Synthesis, characterization and anti-cancer studies of Mn(II), Cu(II), Zn(II) and Pt(II) dithiocarbamate complexes - crystal structures of the Cu(II) and Pt(II) complexes

Article abstract of DOI:10.1016/j.ica.2020.119431

Mn(II), Cu(II), Zn(II) and Pt(II) complexes of 2-((p-tolylamino)methyl)phenolyldithiocarbamate were synthesized and characterized by elemental analyses and spectroscopic techniques. Spectroscopic studies indicate four coordinate geometry around the metal(

Full text of DOI:10.1016/j.ica.2020.119431

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Research paper
Synthesis, characterization and anticancer studies of Mn(II), Cu(II), Zn(II) and
Pt(II) dithiocarbamate complexes-crystal structures of the Cu(II) and Pt(II)
complexes
Peter A. Ajibade, Amos A. Fatokun, Fartisincha P. Andrew
PII:
S0020-1693(19)31730-X
https://doi.org/10.1016/j.ica.2020.119431
ICA 119431
DOI:
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Inorganica Chimica Acta
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Please cite this article as: P.A. Ajibade, A.A. Fatokun, F.P. Andrew, Synthesis, characterization and anticancer
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complexes, Inorganica Chimica Acta (2020), doi: https://doi.org/10.1016/j.ica.2020.119431
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Synthesis, characterization and anticancer studies of Mn(II), Cu(II), Zn(II) and Pt(II)
dithiocarbamate complexes-crystal structures of the Cu(II) and Pt(II) complexes
a
b
a
Peter A. Ajibade *, Amos A. Fatokun *, Fartisincha P. Andrew
aSchool of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X01,
Scottsville, Pietermaritzburg, 3209 South Africa
bSchool of Pharmacy and Biomolecular Sciences, Faculty of Science, Liverpool John Moores
University, Liverpool L3 3AF, UK
ABSTRACT
Mn(II),
Cu(II),
Zn(II)
and
Pt(II)
complexes
of
2-((p-
tolylamino)methyl)phenolyldithiocarbamate were synthesized and characterized by elemental
analyses and spectroscopic techniques. Spectroscopic studies indicate four coordinate
geometry around the metal(II) ions and single crystal X-ray crystallography confirmed the
molecular structures of Cu(II) and Pt(II) complexes as distorted square planar. In vitro
cytotoxic effects of the complexes, indicative of potential anti-cancer properties, were
evaluated using human cancer cell lines HeLa and MRC5-SV2, and a normal cell line, MRC5.
The complexes exhibited significant toxicity against the cancer cell lines, with IC values of
5
0
less than 50µM after 48 h of exposure. Cu(II) and Zn(II) were the most potent and were
virtually equipotent in their cytotoxicity against each of the two cancer cells, but only Zn(II)
exhibited higher selectivity for a cancer cell than for a normal cell. Mn(II) complex was the
least potent, while Pt(II) was the least cancer cell-selective, exhibiting significantly higher
toxicity against the parental (normal) MRC-5 cell than against its cancer variant, MRC5-SV2.
These compounds could, therefore, inspire the development of inorganic drug leads to generate
novel anti-cancer drugs to be delivered directly to the cancerous tissue or through special
delivery systems.
Keywords: Dithiocarbamate; Metal(II) complexes; cytotoxicity; anticancer; cancer cells;
selectivity.
*
Corresponding authors: Peter A. Ajibade (ajibadep@ukzn.ac.za); Amos A. Fatokun
(A.A.Fatokun@ljmu.ac.uk)
1

1
. Introduction
The development of metallo-pharmaceuticals has grown rapidly since the discovery of cisplatin
and analogues [1, 2]. However, these compounds are associated with side effects such as severe
toxicity, intrinsic or acquired resistance and narrow activity range [3, 4]. Some of these side
effects are due to reduction in cisplatin uptake and intracellular accumulation [5]. This
necessitates the search for alternative metallo-based compounds other than platinum [6-14].
−
Dithiocarbamate (R NCS ) ions strongly coordinate and stabilize metal ions in different
2
2
oxidation states due to the high electron density on the sulphur atoms of the dithiocarbamato
moieties [15]. Metal dithiocarbamates have been shown to possess promising biological
activities [16, 17]. Recent studies have shown that metal dithiocarbamates bind DNA in
different ways, with varying cytotoxic activities [3, 18-25]. They inhibit NF-kB, which is
known to promote tumor cell proliferation [26-28]. In continuation of our efforts to develop
novel metallo drug candidates [3, 29, 30], we present the synthesis, characterization and in
vitro anticancer studies of Mn(II), Cu(II), Zn(II) and Pt(II) complexes of 2-((p-
tolylamino)methyl)phenolyldithiocarbamate. The molecular structures of the Cu(II) and Pt(II)
complexes are presented. Assessment of the anticancer potentials of the complexes focused on
their ability both to potently exhibit cytotoxicity and to selectively kill cancer cells, using two
cancer cell lines (HeLa, MRC5-SV2) and a normal cell line (MRC5) parental to the MRC5-
SV2.
2
. Experimental
2
.1 Materials and methods
All solvents used in this study were analytical grade and used as obtained without further
purification. The infrared spectra of the ligand and metal complexes were recorded on Agilent
2

