Zn thiosacharinates: From ionic to polymeric structures. Synthesis, characterization and cell proliferation inhibition studies

Article abstract of DOI:10.1016/j.ica.2018.04.040

A series of Zn thiosacharinates complexes with nitrogen donor co-ligands were synthesized: [Zn(tsac)₂(o-phen)], [Zn(tsac)₂(TMDP)]_n, [(4,4′-bipy)H₂][Zn(tsac)₄] [Zn(tsac)₂(2,2′-bipy)], [Zn(tsac)₂(2,2′-bquin)], (tsac, thiosaccharinate anion: 1,1-dioxo-1,2-benzisothiazole-3-thiolato, C₇H₄NO₂S₂^?, o-phen: 1,10′-phenantroline, TMDP: trimethylenedipyridine, 2,2′-bipy: 2,2′-bipyridine, 4,4′-bipy: 4,4′-bipyridine, 2,2′-bquin: 2,2′-biquinoline). They were fully characterized by means of FTIR, ¹³C and ¹H NMR, elemental analysis and conductivity measurements. Three of them, [Zn(tsac)₂(o-phen)], [(4,4′-bipy)H₂][Zn(tsac)₄], [Zn(tsac)₂(TMDP)]_n were also characterized by X-ray single crystal diffractometry and their crystal structures are described herein. DFT geometry optimization for the [Zn(tsac)₂(o-phen)] complex was performed and its vibrational spectra was predicted. Moreover, we studied the effects of the five complexes on cell proliferation, thus providing preliminary evidence for their therapeutic potential as anti-cancer drugs.

Full text of DOI:10.1016/j.ica.2018.04.040

Accepted Manuscript
Research paper
Zn Thiosacharinates: from ionic to polymeric structures. Synthesis, characteri-
zation and cell proliferation inhibition studies
Fermín Delgado, Eleonora Freire, Ricardo Baggio, Verónica González Pardo,
Viviana Dorn, Mariana Dennehy
PII:
S0020-1693(18)30289-5
https://doi.org/10.1016/j.ica.2018.04.040
ICA 18231
DOI:
Reference:
Inorganica Chimica Acta
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Revised Date:
Accepted Date:
20 February 2018
19 April 2018
20 April 2018
Please cite this article as: F. Delgado, E. Freire, R. Baggio, V.G. Pardo, V. Dorn, M. Dennehy, Zn Thiosacharinates:
from ionic to polymeric structures. Synthesis, characterization and cell proliferation inhibition studies, Inorganica
Chimica Acta (2018), doi: https://doi.org/10.1016/j.ica.2018.04.040
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Zn Thiosacharinates: from ionic to polymeric structures.
Synthesis, characterization and cell proliferation inhibition studies
Fermín Delgadoa, Eleonora Freireb,c, Ricardo Baggiob, Verónica González Pardod, Viviana
Dorna, Mariana Dennehya*
a INQUISUR/ Departamento de Química, Universidad Nacional del Sur, Bahía Blanca,
Argentina
b Gerencia de Investigación y Aplicaciones, Centro Atómico Constituyentes, Comisión Nacional
de Energía Atómica, Buenos Aires, Argentina
c Escuela de Ciencia y Tecnología, Universidad Nacional General San Martín, Buenos Aires,
Argentina.
d INBIOSUR/Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur,
Bahía Blanca, Argentina
*Correspondence e-mail: mdennehy@uns.edu.ar
Abstract
A series of Zn thiosacharinates complexes with nitrogen donor co-ligands were synthesized:
[Zn(tsac)2(o-phen)], [Zn(tsac)2(TMDP)]n, [(4,4’-bipy)H2][Zn(tsac)4] [Zn(tsac)2(2,2’-bipy)],
[Zn(tsac)2(2,2’-bquin)], (tsac, thiosaccharinate anion: 1,1-dioxo-1,2-benzisothiazole-3-thiolato,
-
C7H4NO2S2 , o-phen: 1,10’-phenantroline, TMDP: trimethylenedipyridine, 2,2’-bipy: 2,2’-
bipyridine, 4,4’-bipy: 4,4’-bipyridine, 2,2’-bquin: 2,2’-biquinoline). They were fully
1
characterized by means of FTIR, 13C and H NMR, elemental analysis and conductivity
measurements.
Three
of
them,
[Zn(tsac)2(o-phen)],
[(4,4’-bipy)H2][Zn(tsac)4],
[Zn(tsac)2(TMDP)]n were also characterized by X-ray single crystal diffractometry and their
crystal structures are described herein. DFT geometry optimization for the [Zn(tsac)2(o-phen)]
complex was performed and its vibrational spectra was predicted. Moreover, we studied the
effects of the five complexes on cell proliferation, thus providing preliminary evidence for their
therapeutic potential as anti-cancer drugs.
Keywords: Zinc, thionate, biological activity, crystal structure, nitrogenated ligands, cell
proliferation inhibition
Introduction
Zn shows an indispensable role and it is considered as a fundamental trace element for living
organisms. An increased amount in the published research shows the importance of this metal
complexes and refutes its “boring element” tag. It acts as a divalent cation when it binds to
enzymes and other proteins on its biochemical functions. Moreover, coordination complexes
with the presence of Zinc (II) ion are essential in the function of several bio-molecules. It acts as
the active site of enzymes (it is vital for the functionality of more than 300 enzymes) [1,2].
Diverse metabolic paths that are dependent on this metal have been recognized and studied so
far. Additionally, several Zinc based compounds have been used as antifungal and antibacterial
[3,4]. On the other hand, the coordination chemistry of different types of poly-dentate organic
nitrogen–sulfur ligands is an interesting and developing field of research and has generated

