Synthesis, spectroscopic characterization, X-ray structure and evaluation of binding parameters of new triorganotin(IV) dithiocarboxylates with DNA

Article abstract of DOI:10.1016/j.ejmech.2009.04.031

Three new triorganotin(IV) dithiocarboxylates (1-3) with general formula R₃SnL, where R = C₄H₉ (1), C₆H₁₁ (2), C₆H₅ (3) and L = 4-(4-nitrophenyl)piperazine-1-carbodithioate, have

Full text of DOI:10.1016/j.ejmech.2009.04.031

European Journal of Medicinal Chemistry 44 (2009) 3986–3993
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, spectroscopic characterization, X-ray structure and evaluation of
binding parameters of new triorganotin(IV) dithiocarboxylates with DNA
,
,
a
Zia-ur Rehman a c, Afzal Shah a, Niaz Muhammad a, Saqib Ali a , Rumana Qureshi ,
*
Auke Meetsma b, Ian Sydney Butler c
a Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan
b Crystal Structure Center, Chemical Physics, Zernike, Institute for Advanced Materials, University of Groningen, Nijenborgh 4, NL-9747 AG Groningen, The Netherlands
c Department of Chemistry, McGill University, 801 Sherbrook Street West, Montreal, Quebec, Canada H3A2K6
a r t i c l e i n f o
a b s t r a c t
Article history:
Three new triorganotin(IV) dithiocarboxylates (1–3) with general formula R3SnL, where R ¼ C4H9 (1),
C6H11 (2), C6H5 (3) and L ¼ 4-(4-nitrophenyl)piperazine-1-carbodithioate, have been synthesized and
characterized by elemental analysis, Raman, FT-IR, multinuclear NMR (1H, 13C and 119Sn) and mass
spectrometry. The crystal structure of complex 3 confirmed distorted trigonal-bipyramidal geometry
around Sn atom. The interaction of compounds 1–3 with DNA was investigated by cyclic voltammetry
(CV) and UV–vis spectroscopy. The positive peak potential shift in CV and hypochromic effect in spec-
troscopy evidenced intercalative mode of interaction. The results indicate that the binding affinity varies
in this sequence: 1 >3 > 2.
Received 30 December 2008
Received in revised form
9 April 2009
Accepted 16 April 2009
Available online 3 May 2009
Keywords:
Triorganotin(IV) dithiocarboxylates
Spectroscopy
Ó 2009 Published by Elsevier Masson SAS.
X-ray diffraction
DNA interaction
Binding constant
1. Introduction
genetic transformation machinery. Therefore, extensive studies
have been focused on modifying the intercalative ligand [4].
There has been much interest in recent years in studying the
interaction of coordination complexes with DNA due to their
potential candidature as anti-tumor agents after the discovery of
clinically used cisplatin. However, the serious negative side effects
of platinum-pharmaceuticals diverted the attention of the
researchers to non-platinum chemotherapeutics with positive, low
or no side effects. Among these organotins received utmost atten-
tion on account of their potential apoptotic inducing character and
high therapeutic index [1–3]. Their DNA binding studies are of
paramount importance in the development of new anticancer
agents and DNA molecular probes. The interaction of small mole-
cules with the DNA is of three types: (i) electrostatic interaction
with the anionic phosphate of DNA backbone, (ii) intercalation into
the stacked base pairs of DNA and (iii) groove binding. The pre-
requisite for useful applications of coordination complexes requires
their direct binding to DNA through intercalation, in which the
compound causes unwinding of the local structure of DNA, which
culminates in the damage of the DNA storage, transcription and
Organotin(IV) dithiocarboxylates are the subject of intensive
investigations due to their structural diversity, anti-tumor activity
and biological applications [5,6]. The coordination with the Sn atom
depends not only on factors such as structure of the organic groups,
but also whether the 1,1-dithiolate moiety behaves as monodentate
or bidentate. Based on these factors triorganotin(IV) dithiocarbox-
ylates either exhibit tetrahedral or trigonal-bipyramidal geometry.
In continuation of our work, and as part of ongoing study of
dithiocarboxylate complexes of organotin(IV) and of their coordi-
nation chemistry [7,8], we have synthesized, characterized three
triorganotin(IV) derivatives of 4-(4-nitrophenyl) piperazine-1-car-
bodithioate and evaluated their binding parameters with DNA. The
structure of the ligand salt is demonstrated in Scheme 1(a).
2. Results and discussion
2.1. Proposed mechanism of ligand and complexes 1–3 synthesis
The nucleophilic attack of 4-(4-nitrophenyl)piperazine on
carbon disulfide gave 4-(4-nitrophenyl)piperazine-1-carbodithioic
acid as intermediate which undergoes acid–base reaction with
unreacted 4-(4-nitrophenyl)piperazine to gave 4-(4-nitrophenyl)
* Corresponding author. Tel.: þ925190642208; fax: þ92512873869.
E-mail address: drsa54@yahoo.com (S. Ali).