-1
Cary 630 FTIR spectrometer (4000-650 cm ), melting points were recorded on Gallenkamp
1
13
melting point apparatus and H and C NMR were recorded on Bruker Avance III 400 MHz,
with the carbon and proton shifts presented in ppm in relation to the relevant deuterated solvent
signals. The elemental analyses were recorded on Thermoscientific Flash 2000. The UV-
Visible spectra were recorded on Agilent Cary 100 UV-Visible spectrophotometer. The molar
conductivity and mass spectrometry were recorded on Jenway 4510 conductivity meter and
Waters Micromass LCT Premier TOF-MS, respectively. Cell culture media and reagents
(DMEM, L-glutamine, antibiotic-antimycotic solution, trypsin solution (TrypLE), phosphate-
buffered saline) were obtained from Life Technologies (ThermoFisher Scientific, UK) and
Fetal Bovine Serum from Sigma-Aldrich (UK). Chemicals (including doxorubicin) were
obtained from Sigma-Aldrich and Tocris Bioscience (Biotechne), UK.
2
.2 Synthesis of (2-((p-tolylamino)methyl)phenol)
The secondary amine, (2-((p-tolylamino)methyl)phenol), used for the synthesis of the
dithiocarbamate ligand was synthesized according to literature [31]. P-toluidine (2.143 g, 0.025
mol) was added to salicylaldehyde (2.7 mL, 0.025 mol) and refluxed at 80°C for 8 h. The
solvent was then removed under vacuum to give a yellow oily (Schiff base) product, which
was then reduced to secondary amine with sodium borohydride (1.5132 g, 0.04 mol) added in
portions at room temperature and stirred for 20 h. The resulting product was extracted with
dichloromethane and washed with water to give a solid product after removing the solvent.
1
Yield, 3.8817 g, 91 %, H NMR (400 MHz, (CD ) CO, δ, ppm); 8.68(s, 1H), 7.25(d, 1H),
3
2
1
3
7
.05(m, 1H), 6.93(d, 2H), 6.81(m, 2H), 6.66(d, 2H), 5.08(s, 1H), 4.35(d, 2H), 2.18(s, 3H), C
NMR (400 MHz, (CD ) CO, δ, ppm); 45.26(—CH —NH—), 20.47(—CH ), 114.60, 116.12,
3
2
2
3
1
29.47, 147.45(—NH—C H ), 156.62, 128.70, 126.42, 120.26, 127.03, 130.24((OH)C H —),
6 4 6 4
3

-1
FTIR (solid, cm ); 3368 (b), 2903 (m), 2811 (m), 1616 (s), 1582 (s), 1486 (s), 1382 (s), 1222
+
(
s), TOF MS ES+: Calcd C H NO, m/z: [M] : 213.12, Found: 214.12
1
4
15
2
.3 Synthesis of the dithiocarbamate ligand
The potassium salt of the dithiocarbamate ligand was prepared thus: Aqueous solution of KOH
4 mmol, 0.2244 g) was added to THF solution of the secondary amine (4 mmol, 0.8531 g) and
(
stirred for one hour at room temperature. The mixture was brought down to 0-4 °C and CS (4
2
mmol, 0.24 mL) was added and stirred for 5 h; diethyl ether was added to form pale yellow
precipitate, washed with diethyl ether and dried over silica.
Dithiocarbamate ligand (L): Yield, 1.2446 g, 95 %, m.p 165, Anal. Cal for C H KNOS : C,
1
5
14
2
-1
2
-
5
5.01; H, 4.31; N, 4.28; S, 19.58. Found: C, 54.76; H, 4.08; N, 4.36; S, 19.33, Ʌ (Ω cm mol
m
1)
; 64.31, H NMR (400 MHz, CD CN, δ, ppm): 10.13(s, 1H), 7.09(m, 1H), 7.04(q, 2H), 6.77(t,
1
3
3
H), 6.52(m, 1H), 6.40(q, 1H), 5.65(s, 2H), 2.09(s, 3H), UV-Vis (CH CN, λmax), 287 nm
3
-1
+
−1
(
34843 cm ), TOF MS ES+, m/z [2M-K] : 615.06, FTIR (ν/cm ); 1581 (νC–N), 932 (νC–S),
3
361 (νO–H).
2
.4 Synthesis of the metal(II) complexes C1-C4
The metal(II) complexes (C1-C4) were prepared thus: To aqueous solution of the potassium
salt of 2-((p-tolylamino)methyl)phenolyldithiocarbamate (0.62 mmol, 0.2031 g), aqueous
solutions of the corresponding metals: MnCl ·4H O (0.31 mmol, 0.0614 g), CuCl ·2H O (0.31
2
2
2
2
mmol, 0.0528 g), ZnCl (0.31 mmol, 0.0409 g), and K PtCl (0.31 mmol, 0.1287 g) were added
2
2
4
and stirred for 4-12 h. The products were filtered, washed with water and dried over vacuum
4

to obtain the metal (II) complexes. Crystals suitable for single crystal X-ray crystallography
were obtained by slow evaporation of dichloromethane solution of Cu(II) complex and slow
diffusion of hexane into chloroform solution of Pt(II) .
[
Mn(L) ], (C1): Yield; 0.1915 g, 98 %, brown solid, Anal. Cal for [C H MnN O S ]: C,
2 30 28 2 2 4
5
7.04; H, 4.47; N, 4.43; S, 20.30. Found: C, 56.92; H, 4.09; N, 4.64; S, 19.87, m.p; 139 °C, Λm
-1
2
-1
-1
−1
(
Ω cm mol ): 5.46, UV-Vis (CH CN, λ ); 270 nm (37037 cm ), FTIR (ν/cm ); 1592 (ν
3 max C–
N), 956 (νC–S), 3267 (νO–H).
-1
2
-1
[
Cu(L) ], (C2): Yield; 0.1948 g, 98 %, brown solid, m.p; 172 °C, Λ (Ω cm mol ): 4.16,
2
m
Anal. Cal for [C H CuN O S ]: C, 56.27; H, 4.41; N, 4.37; S, 20.03. Found: C, 56.16; H,
3
0
28
2
2 4
-1
-1
4
.77; N, 4.89; S, 20.32, UV-Vis (CH CN, λ ); 281nm (35587 cm ), 442 nm (22624 cm ),
3 max
+
−1
TOF MS ES+: Calcd C H CuN O S , m/z: [M] : 640.36, Found: 639.03, FTIR (ν/cm );
3
0
28
2
2 4
1
596 (νC–N), 951 (νC–S), 3296 (νO–H).
[
Zn(L) ], (C3): Yield; 0.1716, 85 %, white solid, m.p; 175 °C, Anal. Cal for
2
[
C H ZnN O S ]: C, 56.11; H, 4.39; N, 4.36; S, 19.97. Found: C, 56.34; H, 4.17; N, 4.05; S,
3
0
28
2
2 4
-1
2
-1
-1
1
2
0.22, Λ (Ω cm mol ): 2.66, UV-Vis (CH CN, λ ); 281 nm (35587 cm ), H NMR (400
m 3 max
MHz, (CD ) SO, δ, ppm); 9.44(s, 1H), 7.30(d, 1H), 7.06(m, 5H), 6.79(m, 1H), 6.71(d, 1H),
3
2
1
3
5
5
1
.34(s, 2H), 2.23(s, 3H), C NMR (400 MHz, (CD ) SO, δ, ppm); 208.06 (C—S), 20.55 (CH )
3 2 3
6.82 (CH ), 114.97, 126.49, 128.59, 154.73 (—C H OCH ), 118.71, 121.41, 128.31, 129.19,
2
6
4
3
−
1
36.87, 142.70 (—C H OH), FTIR (ν/cm ); 1596 (νC–N), 951 (νC–S), 3327 (νO–H). TOF MS
6
4
+
ES+: Calcd C H ZnN O S , m/z: [M] : 640.03, Found: 639.02
3
0
28
2
2 4
5