considerable recent interest [5,6]. Complexes of these systems are involved in the catalysis of
different biological processes and thus, they receive attention nowadays. For all these reasons,
sulfur-rich zinc sites in metallo-proteins could be better understood with the synthesis and
characterization of ternary Zinc-thionate complexes. Among the different possible co-ligands,
bi-pyridyl ligands are good building blocks that allow the construction of a variety of complexes
with defined geometry and symmetry and could enable the formation of strong complexes.
These type of N,N-bidentate ligands are also of importance due to their possible activity against
different types of bacteria.
Because of the bulky S atom with the vicinity of the amide N atom, considerable bridging
capabilities are found for heterocyclic thionates, the deprotonated form of thiones. As other
heterocyclic chalcogenones, thiosaccharine (the thione form of saccharin, C6H4S(O)2NHC(S),
1,1-dioxo-1,2-benzisothiazole-3-thione) can bind a metal ion in its anionic form either as
monodentate species either via the thionate sulphur atom or the thioamido nitrogen atom, or as
an ambidentate ligand via a variety of bonding modes. The coordination chemistry of
thiosaccharine with several transition metals (Cd, Tl, Pd, Pt, Ag, Au, Cu, Bi) has been
previously investigated and reported in detail [7,8,9 and references therein]. So far, the
versatility of this anion has been extensively demonstrated in the different complexes described.
At this point, surprisingly, the coordination of Zn to this thionate remains unexplored.
For this reason, in the present work, we report the synthesis and full characterization of a series
of Zn thiosaccharinates with N ancillary aromatic co-ligands, [Zn(tsac)2(o-phen)] (1),
[Zn(tsac)2(TMDP)]n (2), [(4,4’-bipy)H2][Zn(tsac)4] (3), [Zn(tsac)2(2,2’-bipy)] (4) and
[Zn(tsac)2(2,2’-bquin)] (5). Moreover, we inform here their effects on cell proliferation
inhibition, thus providing preliminary evidence for their therapeutic potential as anti-cancer
drugs.
2. Experimental
2.1. General remarks
All reagents were of commercial analytical quality and used without further purification. The
solid thiosaccharin (Hthiosaccharinate) in its α-form was synthesized when Lawesson’s reagent
(3.64 g; Fluka) reacted with acid saccharin (3.00 g; Mallinckrodt) in toluene solution (25 mL),
following the technique published by Schibye et al. [10]. The FTIR spectra of the substances as
-1
KBr dispersions were registered in the 4000–400 cm range on a Thermo Scientific Nicolet
iS50 FTIR-NIR spectrometer. Nuclear magnetic resonance (NMR) spectra were recorded on a
Bruker ARX-300 spectrophotometer using the residual solvent peak as an internal reference.
The NMR studies were performed in deuterated dimethylsulfoxide, DMSO-d6 solutions. The C,
H, and N elemental analyses were performed with a CE440 Elemental Analyzer. and were
found to be in good agreement with the calculated values. Conductivity measurements were
performed with a digital OAKTON conductimeter, which was calibrated with a KCl aqueous
solution (744.7 ppm, 1413 µS). The conductivity measurements were performed in DMSO.
2.2 Synthesis of the complexes
[Zn(tsac)2(o-phen)] (1)
The [Zn(tsac)2(o-phen)] complex was prepared by addition of a dissolution of Zn(NO3)2·6H2O
(14.85 mg, 0.049 mmol, 2 mL) into a thiosaccharine solution (20 mg, 0.1 mmol/ ethanol:water
1:1, 2 mL). A o-phenantroline solution was finally added drop by drop (ethanol:water 1:1, 2
mL) and a yellow power was obtained. The resulting yellow solid was filtered and washed