0223-5234/$ – see front matter Ó 2009 Published by Elsevier Masson SAS.
doi:10.1016/j.ejmech.2009.04.031

Z.-u. Rehman et al. / European Journal of Medicinal Chemistry 44 (2009) 3986–3993
3987
is monodentate [9]. In our present study the appearance of two
bands for C–S, in complexes 1 and 2, is in agreement with mono-
dentate bonding of 1,1-dithiolate moiety with Sn. The unsplitting of
the C–S peak in compound 3 is an indicative of bidentate coordina-
tion of dithiocarboxylate group, and is consistent with crystal
structure of 3. The stretching vibration peaks of the C–N, in the
studied complexes, were located at 1478–1497 cmꢀ1. These values lie
between the range of C–N single bonds (1250–1360 cmꢀ1) and C]N
double bond (1640–1690 cmꢀ1) which is an indication of partial
double bond character in C–N bond [6]. The appearance of new peaks
at 514 cmꢀ1 and 510 cmꢀ1 in compounds 1 and 2 is assigned to Sn–C.
a
6
5
3
2
S
1
3a
N
6a
2a
S-H N
5a
5'a
α
O2N
N
N
NO2
7a
6'a
+
2
4
7
4a
6'
5'
3' 2'
2'a 3a'
γ
γ
β
β
b
δ
β
CH3
α
,
R =
α
,
δ
δ
γ
Scheme 1. Numbering scheme of ligand-salt and organic groups.
2.3. NMR spectra
piperazinium
4-(4-nitrophenyl)piperazine-1-carbodithioate
(L-salt). The reaction of the ligand salt with R3SnCl (R ¼ C4H9, C6H11
and C6H5) gave R3SnL and 4-(4-nitrophenyl)piperazinium chloride
as shown in Scheme 2. This mechanism has been proposed on the
basis of multinuclear NMR (1H and 13C) study of the ligand and
successfully analyzing the crystal structure of the by-product, 4-(4-
nitrophenyl) piperazinium chloride and is shown in Fig. 3.
The 1H NMR spectra of the investigated compounds were
recorded in DMSO. The assignment of the proton resonances was
made by their peak multiplicity, intensity pattern and comparison
of the integration values of the protons with the expected
composition. The disappearance of duplication peak pattern due to
4-(4-nitrophenyl)piperazinium ion and appearance of proton
signals for the organic groups attached to Sn confirmed the
formation of complexes 1–3.
2.2. Vibration spectra
In the spectra of complexes 1 and 2, the protons of piperazine
moiety of the ligand showed two multiplets (4.15 and 3.62 ppm) in
the aliphatic region while aromatic part of the ligand gave two
doublets due to two non-equivalent sets of protons. The tributyl-
and tricyclohexyl-groups attached to the Sn illustrated proton
resonances at 1.75–0.089 ppm and 2.04–1.24 ppm, respectively.
Difficulty in obtaining the nJSn–H coupling in these two complexes
due to complex nature of the proton resonances of tributyl- and
tricyclohexyl-groups attached to the Sn, renders almost no infor-
mation about the geometry around Sn atom. In the case of tri-
phenyltin derivative of the ligand, the proton spectrum is
informative regarding the geometry around the Sn. The signals for
In Raman spectra, the appearance of Sn–S peak in the region of
362–384 cmꢀ1 is an indication of the formation of complexes. Very
sharp Sn–C peak was observed at 515 and 510 cmꢀ1 in complexes 1
and 2, whereas in triphenyltin(IV) derivative a weak Sn–C peak was
observed at 263 cmꢀ1
.
Of particular interest in the IR spectra are the C–N, C–S stretching
frequencies. Both can be used to differentiate between mono and
bidentate modes of coordination of 1,1-dithiolate moiety. The pres-
ence of single band in the region of 900–1000 cmꢀ1 due to
y(C–S) is
an indication of bidentate character whereas the presence of two
bands with separation value > 20 cmꢀ1 suggests that ligand bonding
S
4 h stirring
273 K
Dry MeOH
+
O2N
N
NH
CS2
O2N
N
N
SH
N
O2N
NH
..
S
O2N
N
N
S-H N
N
NO2
+
2
R3SnCl
6 h reflux
Dry MeOH
R
S
NH Cl-
O2N
N
N
N
N
O2N
N
+
+
2
S
R
Sn
R
or
R
R
S
O2N
R
Sn
S
R = C4H9, C6H11, C6H5
Scheme 2. Synthetic mechanism of ligand-salt and complexes.

3988
Z.-u. Rehman et al. / European Journal of Medicinal Chemistry 44 (2009) 3986–3993
Fig. 1. ORTEP drawing of Ph3SnL (3) with atomic numbering scheme.
protons of the phenyl groups attached to the Sn were distinguished
into two sets. The ortho protons were observed at down field
(7.76 ppm) and those for meta and para protons at upfield
(7.39 ppm). In addition, the difference in chemical shift resonance
between ortho and meta and para (0.37 ppm) is an indication of
anisobidentate bonding of 1,1-dithiolate moiety in solution. All
these observations are in agreement with the previously reported
literature for a series of triphenyltin dithiocarboxylates [10]. Almost
no significant change was observed in the aromatic and piperazine
protons of ligand moiety in the 1H spectrum of the complex 3.
The 13C NMR chemical shifts due to butyl, cyclohexyl and phenyl
groups, attached to Sn atom, were observed at positions comparable
to the other similar compounds [11,12]. The 13C NMR chemical shifts
due to the ‘CS2’ carbon atom in the investigated complexes were
found in the range 200.1–195.9 ppm. Coordination of the Sn atom in
triorganotins has been related to the 1J (119Sn–13C) coupling constant.
In compounds 1 and 2 the 1J (119Sn–13C) coupling constant observed
was 346.6 Hz (107.2ꢁ) and 330 Hz (105.7ꢁ) which is in agreement
with analogous four-coordinated organotin derivatives [13].