[
Pt(L) ], (C4): Yield; 0.2052 g, 86 %, yellow solid, Anal. Cal for [C H PtN O S ]: C, 46.68;
2 30 28 2 2 4
-
H, 3.66; N, 3.63; S, 16.62. Found: C, 46.43; H, 3.39; N, 3.07; S, 16.16, m.p 221°C, Λ (Ω
m
1
2
-1
-1
-1
1
cm mol ): 4.65, UV-Vis (CH CN, λ ); 259 nm (38610 cm ), 360 nm, (27777 cm ), H
3
max
NMR (400 MHz, (CD ) SO, δ, ppm); 9.66(d, 1H), 7.12(m, 6H), 6.73(m, 2H), 5.09(d, 2H),
3
2
1
3
2
.24(d, 3H), C NMR (400 MHz, (CD ) SO, δ, ppm); 213.25 (C—S), 21.15 (CH ) 51.67
3 2 3
(
CH ), 115.62, 127.15, 130.25, 155.89 (—C H OCH ), 119.38, 120.15, 129.79, 136.84,
2 6 4 3
−
1
1
38.90, 155.88 (—C H OH), FTIR (ν/cm ); 1597 (νC–N), 948 (νC–S), 3400 (νO–H), TOF MS
6 4
+
ES+: Calcd C H PtN O S , m/z: [M] : 771.90, Found: 772.11
3
0
28
2
2 4
2
.5 Single crystal X-ray crystallography
The crystallographic data were obtained on a Bruker SMART APEX2 area detector
diffractometer using MoK radiation (0.934 Å). The structure was solved with the ShelXS-
a
2
013 [32] structure solution program using the Intrinsic Phasing solution method and by using
Olex2 [33] as the graphical interface. The model was refined with version 2016/6 of ShelXL
34] using Least Squares minimization.
[
2
.6 In vitro cytotoxicity studies
Three cell lines grown as adherent monolayer cultures were used for the cytotoxicity
experiments: Two cancer cell lines (the human cervical adenocarcinoma cell line HeLa and the
human foetal lung cancer cell line MRC5-SV2) and one normal cell line (the human foetal lung
fibroblast cell line MRC5, which is the parental cell line from which MRC5-SV2 was derived).
This approach allows the assessment of the differential sensitivities of cancer and normal cell
lines to potential anti-cancer compounds in order to assess the selectivity, or otherwise, of such
test compounds for cancer cells. Experiments were conducted largely as previously reported
6

2
[
4, 35]. The cells were grown in 75cm tissue culture flasks using Dulbecco’s Modified Eagle
Medium (DMEM) supplemented with 10% Foetal Calf Serum, 2mM L-glutamine and 1%
antibiotic-antimycotic solution (containing penicillin, streptomycin and amphotericin B). They
o
were incubated at 37 C in a humidified atmosphere of 5% CO . All solutions to which the
2
o
cultures were exposed were pre-warmed to 37 C. Upon attaining 80-90% confluency in the
flask, the cultures were rinsed with phosphate-buffered saline (PBS), trypsinised, harvested
into a suspension using the growth medium, counted with a haemocytometer, and seeded into
4
micro-clear, flat-bottom 96-well plates at a density of 7.5 x 10 cells per ml (100µL/well,
equating to 7500 cells per well). After a period of 24 h, cultures were exposed to a range of
concentrations prepared in growth medium (compound stocks were prepared in DMSO but
final DMSO concentration that cells were exposed to was not more than 0.1%v/v) as indicated
in the results section and added to the cultures, each in triplicate, and plates were incubated for
up to 48 h, after which viability was assessed using the MTT (3-(4,5-Dimethyl-2-thiazolyl)-
2
,5-diphenyl-2H-tetrazolium bromide) assay. This was done by adding to each well 10µL of
MTT solution (5mg/mL, prepared in sterile PBS) and incubating the plates for 3 h, after which
the content of each well was aspirated and 100µl of DMSO was added to dissolve the insoluble
formazan. The absorbance of each well was then read at a wavelength of 570nm using the
CLARIOstar plate reader (BMG Labtech). These values are indicative of the viability of the
cultures following treatments with the compounds. Changes to the morphology of the cells
caused by the treatments were monitored on an Olympus CKX41 microscope fitted with an
Olympus DP71 U-TVIX-2 camera. Images were captured using the Olympus cellSens entry
software.
For each treatment the mean of the triplicate values was calculated. The mean of the negative
control culture was then set to 100% and the mean viability for each concentration normalised
7

to it. Values are shown as Mean ± SEM (standard error of the mean). Statistical analyses were
done using GraphPad (Version 8.0.1) (GraphPad Software, Inc., CA, USA). Statistically
significant differences between the means were determined using analysis of variance
(ANOVA) followed by a post-hoc test for multiple comparisons (Tukey test). A P-value of less
than 0.05 was considered statistically significant. IC50 value for each compound was
determined using GraphPad by fitting the data to the non-linear regression “log [inhibitor]
versus response (3 parameters or 4 parameters (variable slope))”. To calculate the Selectivity
Index (SI) for each compound, the IC value for its cytotoxic effect in the normal cell MRC5
5
0
was divided by the IC value for its cytotoxic effect in the cancer variant MRC5-SV2.
5
0
3
. Results and discussion
3
.1 Syntheses
The compounds were prepared as shown in Scheme 1. The complexes (C1-C4) were obtained
as solid in good yield ranging from 67-98%. The molar conductance of the complexes in
comparison with that of the ligand in dichloromethane revealed that they were neutral as
expected [35]. The elemental analysis and spectroscopic data agree with the proposed four
coordinate geometry with two molecules of the dithiocarbamate ligands bonded to the metal(II)
ions. Single crystal X-ray crystallography of Cu(II) and Pt(II) complexes revealed
mononuclear four coordinate compounds.
8