with cold water. Crystals suitable for X-ray diffraction studies were produced by slow
diffusion of diethyl ether to the mother solution. Yield: 74 % Molar Conductivity (µS M-1) =
22.4. Calculated analytical percent composition for C26H16N4O4S4Zn: C=48.516%; H=2.267%;
N=8.592%; Found: C= 48.638%; H=2.511%; N=8.725%. Soluble in dimethyl sulfoxide and
dimethyl formamide. Non-soluble in other solvents (methanol, chloroform, dichloromethane,
acetone, water). UV-Visible [DMSO, λmax nm]: 341
1H NMR (300 MHz, DMSO) δ 8.72-9.21 (m, 1H), 8.94 (m, 1H), 8.31 (m, 1H), 8.03-8.21 (m,
13
1H), 7.91 (m, 1H), 7.57-7.72 (m, 3H). C NMR (75 MHz, DMSO) δ 191.81 (C1), 149.09 (C8),
140.02 (C10), 139.36 (C12), 137.94 (C7), 136.52 (C2), 132.12 (C4), 130.91 (C5), 128.70 (C11),
127.37 (C13), 125.10 (C3), 125.81 (C9), 119.03 (C6).
[Zn(tsac)2(TMDP)]n (2)
The complex was synthesized by addition of 4,4′-trimethylenedipyridine (6.2 mg, 0.031 mmol)
and thiosaccharine (12.7 mg, 0.0638 mmol), respectively, to a solution of Zn(NO3)2∙6H2O (10.2
mg, 0.0342 mmol) in ethanol:water (4 ml), and kept under mechanical stirring at room
temperature. The resulting yellow solid was filtered off and washed with cold water. By slow
evaporation of the mother solution single crystals appeared. They were washed with water and
analysed using X-ray diffraction. Yield: 82%. Molar conductivity (µS M-1) = 28.3. Analytical
percent composition calculated for C27H22N4O4S4Zn: C=49.127%; H=3.359%; N=8.487%.
Found:C=48.811%; H=2.981%; N=8.378%.
Soluble in DMSO and DMF. Slightly soluble in water, ethanol, methanol, chloroform.
Insoluble in acetone and methane dichloride. UV-Visible [DMSO, λmax nm]: 347
1H NMR (300 MHz, DMSO) δ 8.46 (dd, 4H), 7.92 (m, 2H), 7.58-7.72 (m, 6H), 7.28 (dd, 4H),
2.64 (t, 4H), 1.93 (m, 2H). 13C NMR (75 MHz, DMSO) δ 191.71 (C1), 151.07 (C10), 149.31
(C8), 137.98 (C7), 136.56 (C2), 132.05 (C4), 130.82 (C5), 125.07 (C3), 124.04 (C9), 119.01
(C6), 33.80 (C11), 30.12 (C12).
[(4,4’-bipy)H2][Zn(tsac)4] (3)
It was obtained by addition of 4,4'-bipyridine (7.7 mg, 0.049 mmol) and thiosaccharine (20.3
mg, 0.102 mmol), to a dissolution of Zn(NO3)2·6H2O (15.2 mg, 0.0511 mmol) in water/ethanol
1:1, with mechanical stirring at ambient temperature. The resulting yellow precipitate was
washed with water and dried. Yellow crystals, suitable for X-ray diffraction studies were
obtained. Yield: 26.9%. Molar Conductivity (µS M-1) = 138.7.
Analytical percent composition calculated for C38H26N6O8S8Zn: C=44.901%; H=2.580%;
N=8.270%. Found: C=45.996%; H=2.473%; N=8.446%.
Soluble in dimethyl sulfoxide and dimethyl formamide. Slightly soluble in water, ethanol,
methanol and chloroform. Insoluble in acetone and dichloromethane. UV-Visible [DMSO, λmax
nm]: 340
1H NMR (300 MHz, DMSO) δ 8.98 (dd, 4H), 8.30 (dd, 4H), 7.87-8.02 (m, 4H), 7.73-7.81 (m,
4H), 7.35-7.72 (m, 10H). 13C NMR (75 MHz, DMSO) δ 191.56 (C1), 148.94 (C8), 145.88
(C10), 137.88 (C7), 136.35 (C2), 132.28 (C4), 131.11 (C5), 125.16 (C3), 122.38 (C9), 119.15
(C6).
[Zn(tsac)2(2,2’-bipy)] (4)
This complex was prepared in a similar way as (1): Zn(NO3)2·6 H2O (11 mg, 0.037 mmol in 2
ml de ethanol-water) were added to a thiosaccharine dissolution (20 mg, 0.1 mmol / 2 ml
ethanol-water 1:1). A 2,2’-bipyridine dissolution was then added (5.8 mg, 0.0371 mmol/ 2 ml
de ethanol-water). A light yellowish precipitate was formed and filtered. It was washed with

distilled water. By slow diffusion of ethyl ether to a saturated ethanol-water solution very thin
needles appeared. Yield: 85%. Molar conductivity (µS M-1) = 18.2. Analytical percent
composition calculated for C24H16N4O4S4Zn: C=46.642%; H=2.6093%; N=9.0648%. Found:
C=46.422%; H=2.335%; N=8.893%.
Soluble in dimethyl sulfoxide and dimethylformamide. Slightly soluble in water, ethanol,
methanol, acetone and chloroform. UV-Visible [DMSO, λmax nm]: 343
1H NMR (300 MHz, DMSO) δ 8.60-8.90 (d, 1H), 8.73 (d, 1H), 8.34 (t, 1H), 7.94 (m, 1H), 7.83
(m, 1H), 7.58-7.75 (m, 3H). 13C NMR (75 MHz, DMSO) δ 191.73 (C1), 148.47 (C9), 141.43
(C10), 137.81 (C7), 137.75 (C12), 136.33 (C2), 132.19 (C4), 131.03 (C5), 127.09 (C8), 125.14
(C3), 122.79 (C11), 119.07 (C6).
[Zn(tsac)2(2,2'-bq)](5)
A Zn(NO3)2·6H2O dissolution (10.3 mg, 0.0346 mmol / 2 ml ethanol:water 1:1) was added to
another dissolution of thiosaccharine (12.3 mg, 0.062 mmol / 2 ml ethanol:water 1:1). Finally,
solid 2,2’-biquinoline was added (9.4 mg, 0.0367 mmol / 2 ml ethanol:water 1:1). A pale yellow
powder was then obtained. Yield: 90%. Molar conductivity (µS M-1) = 26.3. Analytical percent
composition calculated for C32H20N4O4S4Zn: C=53.520%; H=2.807%; N=7.801%. Found:
C=53.884%; H=2.761%; N=7.698%.
Soluble in DMSO and DMF. Almost insoluble in water, ethanol, methanol, acetone,
dichloromethane and chloroform. [DMSO, λmax nm]: 339
1H NMR (300 MHz, DMSO) δ 8.80 (dd, 1H), 8.58 (dd, 1H), 8.19 (dd, 1H), 8.08 (dd, 1H), 7.89-
13
7.95 (m, 1H), 7.85 (td, 1H), 7.53-7.73 (m, 4H). C NMR (75 MHz, DMSO) δ 191.54 (C1),
155.21 (C16), 147.16 (C8), 137.80 (C7), 137.36 (C14), 136.32 (C2), 132.16 (C4), 130.99 (C5),
130.18 (C10), 129.31 (C12), 128.16 (C13), 128.03 (C11), 127.42 (C9), 125.10 (C3), 119.05
(C6), 118.87 (C15).
2.3 X-ray crystallography
Single crystal X-ray diffraction measurements of (1), (2) and (3) were carried out with
Mo Ka radiation using an Xcalibur, Eos, Gemini diffractometer. Absorption was
corrected for by multi-scan methods, CrysAlis PRO (Rigaku OD, 2015). H-atom
parameters were constrained. Computer programs used: CrysAlis PRO (Rigaku OD,
2015) [Diffractometer control and data reduction], SHELXS97 (Sheldrick, 2008)
[Structure resolution], SHELXL2014/6 (Sheldrick, 2015) [Model refinement], XP in
SHELXTL (Sheldrick, 2008), PLATON (Spek, 2009) [Analysis of the results].
2.4 Cell line culture and proliferation assays
SVEC cell line stably expressing the viral G protein couple receptor was used (vGPCR cells).
vGPCR cells injected into immunosuppressed mice promotes tumour formation; thus inducing
angiogenic lesions similar to those developed in Kaposi sarcoma [11,12]. These transfected
cells were cultured in DMEM 2.5% foetal bovine serum (FBS) and selected with 500 µg/mL
G418 (Cellgro, Manassas, VA). For proliferation studies, cells were seeded in 24-well plates
at a density of 12,000 cells per well. After overnight growth, cells were treated with each
ternary Zn(II) complexes (1,2,3, 4 and 5) or vehicle (DMSO, 0.1%) in triplicate during 48 h.
The time was selected based on the duplication cells time for these growth conditions