The mono or bidentate bonding of the ligand to the organotin
moiety, in the complexes, was further confirmed by 119Sn NMR
spectroscopy. It has been reported that d (
119Sn) values (in ppm) for
organotin(IV) dithiocarboxylate with four-coordinate Sn vary from
þ120 to ꢀ145 ppm while 119Sn signal in the range of ꢀ150 to
ꢀ250 ppm corresponds to five-coordinate Sn [14]. In case of
complexes 1 and 2, the 119Sn spectra gave only a sharp singlet at
39.6 ppm and ꢀ17.5 ppm confirmed the formation of a single
species with the tetrahedral geometry around Sn while complex 3
gave signal (ꢀ195 ppm) in the region for five-coordinated Sn atom.
2.4. Mass spectra
Mass-spectral data for 1–3 showed rich ion distributions but our
interest lies in Sn containing ions. These ions were easily and
quantitatively identified from the characteristic isotopic peak
pattern for Sn [15]. The mass-spectral data reported here are related
to the principal isotope 120Sn. Complexes 1–3 show no molecular
ion (Mþ) as is generally the case for main group organometallic
Fig. 2. Packing of molecules in a unit cell of Ph3SnL (3).

Z.-u. Rehman et al. / European Journal of Medicinal Chemistry 44 (2009) 3986–3993
3989
Table 2
Selected bond lengths (Å) and angles (ꢁ) for Ph3SnL (3).
Sn–S2
2.4419 (14)
2.114 (5)
2.135 (5)
3.179
Sn–C24
S–C11
S2–C11
2.151 (5)
1.674 (5)
1.760 (4)
Sn–C12
Sn–C18
Sn–S1
S2–Sn–C12
S2–Sn–C18
S2–Sn–C24
C12–Sn–C18
C12–Sn–C24
C18–Sn–C24
Sn–C12–C13
Sn–C18–C19
Sn–C24–C25
Sn–S2–C11
108.73 (13)
118.29 (11)
90.15 (12)
115.57 (18)
112.44 (18)
108.96 (18)
120.3 (4)
123.0 (3)
119.6 (3)
99.33 (15)
S1–Sn–C12
S1–Sn–C18
S1–Sn–C24
S1–Sn–S2
S1–Sn–C24
S1–C11–S2
Sn–C12–C17
Sn–C18–C23
Sn–C24–C29
Sn–S1–C11
77.54
87.53
152.35
62.27
152.35
120.0 (3)
120.3 (4)
118.7 (4)
121.2 (4)
76.65
a square-pyramidal geometry, and the value of
sponds to perfectly trigonal-bipyramidal geometry. Thus, the
a
¼ 120ꢁ corre-
s
value is equal to zero for a perfect square-pyramidal and unity for
a perfect trigonal-pyramidal [16,17]. The calculated value for the
s
Fig. 3. ORTEP drawing of 4-(4-nitrophenyl)piperazinium chloride with atomic
complex is 0.57. The value indicates a highly distorted trigonal-
bipyramidal arrangement around Sn atom with C24 from a phenyl
group and the S1 from the dithiocarboxylate in the axial positions
while C12 and C18 from two phenyl groups and S2 in the plane
positions. The sum of the equatorial angles, [S2–Sn–C12 ¼ 108.73
(13)ꢁ, S2–Sn–C18 ¼ 118.29 and C12–Sn–C18 ¼ 115.57 (11)ꢁ], is
342.59ꢁ instead of the ideal 360ꢁ. Being a part of chelate, the angle
S2–Sn–S1 is not 90ꢁ but only 62.27ꢁ, so the S1 cannot occupy
exactly the corresponding trans apical position of C24 and the angle
between the apical groups is 152.35ꢁ. The Sn–C bond length, C24 =
2.151 (5) Å, is very similar to equatorial ones, Sn–C18 = 2.135 (5) Å
and in agreement with Sn–C values reported for
Ph3SnS2CN(CH3)(C4H9) [18]. Finally, the C–S bond lengths are
characteristic of the 1,1-dithiolate moiety and are intermediate
between the values expected for single and double bonds [19].
numbering scheme.
compounds, however, for compounds 1–3, the different fragments
observed are consistent with structures proposed on the basis of
other spectroscopic techniques.
2.5. X-ray structure of compound (3)
The molecular structure and packing of molecules in a unit cell
of compound 3 are depicted in Figs. 1 and 2, respectively, while
crystal data and selected bond lengths and bond angles are given in
Tables 1 and 2, respectively. The geometry around the Sn atom is
distorted trigonal-bipyramidal, the equatorial plane being defined
by the two carbons of the phenyl groups and a sulfur atom of the
dithiocarboxylate ligand. According to Addison et al., the geometry
around the Sn atom can be characterized by the value of
s
¼ (
b
ꢀ
a)/
60 [16], where
b
is the largest of the basal angles around the Sn
2.6. Cyclic voltammetry of compounds 1–3 binding to DNA
atom. For compound 3, it is S1–Sn–C24 ¼152.35ꢁ. The second
largest of the basal angles around the Sn atom,
S2–Sn–C18 ¼ 118.29ꢁ. The angle values
a
for compound 3 is
The cyclic voltammetric behavior of 3 mM compound 1 and the
effect of addition of different concentrations of DNA on its elec-
trochemical response in 10% aqueous dimethylsulphoxide (DMSO),
a
¼
b
¼ 180ꢁ correspond to
Table 1
Crystal data and structure refinement parameter for Ph3SnL (3).