NH2
CH3
OH
CHO
OH
1
. reflux 8h, MeoH
+
2
. NaBH4, 20h, MeOH:DCM
HN
CH3
H C
CH3
S
3
KS
N
OH
M(II)
H2O
S
S
N
M
N
S
S
H C
3
M = Mn, Cu, Pt, Zn
OH
HO
Scheme 1. General synthetic pathway for the preparation of the ligand and the complexes
3
.2 Spectroscopic studies
-1
The intense bands observed at 1581 and 932 cm in the FTIR spectrum of the free ligand were
assigned to the thioureide ν(C—N) and ν(C—S) stretching vibrations of the N—CSS moiety
-1
and the broad band observed at 3361 cm was assigned to ν(O—H). In the metal complexes,
-1
the ν(C—N) stretching vibrations shifted by 14 cm to higher energies, which indicates an
increase of the carbon—nitrogen double bond character [29, 30, 37]. The ν(C—S) stretching
-1
-1
vibrations observed at 932 cm in the ligand shifted to 956, 951, 951, and 948 cm in the
spectra of Mn(II), Cu(II), Zn(II) and Pt(II) complexes, respectively. This confirms the
coordination of the ligand to the metal(II) ions in a bidentate chelating mode via the two sulphur
atoms [38-40].
The electronic spectra of the ligand and corresponding metal(II) complexes in dimethyl
-1
sulfoxide are presented in Figure 1. The band at 287 nm (34843 cm ) in the electronic
9

*
spectrum of the ligand is assigned to the intraligand n—π and π—π transitions of the N—CSS
5
moiety of the dithiocarbamate. The Mn(II) (C1) is a d complex with zero crystal field
stabilization energy in which electronic transitions are both spin and Laporte forbidden, hence
-1
no d-d transition was observed [41]. The band observed at 270 nm (37037 cm ) is assigned to
ligand to metal charge transfer transitions typical of four coordinate Mn(II) complex [42].
In the electronic spectra of copper(II) complexes in square planar geometry, two absorption
2
2
2
2
bands in the visible region due to B → A and B → E are expected [43, 44]; however, in
1
g
1g
1g
g
-1
2
2
Cu(II) complex (C2), the only band at 442 nm (22624 cm ) is assigned to B → A , while
1
g
1g
the second band was not observed. In the Zn(II) complex (C3), the band at 281 nm (35587
-1
cm ) is assigned to ligand to metal charge transfer transitions (LMCT) [43]. The electronic
spectrum of the Pt(II) complex (C4) showed strong and intense absorption at 259 nm (38610
-1
*
cm ) and is assigned to intraligand (π—π ). The d-d-transition is masked by charge transfer
-1
transition observed at 360 nm (27777 cm ) [45].
3
.3 Molecular structures of the Cu(II) and Pt(II) complexes
The molecular structures of the Cu(II) and Pt(II) complexes are shown in Figures 2 and 4. The
crystallographic data and structure refinements are presented in Table 1. Selected bond lengths
and bond angles are listed in Tables 2 and 3 for Cu(II) and Pt(II), respectively. The Cu(II)
complex C2 crystalized out as centrosymmetric mononuclear entity consisting of two
molecules of the dithiocarbamate ligand symmetrically bonded to the Cu(II) ions (Figure 2).
The geometry around the copper(II) ion in the complex is a four coordinate distorted square
planar geometry ascribed to the cis S1—Cu1—S2 of (77.803(19)°) and trans S1—Cu1—S21
of (102.197(19)°) bite angles. The average Cu—S bond length is 2.30 Å in agreement with
1
0

reported four coordinate copper(II) dithiocarbamate complexes [29, 46, 47]. The thioureide
2
N—CSS is planar with sp hybridized carbon and the N—CSS bond length of 1.318(3) Å. This
is shorter than the C—N single bond (1.465 Å) and longer than C═N double bond (1.279 Å).
This indicates partial double bond character of the N—C due to the delocalized π-electron
density over the thioureide (NCS ) moiety [48]. The thioureide S1—C1 and S2—C1 are
2
1
.730(2) Å and 1.723(2) Å, which are shorter than normal C—S single bond length (1.81 Å)
but longer than C═S bond length (1.69 Å) [29, 46, 47].
The molecular structure is sustained in the unit cell by non-classical intra molecular C—H···S
and secondary inter molecular O—H···S hydrogen bonding (Figure 3). The two aryl rings of
the N-substituent are not coplanar with dihedral angle of 67.13° between the two planes (C2,
C3, C4, C5, C7, C8 and C10, C11, C12, C13, C14, C15). The non-coplanar nature of these
rings may provide some required minimum degree of steric shelter needed for effective drug
delivery because of anticipated moderate ligand exchange kinetics.
The Pt(II) complex crystalized out in an orthorhombic crystal system and space group P2 2 2 .
1
1 1
The compound is a monomeric (Figure 4) four-coordinate platinum(II) center with two
molecules of the ligand in a distorted square planar geometry duet to the S1—Pt1—S2
(
74.92(12)°) and S3—Pt1—S4 (74.68(12)°) bite angles. The unequal platinum-sulfur bond
lengths: Pt1—S1 (2.303(3) Å), Pt1—S2 (2.321(3) Å), Pt1—S3 (2.329(4) Å), Pt1—S4
2.336(3) Å) indicate the ligands are asymmetrically bonded to the platinum(II) ion [49].
(
The thioureide C—N bond lengths: N1—C8 (1.290(17) Å) and N2—C16 (1.295 Å) are shorter
than normal carbon-nitrogen single bond (1.465 Å) and greater than carbon-nitrogen double
bond (1.279 Å) strong carbon-nitrogen double bond character as a result of π-electron density
delocalization within the NCS moiety. Also, the thioureide C—S bond lengths are unequal in
2
1
1