and is appropriate to visualize an inhibition of the cell proliferation. At the end of the
treatment, cells were harvested and counted in a Neubauer chamber; proliferation was
quantified as the percentage of living cells [12].
2.5 Theoretical calculations
The theoretical calculations were performed with Gaussian09 [13]. The initial geometry
optimization of complex 1 was performed with the semi empirical PM3 method. The geometry
thus obtained was used as starting point for the density functional theory (DFT) [14]
calculations, that were performed with the B3LYP functional [15], which is known to be an
appropriate methodology for the study on metal thiosacharinates complexes with nitrogen donor
co-ligands [9]. Zero point energy was computed at the 6-31+G* level for C, H, S, N and O
atoms and employing the LANL2DZ effective core potential basis set for Zn. The
characterization of the stationary point was done by Hessian matrix calculations of geometries
obtained with full optimization for a minimum. The vibrational frequency analysis showed no
imaginary frequencies. All calculations were performed in gas phase. The structure figure (see
Supp. Info S22) was built with the VMD program.
3. Results and Discussion
3.1 Crystal structures
Table 1 summarizes crystal data, data collection procedures, structure determination
methods and refinement results for complexes (1), (2) and (3). Table 2 presents some
selected distances and angles, and Table 3 shows the most relevant H-bonding
interactions.
Figures 1-3, in turn, show molecular representations of the complexes. Full structural
information has been deposited in cif format at the Cambridge Crystallographic Data
Centre, under deposition numbers CCDC 1812462 (1), CCDC 1812463 (2) and CCDC
1812464 (3).
Table 1. Crystal and refinement data
[Zn(tsac)2(o-phen)] [Zn(tsac)2(TMDP)]n [(4,4’-bipy)H2][Zn(tsac)4]
(1)
(2)
(3)
Crystal data
Chemical formula C26H16N4O4S4Zn
C27H22N4O4S4Zn C38H26N6O8S8Zn
660.09 1016.50
Monoclinic, P21/c Orthorhombic, Fddd
Mr
642.04
Crystal system,
space group
Monoclinic, I2/a
Temperature (K)
293
295
293
15.0832 (4),
10.4741 (3),
16.6559 (6)
11.8808 (5),
16.0116 (7),
15.4802 (5)
10.2455 (6), 26.4252 (9),
29.2967 (11)
a, b, c (Å)

90, 91.275 (3), 90 90, 96.684 (3), 90 90, 90, 90
 (°)
V (Å3)
Z
2630.69 (14)
2924.79 (19)
7931.8 (6)
4
4
8
 (mm-1)
1.29
1.17
1.10
Crystal size (mm) 0.32 × 0.22 × 0.18 0.18 × 0.18 × 0.14 0.28 × 0.20 × 0.16
Data collection
Tmin, Tmax
0.72, 0.78
0.73, 0.81
0.72, 0.86
No. of measured,
independent and
observed [I >
5737, 2851, 2213 25094, 6761, 4812 14567, 2430, 1932
2s(I)] reflections
Rint
0.021
0.675
0.066
0.670
0.036
0.685
(sin )max (Å-1)
Refinement
R[F2 > 2(F2)],
0.034, 0.090, 1.01 0.068, 0.210, 1.01 0.035, 0.091, 0.98
R(F2), S
No. of reflections 2851
No. of parameters 177
6761
2430
361
140
ρmax, ρmin (e Å-3)
0.27, -0.34
1.34, -0.82
0.37, -0.26
Table 2
Selected bond distances and angles [Å,°]
(1)
Zn1—N1B
2.0723 (19)
2.144
S2A—C7A
1.698 (2)
1.735
Zn1—N1B (calculated)
S2A—C7A
(calculated)
Zn1—S2A
2.2952 (7)
2.415
N1A—C7A
1.308 (3)
1.306
Zn1—S2A (calculated)
N1A—C7A
(calculated)
N1B—Zn1—N1Bi
80.81 (11)
117.1
N1B—Zn1—S2Ai
110.50 (5)
N1B—Zn1—N1Bi
N1B—Zn1—S2Ai
(calculated)
(calculated)
N1B—Zn1—S2A
N1B—Zn1—S2A
120.16 (5)
S2A—Zn1—S2Ai
111.91 (4)
107.2
S2A—Zn1—S2Ai