-8
Empirical formula
Formula mass
Crystal system
Space group, no.
a (Å)
C29H27N3O2S2Sn
632.39
Triclinic
P-1, 2
a
-6
9.546 (2)
-4
b (Å)
C (Å)
10.986 (2)
13.650 (3)
91.966 (3)
98.752 (3)
107.833 (3)
1341.9 (5)
2 (1)
d
a
b
g
(ꢁ)
(ꢁ)
(ꢁ)
-2
0
V (Å3)
Z (Z0)
Crystal habit/size (mm)
Block/0.55 ꢂ 0.33 ꢂ 0.24
T (K)
100 (1)
2
m
(Mo K
a
) (cmꢀ1
)
11.4
Total reflections
11783
Independent reflections
All
6288
4
-0.8
-1
-1.2
-1.4
-1.6
For Fo ꢃ 4.0
s
(Fo)
5541
0.0388
P
P
E / V vs. SCE
R(F) ¼ (jjFoj ꢀ jFcjj)/ jFoj
For Fo > 4.0
s(Fo)
P
P
Fig. 4. Cyclic voltammograms of 3.00 mM 1 in 10% aqueous DMSO with 0.1 M TBAP as
supporting electrolyte in the absence (a) and presence of 3.0 ꢂ 10ꢀ5 (b), 6.5 ꢂ10ꢀ5 (c)
and 1.05 ꢂ10ꢀ4 M DNA (d) at 25 ꢁC temperature. Glassy carbon electrode (0.071 cm2)
was used as working electrode and all potentials were reported vs. SCE at 100 mV sꢀ1
scan rate.
wR(F2) ¼ [ [w(F2o ꢀ Fc2)2]/ [w(Fo2)2]]1/2
0.1195
1.239
2.51–28.28
6288/0/334
Goodness-of-fit
q
range for data collections (ꢁ)
Data/restraints/parameters

3990
Z.-u. Rehman et al. / European Journal of Medicinal Chemistry 44 (2009) 3986–3993
Table 3
-8
-6
-4
-2
0
Voltammetric parameters of compounds 1–3 in the absence and presence of DNA.
a
Substance
n
/V sꢀ1
[DNA]/
Epa/V
Epc/V
Efꢁ/V
Df 109/
Db 109/
b
mM
cm2 sꢀ1
cm2 sꢀ1
1
0.1
0.1
0.1
0.1
0.1
0.1
0
30
0
32
0
50
ꢀ1.181
ꢀ1.132
ꢀ1.193
ꢀ1.161
ꢀ1.188
ꢀ1.156
ꢀ1.261
ꢀ1.225
ꢀ1.293
ꢀ1.271
ꢀ1.288
ꢀ1.249
ꢀ1.221
ꢀ1.178
ꢀ1.243
ꢀ1.216
ꢀ1.238
ꢀ1.202
8.05
–
15.13
–
8.62
–
–
7.39
–
8.86
–
5.36
1–DNA
2
2–DNA
3
3–DNA
2
DNA as electrostatic interaction with anionic phosphate backbone
of DNA is evidenced by the negative peak potential shift [21]. The
voltammetric behavior of compound 3 in the absence and presence
of DNA (Fig. 6) is analogous to the CV behavior of compounds
1 and 2. Peaks associated with the reduction of SnIV/II and reox-
idation to SnII/IV appeared at ꢀ1.288 and at ꢀ1.188 V respectively. In
the presence of 5.0 ꢂ 10ꢀ5 M DNA, the cathodic and anodic peaks
appeared at ꢀ1.249 and ꢀ1.156 V accompanied with 19% reduction
of the cathodic peak current. Such peculiar voltammetric charac-
teristics signify intercalative interaction of compound 3 with DNA.
The voltammetric parameters are given in Table 3.
4
-0.8
-1
-1.2
-1.4
-1.6
E / V vs. SCE
Fig. 5. Cyclic voltammograms of 3.00 mM 2 in 10% aqueous DMSO with 0.1 M TBAP as
supporting electrolyte in the absence (a) and presence of 3.2 ꢂ 10ꢀ5 M DNA (b) at 25 ꢁ
C
temperature. Glassy carbon electrode (0.071 cm2) was used as working electrode and
all potentials were reported vs. SCE at 100 mV sꢀ1 scan rate.
containing 10ꢀ1 M tetra-n-butylammonium perchlorate as sup-
porting electrolyte at 100 mV sꢀ1 are depicted in Fig. 4. The free
drug registered a single cathodic peak at ꢀ1.261 V and an anodic
peak at ꢀ1.181 V upon scan reversal, in the potential range of ꢀ1.0
to ꢀ1.5 V. The appearance of these two peaks is an indication of
interconversion of Snþ4 to Snþ2 and vice versa during the whole
process [19]. The peak potentials separation of 80 mV, greater than
the ideal value of 60 mV for a fully reversible redox process may be
due to kinetic complications. With the stepwise addition of DNA,
a gradual shift of the peak potential in positive direction accom-
panied with the decrease in peak current was observed. The posi-
tive shift in peak potentials is suggestive of intercalative mode of
binding in which the complex inserts itself into the stacked base
pairs domain of DNA [20]. The decay in peak current is attributed to
the decrease in the concentration of the free complex due to the
formation of heavy drug–DNA association complex with concomi-
tant lower diffusion coefficient.