the range 1.721-1.755(14) Å and lie between C—S (1.815 Å) and C=S (1.671 Å) bond lengths.
This indicates the delocalization of π-electrons in the S—C—S group [50]. The unit cell
packing of [Pt(L) ] consists of four molecules in a unit cell with non-classical intramolecular
2
C—H···S and O—H···S hydrogen bond interactions.
3
.4 Assessment of the potential anticancer properties of the complexes
The cytotoxicity of complexes C1-C4 against cancer cell lines was assessed to determine their
potential anti-cancer properties. The three cell lines used, HeLa (cervical cancer cell line),
MRC5-SV2 (lung cancer cell line) and MRC5 cells (normal (healthy) lung fibroblast cells),
were exposed to the standard drug, cisplatin, and to each of C1-C4, for 24 and/or 48 hours.
Cisplatin (6.25-100µM) significantly reduced the viabilities of HeLa, MRC5-SV2 and MRC-
5
8
cells in a concentration-dependent manner, with IC values, respectively, of 11.1 ± 3.3µM,
50
.6 ± 0.3µM and 15.0 ± 0.4µM for 48 h of exposure (Table 4).
The extent of viability reductions caused by cisplatin (or each of the complexes) was consistent
with the degree of morphological damage inflicted on the cells (Figure 7). The concentration-
dependence of the toxic effects (for cisplatin and the complexes) was also demonstrated
morphologically by the progressive worsening of the toxicity phenotype with increasing
concentrations. Compared to the negative control cultures that remained adhered to the
substratum, appeared confluent and demonstrated network processes consistent with the typical
morphology of the different cell types used, the toxicity phenotype was characterized by a
rounding up of the cells, shrinkage of the cells and, in some cases, significant loss of cells
(Figure 7).
1
2

The MRC5-SV2 cell was more sensitive to cisplatin than the HeLa cell, whereas the MRC5
cell was less sensitive to cisplatin than the HeLa cell. On the other hand, both the MRC5-SV2
and the MRC5 cells were more sensitive to the complexes than the HeLa cell. The Selectivity
Index (SI) values for cisplatin and the complexes were also determined. SI is the ratio of the
IC value for the toxicity of a compound against a normal cell line (MRC5 in this case) and
5
0
the IC value for its toxicity against a cancer cell line or a cancerous variant of the normal cell
5
0
line (MRC5-SV2 in this case) [51]. A SI greater than 1 suggests the compound is more selective
for the cancer cell (desirable), while a SI less than 1 suggests the compound is more toxic to a
normal cell than a cancer cell (undesirable). Cisplatin had a Selectivity Index (SI) of 1.7 (48 h)
(Table 4), meaning it was nearly twice as toxic to the cancer cell line MRC5-SV2 as it was to
its parental (normal) cell line MRC5.
The complexes elicited varying degrees of toxicity. Mn(II) complex (C1) was the least toxic
(
Figure 6D-F), with IC values (48 h) of 45.6 ± 3.9µM, 37.7 ± 3.0µM, and 29.9 ± 3.9µM, for
50
the HeLa, MRC5-SV2 and MRC5 cells, respectively, translating to a SI of 0.8 (Table 4), which
implies it was more toxic to the normal cell line MRC5 than to the cancer variant MRC5-SV2.
Both Cu(II) (C2) and Zn(II) (C3) complexes exhibited concentration-dependent toxic effects,
both on viability (Figure 6A-C for Cu(II) and Figure 6D-F for Zn(II)) and on morphology
(Figure 7). There was no difference between the toxicities of Cu(II) at 24 h and 48 h.
While Cu(II) and Zn(II) complexes elicited similar toxicity potencies against the two cancer
cell lines (HeLa and MRC5-SV2), Cu(II) complex was more toxic to the MRC5 cell line than
Zn(II) complex. The IC values for the effects (48 h) of Cu(II) on HeLa, MRC5-SV2 and
5
0
MRC5 cells are 30.1 ± 3.5µM, 17.9 ± 2.1µM, and 14.0 ± 3.5µM, respectively, and for Zn(II)
the values are 28.1 ± 1.8µM, 19.8 ± 0.2µM, and 22.3 ± 1.9µM (Table 4). Cu(II) produced a SI
1
3

of 0.8 while the SI for Zn(II) was 1.1. This means Cu(II) complex exhibited greater toxicity
against the normal cell line MRC5 than against its cancer variant MRC5-SV2, whereas Zn(II)
complex exhibited marginally greater toxicity against the cancer cell line MRC5-SV2 than
against its parental (normal) cell line MRC5.
While Pt(II) complex (C4) also reduced the viability of each of the three cell lines in a
concentration-dependent manner (Figure 6D-F) and caused morphological damage, it was less
toxic to both cancer cell lines (HeLa and MRC5-SV2) than either Cu(II) or Zn(II) complex,
but more toxic to the normal cell line MRC5 than either of them (Table 4). This resulted in
Pt(II) being the complex with the least SI (0.3), which establishes it as significantly more toxic
to the normal cell line (MRC5) than its cancer variant (MRC5-SV2). The ranking orders of
potencies for the four complexes are Zn(II)>Cu(II)>Pt(II)>Mn(II) for the HeLa cell line,
Cu(II)>Zn(II)>Pt(II)>Mn(II) for the MRC5-SV2 cell line and Pt(II)>Cu(II)>Zn(II)>Mn(II) for
the MRC5 cell line. Overall, based on the findings, Zn(II) complex appears the most promising
compound that might induce significant death of cancer cells while being selective, at least,
mildly, for those cancer cells over normal cells.
However, further studies of the complexes could determine their SIs in a wider selection of
cancer cells and their parental (normal) cells in order to ascertain whether the complexes could
exhibit differential toxicities and selectivity in different cancer types. Furthermore, as there is
now the possibility of using special delivery systems to target anti-cancer drugs specifically to
cancer cells and thus spare normal cells [52], all the four complexes could still be investigated
for their potential to generate leads for the development of novel, inorganic anti-cancer drugs.
They could lend themselves to further modifications to enhance cancer cell toxicity potency
and selectivity.
1
4