(calculated)
(calculated)
Symmetry code: (i) -x+1/2, y, -z+1.
(2)
Zn1—N2Ci
2.030 (3)
S2A—C7A
N1A—C7A
S2B—C7B
N1B—C7B
1.701 (4)
1.310 (5)
1.703 (4)
1.312 (5)
Zn1—N1C
Zn1—S2A
Zn1—S2B
2.049 (3)
2.3085 (14)
2.3220 (12)
N2Ci—Zn1—N1C
N2Ci—Zn1—S2A
107.60 (13)
109.38 (10)
109.52 (10)
N2Ci—Zn1—S2B
N1C—Zn1—S2B
S2A—Zn1—S2B
108.39 (10)
104.34 (9)
117.15 (5)
N1C—Zn1—S2A
Symmetry code: (i) x+1, y, z.
(3)
Zn1—S2
2.3598 (6)
1.695 (2)
N1—C7
1.311 (3)
S2—C7
S2—Zn1—S2i
S2—Zn1—S2ii
96.75 (3)
S2—Zn1—S2iii
123.25 (3)
109.53 (3)
Symmetry codes: (i) -x+1/4, -y+1/4, z; (ii) x, -y+1/4, -z+1/4; (iii) -x+1/4, y, -z+1/4.
Table 3
Hydrogen-bond geometry (Å, º)
D—H···A
D—H
H···A
D···A
D—H···A
(1)
C2A—H2AA···O1Aii
C2B—H2BA···S2Aiii
0.93
0.93
2.36
2.74
3.072 (3)
3.538 (3)
134
144
Symmetry codes: (ii) -x, y-1/2, -z+1/2; (iii) x-1/2, -y+1, z.
(2)
C2B—H2B···O2Aii
C10C—H10C···S2Aiii
0.93
0.93
2.44
2.95
3.330 (6)
3.777 (4)
159
149
Symmetry codes: (ii) x+1, -y+1/2, z+1/2; (iii) -x, y-1/2, -z+1/2.

(3)
N11—H11N···O1iv
C11—H11···O2iv
C21—H21···O2v
C6—H6···O1vi
0.86
0.93
0.93
0.93
2.47
2.35
2.47
2.55
3.134 (3)
3.137 (3)
3.149 (3)
3.400 (3)
134
142
130
152
Symmetry codes: (iv) x+1/4, -y+1/2, z-1/4; (v) -x+5/4, y, -z+1/4; (vi) -x+3/4, -y+3/4, z.
Figure 1: Molecular representation of [Zn(tsac)2(o-phen)] (1)
Symmetry code: (i) -x+1/2, y, -z+1.

Figure 2. Molecular representation of [Zn(tsac)2(TMDP)]n (2)
Symmetry code: (i) x+1, y, z.
Figure 3. Molecular representation of [(4,4’-bipy)H2][Zn(tsac)4] (3)

Symmetry codes: (i) -x+1/4, -y+1/4, z; (ii) -x+1/4, y, -z+1/4, (iii) x, -y+1/4, -z+1/4.
[Zn(tsac)2(o-phen)] (1)
The solid state structure of complex [Zn(tsac)2(o-phen)] consists in discrete molecular species,
bisected by a twofold rotation axis, with the Zn atom being located in the center of a distorted
tetrahedron, surrounded by two thiosaccharinate anions and by a molecule of ortho-
phenanthroline. The two thiosaccarinate anions monocoordinate through the exocyclic sulfur
atom to the metal center. The o-phenanthroline molecule quelates the metal atom through both
pyridinic N atoms. Bond distances around the Zn atom can be seen in Table 2. Figure 1 is a
molecular representation of the complex. The phenantroline molecule and the two anions
presented almost planar structures, as expected. A comparison of the metal–ligand bond
distances in complex (1) with the distances in other mixed ligand Zn thionates with ortho-
phenantroline, show that they are average Zn-S (Zn-Stsac 2.2952 (7) Å) and Zn-N (Zn-Nphen
2.0723 (19) Å) bond distances for this type of complexes [16, 17]. The tetrahedral deviation is
evidenced by the deviation of the bond angles from the ideal angle of a tetrahedral geometry
(109.5°): N1B—Zn1—S2Ai (110.50 (5)), N1B—Zn1—N1Bi (80.81 (11)), N1B—Zn1—S2A
(120.16 (5)) and S2A—Zn1—S2Ai angles (111.91 (4)). This deviation is attributed to the
steric demand of the chelating di-pyridinic ligands. The Zn-Npy is within the range reported by
García Vazquez for similar complexes with pyridine-2-thione.
[Zn(tsac)2(TMDP)]n (2)
In the [Zn(tsac)2(TMDP)]n complex the metal center adopts a slightly distorted tetrahedral
geometry (angles around the metal center 110.5, 117.7, 107.8 and 105.9º). The anion is
monocoordinated through the exocyclic S atom. The trimetilenedipyridine molecule coordinates
through the nitrogen atoms, bridging two metal centers. In this complex, [Zn(tsac)2(TMDP)],
the Zn-S bond distances (Zn-S(1) 2.326 Å y Zn-S(2) 2.302 Å) are longer than the bond
distances in [Zn(tsac)2(o-phen)] (2.296 Å) but shorter than the distances presented by [(4,4’-
bipy)H2][Zn(tsac)4] (2.357 Å). Regarding the Zn-Npy bond distances (Zn-N(1) 2.071 Å and Zn-
N(2) 2.049 Å) they are within the range reported by Zheng et al. for other Zn complexes
coordinated with similar nitrogenated ancillary ligands [18].
[(4,4’-bipy)H2]2+[Zn(tsac)4]2-] (3)
Among the different zinc complexes reported in the literature, 4,4 -bipyridine has been used as a
two connector in many studies to construct transition metal networks having a wide variety of
structures. The thiosaccharinate complex shows an ionic structure, with the metal center located
at a highly symmetric site (the intersection of three orthogonal two fold axis). This Zn atom is
located in a tetrahedral geometry, surrounded by four symmetry related thiosaccharinate anions,
builds up the anion. The four thionates are coordinated to the metal through the sulfur atom.
Each of the four anions presents a cuasi planar structure. The structure of the complex is
completed by a di-protonated 4,4’-bipyridine molecule, acting as counter anion. In the literature,
4,4’-bipyridine is reported in several Zn compounds as a neutral connector, building polymeric
complexes (as reviewed by A. Erxleben [19]). However, there are also reports of different
compounds with the nitrogenated ligand acting mono-protonated, [(4,4’-bipy)H] + [20] and di-
protonated, [(4,4’-bipy)H2]2+ [21]. The bond distance between the thiocarbonilic S and the Zn
metal atom is longer than the same distance in the complexes (1) and (2), where the Zn atoms