Typical CV behavior of 2 with and without DNA is shown in
Fig. 5. The redox behavior of compound 2 without DNA featured
oxidation and reduction at ꢀ1.293 and ꢀ1.193 V respectively. By the
addition of 3.2 ꢂ 10ꢀ5 M DNA, a 13.38% drop in cathodic peak
current and 22 mV peak potential shift in the positive direction
were observed. These observations unambiguously reflect the
intercalation of the complex into the double helical structure of
The diffusion coefficients of the free (Df) and DNA bound
complexes (Db) were determined by the application of Randles–
Sevcik equation [22,23]:
n1=2
ip ¼ 2:69 ꢂ 105n3=2ACo*D1=2
(1)
where ip is the peak current (A), A is the surface area of the elec-
trode (cm2), C*o is the bulk concentration (mol cmꢀ3) of the elec-
troactive species, D is the diffusion coefficient (cm2 sꢀ1),
n is the
scan rate (V sꢀ1) and n is the number of electrons involved in the
electron transfer reaction.
The linearity of ip vs. n1/2 plots in all cases indicated that the
main mass transport of these complexes (in the absence and
presence of DNA) to the electrode surface is controlled by diffusion
step [24]. The lower diffusion coefficients of the DNA bound species
are responsible for the decay of current signals in CV behavior of 1–
3 (Figs. 4–6). The smaller slopes for the diffusion coefficient of
compounds 1–3 in the presence of DNA could be attributed to their
intercalation into DNA resulting in the formation of slowly diffusing
supramolecular complexes in solution.
Based upon the decay in peak current of complexes 1–3 by the
addition of varying concentration of DNA, the binding constants
(Table 4) were calculated from the plots of 1/[DNA] vs. 1/(1 ꢀ i/io),
according to the following equation [25]:
-8
a
1
Kð1 ꢀ AÞ
1 ꢀ i=io
¼
ꢀ K
(2)
-6
b
½DNAꢄ
where, K is the association constant, i and io are the peak currents
with and without DNA and A is the proportionality constant.
An examination of Table 4 reveals that the binding constants of
the complexes 1–3 with DNA are greater than the K observed for
similar DNA-intercalating Cr complex, [CrCl2(dicnq)2]þ, with K
-4
-2
0
2
Table 4
The association constants and Gibbs free energies of 1–DNA, 2–DNA and 3–DNA
complexes as determined by voltammetry and UV–vis spectroscopy.
4
-0.8
-1
-1.2
-1.4
-1.6
Drug–DNA complex
CV
Spectroscopy
E / V vs. SCE
K/Mꢀ1
ꢀ
21.90
18.76
20.29
D
G/kJ molꢀ1
K/Mꢀ1
ꢀ
21.57
19.18
20.03
D
G/kJ molꢀ1
Fig. 6. Cyclic voltammograms of 3.00 mM 3 in 10% aqueous DMSO with 0.1 M TBAP as
1–DNA
2–DNA
3–DNA
6.90 ꢂ 103
2.40 ꢂ 103
3.60 ꢂ 103
6.05 ꢂ 103
2.30 ꢂ 103
3.25 ꢂ 103
supporting electrolyte in the absence (a) and presence of 5.0 ꢂ 10ꢀ5 M DNA (b) at 25 ꢁ
C
temperature. Glassy carbon electrode (0.071 cm2) was used as working electrode and
all potentials were reported vs. SCE at 100 mV sꢀ1 scan rate.

Z.-u. Rehman et al. / European Journal of Medicinal Chemistry 44 (2009) 3986–3993
3991
1
1.2
1
a
b
0.8
0.6
0.4
0.2
0
0.8
0.6
0.4
0.2
0
300
350
400
450
500
550
600
300
350
400
450
500
550
600
Wavelength/nm
Wavelength/nm
1
c
0.8
0.6
0.4
0.2
0
300
350
400
450
500
550
600
Wavelength/nm
Fig. 7. Absorption spectra of 3 mM 1 in the absence (a) and presence of 2.0 ꢂ 10ꢀ5 (b), 3.0 ꢂ 10ꢀ5 (c), 4.5 ꢂ10ꢀ5 (d), 6.0 ꢂ 10ꢀ5 (e), 7.0 ꢂ 10ꢀ5 (f), 9.0 ꢂ 10ꢀ5 (g), 1.0 ꢂ 10ꢀ4 (h),
1.15 ꢂ10ꢀ4 (i) and 1.25 ꢂ10ꢀ4 M DNA (j) in 10% aqueous DMSO at 25 ꢁC. The arrow direction indicates increasing concentrations of DNA. Absorption spectra of 3 mM 2 in the
absence (a) and presence of 2.0 ꢂ 10ꢀ5 (b), 2.5 ꢂ10ꢀ5 (c), 3.5 ꢂ10ꢀ5 (d), 4.5 ꢂ10ꢀ5 (e), 5.5 ꢂ10ꢀ5 (f), 6.5 ꢂ10ꢀ5 (g), 7.5 ꢂ10ꢀ4 (h), 8.5 ꢂ10ꢀ4 (i) and 9.5 ꢂ10ꢀ4 M DNA (j) in 10%
aqueous DMSO at 25 ꢁC. The arrow direction indicates increasing concentrations of DNA. Absorption spectra of 3 mM 3 in the absence (a) and presence of 2.0 ꢂ 10ꢀ5 (b), 3.5 ꢂ10ꢀ5
(c), 4.5 ꢂ10ꢀ5 (d), 5.5 ꢂ10ꢀ5 (e), 6.5 ꢂ10ꢀ5 (f), 7.5 ꢂ10ꢀ5 (g), 9.5 ꢂ10ꢀ4 (h) and 1.15 ꢂ10ꢀ4 M DNA (i) in 10% aqueous DMSO at 25 ꢁC. The arrow direction indicates increasing
concentrations of DNA.