4
. Conclusion
Mn(II), Cu(II), Zn(II) and Pt(II) dithiocarbamate complexes were prepared and characterized
by elemental analyses, spectroscopic techniques and the Cu(II) and Pt(II) by single crystal X-
ray crystallography. Spectroscopic studies confirmed that two molecules of the
dithiocarbamate ligand coordinate the metal(II) ions in a bidentate chelating mode to form four
coordinate geometry. Single crystal X-ray structures of the Cu(II) (C2) and Pt(II) (C4)
complexes revealed a distorted four coordinate square planar geometry. All the four complexes
showed in vitro cytotoxic activity against the HeLa and MRC5-SV2 cancer cell lines, with IC50
values of less than 50µM. Cu(II) and Zn(II) complexes demonstrated the highest cytotoxicity
potencies (IC values ranging between 20 and 30µM), while Zn(II) was the only ligand that
5
0
exhibited (marginally) selective toxicity against cancer cells. These complexes, therefore, have
potential to generate leads for the development of novel, inorganic anti-cancer compounds.
Acknowledgements
The financial support of Sasol and National Research Foundation (NRF), South Africa is
gratefully acknowledged. FP Andrew thanks Tertiary Education Trust Fund (TETfund) and
Modibbo Adama University of Technology, Nigeria, for the award of doctoral scholarship.
AAF is grateful to the Faculty of Science, Liverpool John Moores University, for the award of
a Seed Corn Grant.
Supplementary information
CCDC-1917884 and 1917887 contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or
1
5

from the Cambridge crystallographic data centre, 12 Union Road, Cambridge, CB2 1EZ, UK;
fax: (+44)-1223-336-033 or email: deposit@ccdc.cam.ac.uk]
References
[1] Grafe C, Semrau S, Hein MW, Beckmann A, Mackensen A, Dörje, F. Fromm, M.F.,
Naunyn-Schmiedeberg's Arch. Pharmacol., 2018, 391, 219-229.
[
[
[
2] M. Aggarwal, S. Chawla, K. Singh, P. Rana, J. Basic Clin. Pharm., 2018, 9, 118-124.
3] F. P. Andrew, P. A. Ajibade, J. Mol. Struct., 2018, 1155, 843-855.
4] R. O. Omondi, D. Jaganyi, S. O. Ojwach, A. A. Fatokun, Inorg. Chim. Acta, 2018, 482,
2
13-220.
5] H. Zhu, H. Luo, W. Zhang, Z. Shen, X. Hu, X. Zhu, Drug Des. Dev. Ther., 2016, 10, 1885-
895.
6] M. R. Williams, B. Bertrand, D. L. Hughes, Z. A. Waller, C. Schmidt, I. Ott, M. O’Connell,
M. Searcey, M. Bochmann, Metallomics 2018, 10, 1655-1666.
7] M. V. Babak, M. Pfaffeneder-Kmen, S. M. Meier-Menches, M. S. Legina, S. Theiner, C.
Licona, C. Orvain, M. Hejl, M. Hanif, M. A. Jakupec, Inorg. Chem., 2018, 57, 2851-2864.
8] D. Havrylyuk, B. S. Howerton, L. Nease, S. Parkin, D. K. Heidary, E. C. Glazer, Eur. J.
Med. Chem., 2018, 156, 790-799.
9] N. Y. S. Lam, D. Truong, H. Burmeister, M. V. Babak, H. U. Holtkamp, S. Movassaghi,
[
1
[
[
[
[
D. M. Ayine-Tora, A. Zafar, M. Kubanik, L. Oehninger, T. Sohnel, J. Reynisson, S.M.F.
Jamieson, C. Gaiddon, I. Ott, C. G. Hartinger, Inorg. Chem., 2018, 57, 14427-14434.
[
10] Q. Du, L. Guo, M. Tian, X. Ge, Y. Yang, X. Jian, Z. Xu, Z. Tian, Z. Liu, Organometallics,
018, 37, 2880-2889.
11] L. H. Abdel-Rahman, A. M. Abu-Dief, R. M. El-Khatib, S. M. Abdel-Fatah, Bioorg.
Chem., 2016, 69, 140-152.
12] J. Dam, Z. Ismail, T. Kurebwa, N. Gangat, L. Harmse, H. M. Marques, A. Lemmerer, M.
L. Bode, C. B. de Koning, Eur. J. Med. Chem., 2017, 126, 353-368.
13] L. H. Abdel-Rahman, A. M. Abu-Dief, R. M. El-Khatib, S. M. Abdel-Fatah, J. Photochem.
Photobiol., 2016, 162, 298-308.
14] C. A. Kumar, R. Nagarajaprakash, W. Victoria, V. Veena, N. Sakthivel, B. Manimaran,
Inorg. Chem. Commun., 2016, 64, 39-44.
2
[
[
[
[
[15] T. Harvey, F. Walsh, A., Nahlé, J. Mol. Liq., 2018, 266, 160-175
[16] Y. J. Tan, Y. S. Tan, C. I. Yeo, J. Chew, E. R. T. Tiekink, J. Inorg. Biochem., 2019, 192,
1
07-118.
1
6