are surrounded by only two thiosaccharinates (2.357 Å in (3) vs 2.296 Å in (1) or 2.326/2.302 Å
in (2)).
The analysis and comparison of the thiocarbonilic moieties within the three different Zn
thiosacharinates show that this group suffers different modifications after the coordination.
These changes are not only related to the coordinated atoms but also to the pka of the di-
pyridines. Whereas complexes (1) and (2) have the same coordination sphere, ZnS2N2, complex
(3) has a different structure, surrounded by four sulfur atoms, ZnS4. The thiocarbonilic S-C
distance varies from (1.698 Å complex (1) to 1.684 Å in (3) and a very similar value for
complex (2) S-C bond distance, 1.685 Å). Linked to this value, the C-N bond distances is
shortened for complex (1) (1.305 Å),but enlarged in complex (2) and (3) respectively (1.305 Å
and 1.312 Å). The C1–S1 bond distance in the “free” thiosaccharinate anion, reported in 2006
[23 d], (1.678(2) Å) is shorter than the three C-S thiocarbonilic bond distances observed for the
Zn thiosacharinates, confirming the coordination. The N-C thiocarbonilic bond distance for the
free anion, (1.324 Å) is in the middle of the range of the values observed for the Zn
thiosacharinates.
In all three compounds (1), (2) and (3), the H-bonding schemes (summarized in Table 3) lead to
weakly connected 3D structures.
Ali et al summarized the molar conductance ranges of metal complexes in different solvents
[22]. The values measured for our Zn complexes, as expected, are in agreement with the crystal
structures found. Ali stated that the molar conductance for non-electrolytic complexes, in
DMSO, should be <50µS M-1. The values found for (1), (2), (3) and (4) are respectively 22.4,
28.3, 18.2 and 26.3 µS M-1, which supports non-electrolytic behavior in solution. For complex
(3), the molar conductivity of 138.7 µS M-1 clearly indicates an electrolytic behavior. The range
reported for 1:1 electrolyte, 50-90 µS M-1, is lower than the value found for (3). This is due to
the fact that complex (3) [(4,4’-bipiyH2][Zn(tsac)4] is a 1:1, anion:cation, electrolyte with [(4,4’-
bipiyH2]++ and ][Zn(tsac)4]=.
3.2. Vibrational and electronic spectra
The five complexes were characterized by FTIR spectroscopy. All the bands due to the ligands
are present in the spectra. A selection of the thiosaccharinate characteristic bands and some of
the co-ligands and their assignments are presented in Table 4. The assignments have been made
considering the theoretical calculations performed for complex previous published theoretical
vibration analysis [23] and based on our previous studies on metallic and ionic thiosaccharinates
[9 and references therein]. The vibrational spectra of complexes (1), (2) and (3) are consistent
with their X-ray structure. The most interesting bands of these compounds are those related to
the five-member ring of the thiosaccharinate anions, located between 1500 and 400 cm-1. The
thione benzene ring vibrations show no significant differences compared with the thione
benzenic ring vibrations of Htsac or PNP(tsac) (bis(triphenylphosphine)-iminium
thiosaccharinate) [24]. The bands attributable to the N-H bond vibrations, namely (NH) and
δ(NH) modes, which in the thiosaccharine molecule appear at 3341 and 1376 cm-1, respectively,
are absent in the spectra of the five new complexes. The (SH) absorption region is also free of
bands (between 3000 and 2550 cm-1). The stretching motion of the reinforced C-N bonds bands
appear in all the complexes at higher wavenumbers compared to the values found for the
thiosaccharinate in PNPtsac (in which the thiosaccharinate is considered as a free anion). Those
bands due to the weakened stretching of the C-S bonds shift (1003, 1006, 1002 and 977 cm-1) to
lower frequencies (for PNP(tsac) (CN):1365, and (CSexo):1010 cm-1). These frequency

