; two well known pathways
are the Fenton and the Haber–Weiss mechanisms [61,62]. Accord-
ing to these, a possible pathway for ROS generation would be:
CuðIIÞL þ eꢂ ! CuðIÞL
CuðIÞL þ O2 ! CuðIIÞL þ Oꢂ
2
2Oꢂ2 þ 2Hþ ! O2 þ H2O2
CuðIÞL þ H2O2 ! CuðIIÞL þ OHꢂ þ ÅOH
4. Conclusions
A series of new Cu(II) complexes containing thiadiazole sulfon-
amide derivatives and 1,10-phenanthroline have been synthesized
and characterized by X-ray diffraction, spectroscopic and magnetic
methods. Complexes 1, 2 and 3 are dimer copper(II) compounds,
where the copper(II) ions are linked by two hydroxo bridges. Com-
plex 4 is a monomer complex. The thiadiazole sulfonamide, acting
as a monodentate ligand, binds to copper(II) through the thiadia-
zole nitrogen atom closest to the sulfonamide group. Complexes
The involvement of reactive oxygen species (ROS) such as hy-
droxyl, superoxide, singlet oxygen-like species and hydrogen per-
oxide in the nuclease mechanism was determined by monitoring
the quenching of the DNA cleavage in the presence of ROS scaveng-
ers. To clarify other aspects of the mechanism, the copper(I)–che-

A. Hangan et al. / Polyhedron 29 (2010) 1305–1313
1313
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line compound. The use of scavengers of ROS indicates that the hy-
droxyl and the superoxide anions are the main radicals that break
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