[17] Zia-ur-Rehman, S. Ibrahim, A. Khan, M. Imran, M. M. Naseer, I. Khan, A. Shah, M. N.
Tahir, Muneeb-ur-Rahman; I. Z. Awan, J. Coord. Chem., 2016, 69, 551-561.
[
18] M. K. Amir, S. Z. Khan, F. Hayat, A. Hassan, I. S. Butler, Inorg. Chim. Acta, 2016, 451,
1-40.
19] S. S. Al-Jaroudi, M. Altaf, A. A. Seliman, S. Yadav, F. Arjmand, A. Alhoshani, H. M.
Korashy, S. Ahmad, A. A. Isab, Inorg. Chim. Acta, 2017, 464, 37-48.
3
[
[20] F. Hayat, Zia-ur-Rehman; M. H. Khan, J. Coord. Chem., 2017, 70, 279-295.
[21] Y. S. Tan, K. K. Ooi, K. P. Ang, A. M. Akim, Y.-K. Cheah, S. N. A. Halim, H.-L. Seng,
E. R. Tiekink, J. Inorg. Biochem., 2015, 150, 48-62.
22] S. Shahraki, H. Mansouri-Torshizi, A. Heydari, A. Ghahghaei, A. Divsalar, A. Saboury,
H. Ghaemi, M. Doostkami, S. Zareian, Iran. J. Sci. Technol. A, 2015, 39, 187-198.
[
[23] Y. Li, H. Qi, X. Li, X. Hou, X. Lu, X. Xiao, Apoptosis, 2015, 20, 787-795.
[24] M. K. Amir, F. Hayat, S. Z. Khan, G. Hogarth, T. Kondratyuk, J. M. Pezzuto, M. N. Tahir,
RSC Adv. 2016, 6, 110517-110524.
25] M. Altaf, M. Monim-ul-Mehboob, A.-N. Kawde, G. Corona, R. Larcher, M. Ogasawara,
N. Casagrande, M. Celegato, C. Borghese, Z. H. Siddik, Oncotarget 2017, 8, 490-505.
26] J. Yin, M. Wu, J. Duan, G. Liu, Z. Cui, J. Zheng, S. Chen, W. Ren, J. Deng, X. Tan, Appl
Biochem. Biotechnol., 2015, 177, 1716-1728.
[
[
[27] M. Xu, K.-N. Wang, K. Wu, X.-P. Wang, Gut Liver, 2015, 9, 411-416.
[28] J. R. Liddell, S. Lehtonen, C. Duncan, V. Keksa-Goldsteine, A.-L. Levonen, G.
Goldsteins, T. Malm, A. R. White, J. Koistinaho, K. M. Kanninen, J. Neuroinflammation, 2016,
3, 49-49.
1
[
[
[
[
[
29] F. P. Andrew, P. A. Ajibade, J. Coord. Chem., 2018, 71, 2776-2786.
30] F. P. Andrew, P. A. Ajibade, J. Mol. Struct., 2018, 1170, 24-29.
31] K. K. Manar, M. K. Yadav, M. G. Drew, N. Singh, Polyhedron 2016, 117, 592-599.
32] G. M. Sheldrick, A short history of shelx. Acta Crystallogr. A, 2008, 64, 112-122.
33] O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. Howard, H. Puschmann, J. Appl.
Crystallogr., 2009, 42, 339-341.
[34] G. M. Sheldrick, Acta Cryst. C, 2015, 71, 3-8.
[35] R. O. Omondi, S. O. Ojwach, D. Jaganyi, A. A. Fatokun, Inorg. Chem. Commun., 2018,
9
4, 98-103.
36] K. M. Oliveira, R. S. Corrêa, M. I. Barbosa, J. Ellena, M. R. Cominetti, A. A. Batista,
Polyhedron, 2017, 130, 108-114.
[
1
7

[
37] A. A. Isab, M. A. J. Ali, S. Sharif, I. U. Khan, S. K. Kang, T. Khalid, M. Saleem, S.
Ahmad, Inorg. Chem. Commun., 2011, 14, 1962-1965.
38] K. Nakamoto, Infrared and Raman spectra of inorganic and coordination compounds.
Wiley: 1977.
39] K. Nakamoto, Infrared and Raman spectra of inorganic and coordination compounds,
applications in coordination, organometallic, and bioinorganic chemistry. Inc, New York 2009.
[
[
[40] G. Faraglia, S. Sitran, D. Montagner, Inorg. Chim. Acta, 2005, 358, 971-980.
[41] R. Khajuria, A. Syed, S. Kumar, S. K. Pandey, Bioinorg. Chem. Appl., 2013, 2013, 1-13.
[42] R. Adams, E. Bishop, R. Martin, G. Winter, Aust. J. Chem., 1966, 19, 207-210.
[43] S. M. Mamba, A. K. Mishra, B. B. Mamba, P. B. Njobeh, M. F. Dutton, E. Fosso-Kankeu,
Spectrochim. Acta A, 2010, 77, 579-587.
[44] H. Singh, L. Yadav, S. Mishra, J. Inorg. Nucl. Chem., 1981, 43, 1701-1704.
[45] C. E. Housecroft, A. G. Sharpe. Inorganic Chemistry (3rd Edition), Pearson Education
Limited 2008.
46] A. N. Gupta, V. Singh, V. Kumar, A. Rajput, L. Singh, M. G. Drew, N. Singh, Inorg.
Chim. Acta, 2013, 408, 145-151.
47] G. M. De Lima, D. C. Menezes, C. A. Cavalcanti, J. A. Dos Santos, I. P. Ferreira, E. B.
Paniago, J. L. Wardell, S. M. Wardell, K. Krambrock, I. C. Mendes, J. Mol. Struct., 2011, 988,
-8.
[
[
1
[48] A. S. Sonia, R. Bhaskaran, J. Mol. Struct., 1134, 2017, 416-425.
[49] R. S. Amim, M. R. Oliveira, G. J. Perpétuo, J. Janczak, L. D. Miranda, M. M. Rubinger,
Polyhedron, 2008, 27, 1891-1897.
50] A. Z. Halimehjani, K. Marjani, A. Ashouri, V. Amani, Inorg. Chim. Acta, 2011, 373, 282-
85.
51] P. A. Segun, O. O. Ogbole, F. M. D. Ismail, L. Nahar, A. R. Evans, E. O. Ajaiyeoba, S.
D. Sarker, Phytother. Res. 2019, 33, 159-166.
52] J.P. Parker, Z. Ude, C. J. Marmion, Metallomics, 2016, 8, 43-60.
[
2
[
[
1
8