movements reproduce the changes in the strength of the bonds within the thioamidate groups
after the coordination. Complex (3) spectrum shows the 4,4’-bipyridine’s N-H stretching band
at 3080 cm-1, in accordance with the reported values for the protonated bipyridine [25]. It is
interesting to note that for complexes (4) and (5), which could not be crystallized, the bands
assigned to the (CSexo) are red shifted for both complexes if compared to the other three. This
fact may be indicating that the anions in these complexes are coordinating in a different mode,
with a weakened CSexo bond. Therefore, we postulate that the thiosaccharinate anion in this
complexes are bridging two metal centers with long Zn-S bonds, as in complex [Ag(tsac)(o-
phen)]n [26] and consequently weakening the Sexo-C bond, which in turn is reflected in the shift
of the (C-Sexo). Thus, based on the elemental analysis and on the FTIR spectra, we propose that
complexes (4) and (5) could be formed by polymeric structures, in which the S atoms bridged
two different Zn atoms, and the nitrogenated coligands quelate to the metal center, as expected.
Table 4. FTIR selected vibration frequencies (cm-1) and mode assignments of complexes 1-5
Assignations
1
1
2
3
4
5
Experimental Calc.(intensity)
(CN)pi
(CN)(S)
as(SO2)
1601m
1423s
1306vs
1242m
1161vs
1006m
805vs
772vs
592vs
558m
1529 (289) 1619m
1431s
1600m
1405s
1273vs
1226vs
1150vs
1002m
819vs
768vs
593vs
552m
1598m
1441m
1310vs
1230m
1157vs
997m
808vs
771vs
587vs
553m
1593m
1470m
1325vs
1234m
1164vs
997m
825vs
790vs
587vs
553m
1326 (170) 1306vs
1249 (406) 1234m
1158 (177) 1158vs
1007 (248) 1003m
802vs
(CH) (CC)
s(SO2) (CC)
(CS) (CNS)
(NS)(CCC)
(CH)pi
772 (224)
768vs
587vs
555m
534m
430vw
(SO2)
(SO2)(CS)
(SO2)
522m
429vw
535vw
432m
541m
431m
539m
431m
(CCC)pi
: stretching, : in plane bending, γ: out of plane bending, : bencenic ring, as: asymmetric, s: symmetric, iso:
isoindolic ring, vs: very strong, s: strong, m: medium, w: weak. Normal modes wavenumbers calculated with
Gaussian
In the electronic spectra of the five complexes recorded in DMSO solutions, only bands due to
the → * transitions of the C–Sexocyclic group were observed. The rest of the expected bands
(e.g. the bands due to the → * transitions of the phenyl rings of the anion or of the other
ligands) where overlapped by the absorption bands of the DMSO solvent.
3.3. 1H and13C NMR spectral studies
The NMR spectra of the new complexes, in DMSO-d6 solutions, were studied and compared to
the NMR responses of other metal thiosaccharinates with nitrogenated ligands. The numbering
scheme of the anions are shown in Scheme 1.
Scheme 1. Atoms numbering for the NMR signals assignments

(1)
(2)
(3)
(4)
(5)
1
In the H-NMR spectra of [Zn(tsac)2(o-phen)], complex (1), the characteristic signals of orto-
phenantroline appear at 9.18 (d, 1H, H8), 8.93 (d, 1H, H10), 8.31 ppm (m, 1H, H13) and the
other proton (H9) appears between 8.03-8.21 ppm. These values are shifted if compared with
those reported by Pazderski et al) [27] (9.11 and 7.79 ppm respectively). Regarding the
thiosaccharinate protons the characteristic signals appear at 7.57-7.72 (m, 3H, H4/H5/H6) and
7.91 (m, 1H, H3) ppm. Those are values well in the range of other metal thiosaccharinates
previously reported [9]. For complex (2), [Zn(tsac)2(TMDP)], the TMDP proton signals appear
at 8.46 ppm (dd, 4H, H8), 7.28 ppm (dd, 4H, H9), 2.64 ppm (t, 4H, H11) and 1.93 ppm (m, 2H,
H12). The thiosaccharinate anions show their proton resonances at 7.92 ppm (m, 2H, H3) and
7.58-7.72 ppm (m, 6H, H4/H5/H6). The 1H-NMR spectra of complex (3), [(4,4’-
bipy)H2][Zn(tsac)4], show the characteristic signals of the 4,4’-bipy: 8.98 ppm (dd, 4H, H8) and
8.30 ppm (dd, 4H, H9). The thiosaccharinate protons appear at 7.87-7.08 ppm (m, 4H, H3),
7.73-7.81 ppm (m, 4H, H6) and 7.35-7.72 (m, 10H, H4/H5/H11). Complex (4) NMR spectra,
shows the 2,2’-bipyridine signals at 8.60-8.90 (m, 1H, H9), 8.73 (d, 1H, H11), 8.34 (t, 1H,
H10), 7.83 (m, 1H, H8). For the thiosaccharinate anions, the characteristic signals appear at 7.94
(m, 1H, H3) and 7.58-7.75 (m, 3H, H4/H5/H6). These signals are shifted if compared with the
values obtained for [Ag2(tsac)2(2,2’-bipy)2], reported in 2007 by Dennehy et al. The 2,2’-bipy
appear for that compound at 7.59, 7.98 (dt,4H), 8.20 (dd,4H) and 8.80 (dd,4H) ppm and the
thiosaccharinate bands are observed at 7.78 (m,1H), 7.90 (d,1H) and 8.11 (d,1H) [28]. In the 1H
NMR spectra of [Zn(tsac)2(2,2’-bq)]n (5), the 2.2’-bq signals appear at 8.80 ppm (dd, 1H, H15),
8.58 ppm (dd, 1H, H14), 8.19 ppm (dd, 1H, H12), 8.08 ppm (dd, 1H, H11), 7.85 (td, 1H, H10)
and 7.53-7.73 (m, 1H, H9). The signals due to the thiosaccharinate protons appear at 7.89-7.95
ppm (m, 1H, H3) and 7.53-7.73 ppm (m, 3H, H4/H5/H6). The 13C NMR spectrum of all
complexes show the expected chemical shifts of the coordinated thioamidic C1 atom around
190 ppm (C1 (1): 191.81(2): 191.71 (3): 191.56 (4):191.73 (5):191.54 ppm). Besides, in order to
assign completely and correctly all the signals of 1H and 13C for each structure, we registered the
2D-HSQC RMN spectra for the complexes (See Supplementary Information I).
3.4 Theoretical calculations
DFT methods were applied to establish the correlation between the physical parameters found
experimentally for the complex 1 and those calculated. The gas phase geometric structure of this
complex was optimized and the vibrational spectrum was predicted. The distances obtained are
a good reproduction of the experimentally observed structural parameters. The observed
differences are in the range of those previously reported for other silver thiosaccharinates [9].
The differences among calculated and experimental angles are due to the packing in the solid
state. The nature of the vibration modes corresponding to complex were in good agreement with
the calculated (see Tables 2 and 4).
3.5 Proliferation assays
It was mentioned in the introduction that several Zinc based compounds have antifungal and
antibacterial uses. This prompted us to test whether the complexes synthetized here have anti-
proliferative actions in endothelial tumor cells. We used endothelial cells transformed by the