reported as 1.20 ꢂ 103 Mꢀ1 [26] suggests their potential candidature
as chemotherapeutic agents. The rationale behind their greater
affinity may be the greater intercalating ability of aromatic 4-(4-
nitrophenyl)piperazine-1-carbodithioate ligand, as compared to
dicnq (2,3-dicyanodipyridoquinoxaline) ligand. So an effort to
further improve the binding affinity of these complexes, our current
research work is concentrated on the extension of aromatic 4-(4-
indicative of their binding to DNA. The peculiar hypochromism
observed here is attributed to the intercalation of these drugs into
the DNA base pairs [28]. The hypochromic effect may presumably be
due to the overlapping of the electronic states of the intercalating
chromophore of the ligand with the DNA bases [29].
Based upon the variation in absorbance, the association
constants of these complexes with DNA were determined according
to Benesi–Hildebrand equation [30]:
nitrophenyl)piperazine-1-carbodithioate system. The greater
K
value of 3 than 2 is due to the planar phenyl groups which can better
intercalate into the double helix of DNA. The reason for greater
association constant of 1 is the additional hydrophobic interaction of
the butyl groups with bases of DNA [27]. The interaction of these
compounds will unwind the DNA helix at the interaction sites which
will lead to perturbation in the DNA replication mechanism that
may culminate in the death of cancerous cells.
Table 4 further reveals that the complex–DNA adduct formation
is a spontaneous process and both spectroscopic and voltammetric
results agree well with each other.
A0
A ꢀ A0
3G
3H—G
3G
3G 3H—G
1
¼
þ
$
(3)
ꢀ
ꢀ
3G K½DNAꢄ
where K is the association constant, A0 and A are the absorbances of
the drug and its complex with DNA, respectively, and 3G and 3H–G
are the absorption coefficients of the drug and the drug–DNA
complex, respectively.
The association constants, shown in Table 4, were obtained from
the intercept-to-slope ratios of A0/(A ꢀ A0) vs. 1/[DNA] plots.
2.7. Electronic absorption spectra of compounds 1–3 binding to DNA
3. Conclusions
The interactions of complexes 1–3 with DNA were further
examined by UV–vis spectroscopy, to get some more clues about
their mode of interaction and binding strength. The absorption
spectra of 1–3 in the absence and presence of different concentra-
tions of DNA are shown in Fig. 7. The binding of complexes 1–3 to
DNA caused a progressive blue shift of 10 (401–391), 8 (400–392)
and 4 nm (398–394), respectively. Such spectral characteristics are
The triorganotin(IV) derivatives of 4-(4-nitropheny)piperazine-
1-carbodithioate ligand exhibit tetrahedral (1 and 2) or distorted
trigonal-bipyramidal (3) geometry both in solution and in solid
state. The voltammetric and spectroscopic techniques were
successfully used for the evaluation of binding parameters of
compounds 1–3 with DNA. The association constants estimated by
UV-titration agree with the electrochemical estimates. Based upon

3992
Z.-u. Rehman et al. / European Journal of Medicinal Chemistry 44 (2009) 3986–3993
the decrease in current and absorption intensity the stability of
adduct formation followed the order: 1 >3 > 2. The results of CV
and UV–vis spectra indicate that all the compounds 1–3 intercalate
4.2.2. Synthesis of tributylstannyl 4-(4-nitrophenyl)piperazine-1-
carbodithioate (1)
Bu3SnCl (0.574 g,1.76 mmol) and L-salt (0.862 g, 1.76 mmol) were
mixed in methanol (80 mL) and the mixture was refluxed for 6 h with
constant stirring, the yellowish product thus obtained was filtered
and recrystallized from chloroform–ethanol (Yield: 0.806 g, 80%).
M.p. 130–131 ꢁC. Elemental Analysis, % Calculated (Found), for
C23H39N3 O2S2Sn: C, 48.26 (48.20); H, 6.87 (6.93); N, 7.34 (7.42); S,
into the double helix of DNA. The negative values of
the spontaneity of complex–DNA binding.