viral G protein coupled receptor (vGPCR) of Kaposi’s Sarcoma-Associated Herpesvirus, a key
molecule to develop Kaposi’s sarcoma disease. Thus, cells were treated with each ternary Zn(II)
complexes (1,2,3,4 and 5) or vehicle (DMSO, 0.1%) at different final concentrations during 48
hours (Figure 4 a-c). Then, proliferation was measured as was described in methods’ section
and results were expressed as percentage of cell number of each complex versus molar
concentration. As is observed in Figure 4 A, .Complex (1) seems to have more anti-proliferative
activity. Gao et al. [29] recently reported the use of two Zn complexes with two chelating
agents, 1,10’-phenantroline and 2,2’-bipyridine and found that both complexes exhibited
important cancer cell inhibitory rate but lower cytotoxicity toward the normal cell lines.
Compound (2) has a polymeric structure in a solid state, within the cell environment this
structural may disrupt into solvated molecular units resulting in terminal mono coordinated
TMDP thus decreasing its biological activity in a dose independent fashion. Complex (3) being
an ionic compound showed as expected low response independent on doses probably to
different response towards membrane crossing. Complexes (4) and (5) have mononuclear
structure with the bipyridine moiety quelating the metal center resulting in a slight biological
effect. These results gives rise to new questions to be explored regarding the significance of the
differences found in the cell response upon either compound and are beyond the scope of this
work.
A
B
C
C
D
Figure 4. Ternary Zn(II) complexes decrease endothelial vGPCR cells number. Cells were
treated with of each complex at different doses: A) compound 1 (1.6-4.7 µM), B) 2 compound
(1.6-4.7 µM), C) 3(1-3 µM), D) compound 4 (1.6-4.9 µM), E) compound 5 (1.4-4.2 µM) or
vehicle (DMSO) in DMEM 2% FBS for 48 h. Cells were then harvested and counted in a
Neubauer chamber. Proliferation was calculated as percentage of leaving cells in treated
conditions versus vehicle (dash line) Percentage values (mean ± S.D.) were then represented in
bar graphs. n=3.
4. Conclusions
Five new ternary Zn(II) complexes were synthesized and characterized. The metal atoms in all
the complexes are coordinated by thiosaccharinate anions and by other nitrogenated ligands. For

three of them, [Zn(tsac)2(o-phen)], [Zn(tsac)2(TMDP)]n and [(4,4’-bipy)H2][Zn(tsac)4], the
crystal structures showed the expected tetrahedral typical structure for Zn(II) thionates. The
anios are coordinated by the exocyclic sulfur atom, not showing coordination through the N
thioamidic atom. The proposed structure for the other two complexes consists in a polymeric
chain formed by thiosaccharinate sulfur bridges. The coordination of the anion was also
confirmed by means of FTIR and NMR studies. Promising results suggested an anti-cancer
activity of these ternary Zn(II) complexes.
5. Acknowledgements
M.D. and F.D. gratefully acknowledge the support of this project (Project M24/Q075) by
SGCyT-UNS. E.F., V.D. and V.G.P. are researchers from CONICET (Consejo Nacional de
Investigaciones Científicas y Técnicas).
6. Supplementary material
Crystallographic data for these structures have been deposited with the Cambridge
Crystallographic Data Centre as supplementary data Nros CCDC 1812462, CCDC 1812463 and
CCDC 1812464 for [Zn(tsac)2(o-phen)], [Zn(tsac)2(TMDP)]n, and [(4,4’-bipy)H2][Zn(tsac)4],
respectively. Copies of the data can be obtained free of charge upon request from The Director,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK. (fax: +44
1233 336033; e-mail: deposit@ccdc.cam.ac.uk; WEB: http://www.csdc.cam.ac.uk). Additional
1
information regarding H and 13C and HSQC NMR spectra for complexes. xyz coordinates,
calculated frequencies and total energy in atomic units for [Zn(tsac)2(o-phen)] are available as
supplementary information.
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Highlights
 Five novel Zn thiosaccharinates with N ancilliary ligands are presented in this paper.
 Three of them ([Zn(tsac)2(o-phen)], [Zn(tsac)2(TMDP)]n, [(4,4’-bipy)H2][Zn(tsac)4] ) were
characterized by X Ray diffraction and their structures are described in the manuscript.
 Coordination of [Zn(tsac)2(2,2’-bipy)] and of [Zn(tsac)2(2,2’-bquin)] were inferred from the
spectroscopic analysis.
 The five complexes exhibited anti-proliferative actions in endothelial tumor cells, thus suggesting
promising an anti-cancer activity.