DG designate
4. Experimental protocols
11.20 (10.98). Raman (cmꢀ1): 651
y(C–S), 1202 y(C]S), 1507 y(C–N),
4.1. Materials and methods
515
y
y
(Sn–C), 362
y
(Sn–S). IR(cmꢀ1):980,1007
y
(C–S),1488
y
(C–N), 514
3
3
(Sn–C).1HNMR(ppm):8.12(d,H6,6 , JH–H ¼ 9.6Hz), 6.76(d,H5,5 , JH–
0
0
Reagents, Ph3SnCl, Cy3SnCl, Bu3SnCl and 4-(4-nitrophenyl
piperazine) were obtained from Aldrich, DMSO with 99.5% purity and
CS2 from Riedal-de-Hae¨n; methanol was dried before use by the
reported method [31]. DNA was extracted from chicken blood by
Falcon method [32]. The purity of DNA was spectroscopically deter-
0
0
¼ 9.6 Hz), 4.36 (m, H3,3 ), 3.58 (m, H2,2 ), 1.75–1.22 (m, CH2, SnBu3),
H
0.89 [(t, CH3, SnBu3, 3J ¼ 7.2 Hz)]. 13C NMR (ppm): 199.9 (C-1), 154.1,
139, 126.3, 112.6 (C–Ar), 50.6 (C-3, 30), 46.1 (C-2, 20), 29.1 (C- 2JSn–
b,
¼ 21 Hz), 27.35 (C-
g,
3JSn–C ¼ 68 Hz), 17.8 [C-
a
, 1JSn–C ¼ 346.6/331.5
C
(
119Sn/117Sn)], 13.9 (C-
d
). 119Sn NMR:
d
¼ 39.6 ppm. EI-MS, m/z (%):
mined from the ratio of absorbance at 260 and 280 nm (A260
/
[C23H39N3OS2Sn]þ 557 (25), [C19H30N3O2S2Sn]þ 516 (80), [C19H30
N3OS2Sn]þ 500 (27), [C19H30N2OS2Sn]þ 486 (20), [C11H12N3O2S2Sn]þ
402 (33), [C11H12N3OS2Sn]þ 386 (2), [C12H27Sn]þ 291 (11), [C8H18Sn]þ
234 (5), [C4H9Sn]þ 177 (37), [Sn]þ 120 (9).
A280 ¼ 1.85). The concentration of the stock solution of DNA (2.3 mM
in nucleotide phosphate, NP) was determined by monitoring the
absorbance at 260 nm using the molar extinction coefficient (3) of
6600 Mꢀ1 cmꢀ1. UV–vis Spectrometer; Shimadzu 1601 was used for
the measurement of absorption spectra.
4.2.3. Synthesis of tricyclohexylstannyl 4-(4-nitrophenyl)
piperazine-1-carbodithioate (2)
Microanalysis was done using a Leco CHNS 932 apparatus.
Raman spectra (ꢅcmꢀ1) were measured with an InVia Renishaw
spectrometer, using argon-ion (514.5 nm) and near-infrared diode
(785 nm) lasers. WiRE 2.0 software was used for the data acquisition
and spectra manipulations. NMR spectra (d6-DMSO) were obtained
using Hg-300 and a Varian Unity 500-MHZ instruments. Electron
impact (70 eV) mass spectra were recorded on a Kratos MS25RFA
instrument. Cyclic voltammetric experiments were performed by
PGSTAT 302 with Autolab GPES version 4.9 Eco Chemie, Utrecht, The
Netherlands. Measurements were carried out in a conventional
three electrode cell with saturated calomel electrode (SCE) from
Fisher scientific company (cat no.13-639-51) as a reference elec-
trode, a thin Pt wire of thickness 0.5 mm with an exposed end of
10 mm as the counter electrode and a bare glassy carbon electrode
(GCE) with a geometric area of 0.071 cm2 as the working electrode.
Compound 2 was prepared in the same way as 1, using the
equimolar amount of L-salt (0.519 g, 1.06 mmol) and Bu3SnCl
(0.427 g, 1.06 mmol), to gave yellow product which was recrystal-
lized from chloroform–ethanol. (Yield: 0.483 g, 70%). M.p. 228–
231 ꢁC. Elemental Analysis, % Calculated (Found), for C29H45N3
O2S2Sn: C, 53.54 (53.47); H, 6.97 (7.00); N, 6.46 (6.49); S, 9.86 (9.77).
Raman (cmꢀ1): 656
y(C–S), 1200 y(C]S), 1507 y(C–N), 510 y(Sn–C),
364
y
(Sn–S). IR (cmꢀ1): 988,1009
y
(C–S),1497
y
(C–N), 510 y
(Sn–C).1H
3
3JH–H ¼ 9.3
0
0
NMR (ppm): 8.12 (d, H6,6
,
JH–H ¼ 9.3 Hz), 6.77 (d, H5,5
,
Hz), 4.37 (m, H3,3 ), 3.58 (m, H2,2 ), 2.04–1.23 (m, SnC6H11). 13C NMR
0
0
(ppm): 200.1 (C-1), 154, 138.9, 126.2, 112.5 (C–Ar), 50.7 (C-3, 30), 46.1
(C-2, 20), 35 [(C-
a
), 1JSn–C ¼ 330 Hz/315.1 Hz (119Sn/117Sn)], 32.3 (C-
b,
2J ¼ 17.1 Hz), 29.5 (C-
g,
3J ¼ 68.6 Hz), 27.2 (C-
d
). 119Sn NMR:
d
¼ ꢀ17.5 ppm. EI-MS, m/z (%): [C29H45N2S2Sn]þ 605 (3), [C23H34N3
Prior to experiments, the GCE was polished with 0.25 mm diamond
O2S2Sn]þ 568 (45), [C23H34N2OS2Sn]þ 538 (7), [C17H30N2S2Sn]þ 446
(5), [C15H26NS2Sn]þ 404 (4), [C18H33Sn]þ 369 (5), [C13H22S2Sn]þ 362
(17), [C9H15N S2Sn]þ 321 (63), [C12H22Sn]þ 286 (3), [C6H11Sn]þ 203
(9), [Sn]þ 120 (10).
paste on a nylon buffing pad. For electrochemical measurements the
test solution was kept in an electrochemical cell (model K64 PARC)
connected to the circulating thermostat LAUDA model K-4R. Argon
gas was used for flushing out oxygen before every electrochemical
assay. Tetra-n-butylammonium perchlorate (TBAP) purchased from
Fluka (99% purity) was used as supporting electrolyte and it was
further purified by recrystallization, using methanol as a solvent.
4.2.4. Synthesis of triphenylstannyl 4-(4-nitrophenyl)piperazine-1-
carbodithioate (3)
Compound 3 was prepared in the same way as 1, using equimolar
amount of L-salt (0.862 g, 1.76 mmol) and Ph3SnCl (0.681 g,
1.76 mmol), to gave yellow product which was recrystallized from
chloroform–ethanol, yielding yellow needle like crystals (Yield:
0.9 g, 80.3%). M.p. 223–226 ꢁC. Elemental Analysis, % Calculated
(Found), for C29H27N3O2S2Sn: C, 55.08 (54.99); H, 4.30 (4.37); N, 6.64
4.2. Synthesis
4.2.1. Synthesis of 4-(4-nitrophenyl)piperazinium 4-(4-nitrophenyl)
piperazine-1-carbodithioate (L-salt)
Dropwise addition of CS2 (in excess) in methanol (50 mL) to 4-
(4-nitrophenyl) piperazine (5 g, 24.15 mmol) in methanol (50 mL)
followed by stirring for 4 h at 0 ꢁC gave the yellowish product. The
yellow product was filtered off and was washed with diethyl ether
(Yield: 4.91 g, 83%). M.p. 180–182 ꢁC. Elemental Analysis, % Calcu-
lated (Found), for C21H26N6O4S2: C, 51.41 (51.37); H, 5.34 (5.33); N,
(6.69); S,10.14 (10.06). Raman (cmꢀ1): 652
y(C–S),1212 y(C]S),1507
y
(C–N), 263
y
(Sn–C), 384
y
(Sn–S). IR (cmꢀ1): 1018
y
(C–S), 1478
y
(C–
3
N). 1H NMR (ppm): 8.07 (d, H6,6
,
JH–H ¼ 9.3), 6.89 (d, H5,5
,
3JH–
0
0
0
0
¼ 9.6), 4.15(m, H3,3 ), 3.62 (m, H2,2 ), 7.76 m (Ho, SnC6H5), 7.39 m
H
(Hm,p, SnC6H5). 13C NMR (ppm): 195.9 (C-1), 154.4, 137.5, 126.4, 112.6
(C–Ar), 51.4 (C-3, 30), 45.5 (C-2, 20), 143.1 (C-
), 136.9 (C- ), 129.8 (C-
), 129.3 (C-
). 119Sn NMR:
a
b
17.13 (17. 12); S, 13.07 (13.01). Raman (cmꢀ1): 664
y
(C–S), 1210
d
g
d
¼ ꢀ195 ppm. EI-MS, m/z (%): [C23H22N3
y
(C]S), 1507
y
(C–N). IR (cmꢀ1): 1030
y
(C–S), 1478
y
(C–N). 1H NMR
O2S2Sn]þ 556 (36), [C17H17N3O2S2Sn]þ 479 (4), [C11H12N3O2S2Sn]þ
402 (3), [C11H12N2S2Sn]þ 356 (3), [C18H15Sn]þ 351 (97), [C12H10Sn]þ
274 (7), [C6H5Sn]þ 197 (44), [Sn]þ 120 (20).
3
0
0
0
0
(ppm): 8.1, 8.0 (d, H6,6 ,6a,6 a
,
JH–H ¼ 9.6 Hz), 7.1, 6.9 (d, H5,5 ,5a,5 a
3
0
0
JH–H ¼ 9.6 Hz). 4.42–4.39, 3.69–3.65 (m, H3,3 ,3a,3 a). 3.50–3.47,
3.27–3.24 (m, H2,2 ,2a,2 a). 13C NMR (ppm): 213.5 (C-1), 154.9, 154.7,
138.4, 137.1, 131.3, 126.3, 114.0, 112.6 (Ar–C). 49.0, 46.3 (C-3, 30, 3a,
30a), 43.1, 40.9 (C-2, 20, 2a, 20a). EI-MS, m/z (%): [C10H14N3O2]þ 208
(4.7), [C10H13N3O2]þ 207 (38.7), [C8H9N2O2]þ 165 (100), [C8H9
N2O]þ 149 (4), [C8H9N]þ 119 (19.8), [C6H5]þ 76 (24.4).
0
0
4.3. X-ray crystallography
For compound 3 crystal, X-ray data were collected on a Bruker
SMART APEX CCD diffractometer using graphite-monochromated

Z.-u. Rehman et al. / European Journal of Medicinal Chemistry 44 (2009) 3986–3993
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Crystallographic data for the structural analysis are available
from Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK on request, quoting the deposition
numbers 698264 and 713879 for complex 3 and 4-(4-nitro-
phenyl)piperazinium chloride, respectively. Copies of this infor-
mation may be obtained free of charge from the Director, CCDC, 12
Union Road, Cambridge, CBZ, IEZ, UK (fax: þ44 1223336; e-mail:
deposit@ccdc.ac.uk or www: http://www.ccdc.cam.ac.uk).
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Acknowledgements
The authors are grateful to Higher Education Commission of
Pakistan for financial support.
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