Table 1. Crystal data and structure refinements for Cu(II) and Pt(II)
Compound
Formula
[Cu(L)2]
[Pt(L)2]
C H CuN O S
C H N O PtS
4
3
0
28
2
2
4
30 28
2
2
-3
Dcalc./ g cm
1.277
0.934
640.32
0.33×0.26×0.14
100(2)
triclinic
P-1
1.333
3.888
771.87
0.37×0.23×0.18
100(2)
-1
μ/mm
Formula Weight
3
Size/mm
T/K
Crystal System
Space Group
orthorhombic
P2 2 2
1
1 1
a/Å
b/Å
c/Å
α/°
β/°
γ/°
7.1091(6)
9.6797(7)
13.6943(10)
69.535(4)
89.651(4)
71.724(4)
832.65(11)
1
28.219(6)
17.750(4)
7.6800(16)
90
90
90
3
V/Å
Z
3846.8(14)
4
Z’
0.5
1
Wavelength/Å
Radiation type
0.71073
MoKa
1.598
28.347
15481
4126
3267
0.0313
183
0.71073
MoKa
2.749
25.995
13956
7216
6642
0.0853
309
Θ /°
min
Θ /°
max
Measured Refl.
Independent Refl.
Reflections Used
Rint
Parameters
Restraints
0
229
Largest Peak
Deepest Hole
GooF
0.394
-0.316
0.996
0.0915
0.0862
0.0510
0.0362
3.376
-1.758
1.035
0.1514
0.1487
0.0655
0.0613
wR (all data)
2
wR2
R1 (all data)
R1
1
9

Table 2. Some selected bond lengths and bond angles for [Cu(L)2]
Atoms
Angle/°
180.0
102.196(19)
102.197(19)
77.803(19)
77.803(19)
180.0
83.78(7)
84.33(7)
113.65(12)
123.86(16)
Atoms
Cu1—S1
Cu1—S1
Cu1—S2
Cu1—S2
S1—C1
S2—C1
O1—C15
N1—C1
C2—C8
C3—C4
C4—C5
Length/Å
2.3076(5)
2.3076(5)
2.2948(5)
2.2948(5)
1.730(2)
1.723(2)
1.369(2)
1.318(3)
1.381(3)
1.386(3)
1.386(4)
1
1
S1 —Cu1—S1
1
S2 —Cu1—S1
1
S2—Cu1—S1
1
1
1
S2 —Cu1—S1
S2—Cu1—S1
S2—Cu1—S2
1
C1—S1—Cu1
C1—S2—Cu1
S2—C1—S1
N1—C1—S1
N1—C1—S2
122.46(16)
1
2
3
Symmetry operation -x,1-y,-z; 1-x,-y,-z; +x,-1+y,+z
Table 3. Some selected bond lengths and bond angles for [Pt(L)2]
Atoms
Angle/°
Atoms
Length/Å
S1— Pt1— S2
S1—Pt1—S3
S1—Pt1—S4
S2—Pt—S3
S2—Pt1—S4
S3—Pt1—S4
C8—S1—Pt1
C8—S2—Pt1
S2—C8—S1
N1—C8—S1
N1—C8—S2
74.92(12)
105.05(12)
178.45(12)
179.86(15)
105.35(12)
74.68(12)
88.1(5)
88.3(5)
108.0(7)
124.1(11)
127.8(11)
Pt1—S1
Pt1—S2
Pt1—S3
Pt1—S4
S1—C8
S2—C8
S3—C16
S4—C16
C4—C5
C4—C7
C5—C6
2.303(3)
2.321(3)
2.329(4)
2.336(3)
1.755(14)
1.721(14)
1.730(14)
1.726(14)
1.390(1)
1.538(15)
1.390(1)
2
0

Table 4: IC values (mean ± SEM) (in µM) and selectivity indices for the toxicities of the
5
0
anti-cancer drug, cisplatin, and Complexes C1-C4 against HeLa, MRC5-SV2 and MRC5
cells. Selectivity Index (SI) is the ratio of the IC value for the toxicity of a compound against
5
0
a normal cell line (MRC5 in this case) and the IC value for its toxicity against a cancerous
5
0
variant of the normal cell line (MRC5-SV2 in this case). A SI greater than 1 suggests the
compound is more selective for the cancer cell (desirable), while a SI less than 1 suggests the
compound is more toxic to a normal cell than a cancer cell (undesirable).
IC (µM)
5
0
Selectivity
HeLa
MRC5-SV2
8.6 ± 0.3
37.7 ± 3.0
17.9 ± 2.1
19.8 ± 0.2
26.9 ± 0.3
MRC5
Index (SI)
Cisplatin (standard)
Mn(L)2], C1
Cu(L)2], C2
Zn(L)2], C3
Pt(L)2], C4
Order of potencies
for complexes)
11.1 ± 3.3
45.6 ± 3.9
30.1 ± 3.5
28.1 ± 1.8
39.7 ± 10.3
15.0 ± 0.4
29.9 ± 3.9
14.0 ± 3.5
22.3 ± 1.9
7.4 ± 0.9
1.7
0.8
0.8
1.1
[
[
[
[
0.3
(
C3>C2>C4>C1 C2>C3>C4>C1 C4>C2>C3>C1
2
1

Figure Legends
Figure 1. Overlay spectra of the ligand (L) and the complexes: (C1) Mn(II), (C2) Cu(II),
(C3) Zn(II) and (C4) Pt(II)
Figure 2. The molecular structure of Cu(II) complex with atom numbering thermal
ellipsoids 50% probability displacement
Figure 3. Molecular packing of Cu(II) viewed down crystallographic b-axis of the unit cell
with the supramolecular layer sustained by intra molecular C—H···S and O—H···S
interactions.
Figure 4. The molecular structure of [Pt(L) ] with atom numbering thermal ellipsoids 50%
2
probability displacement
Figure 5. The unit cell packing of [Pt(L) ] with hydrogen atoms omitted for clarity and
2
hydrogen bonds in dash green lines
Figure 6: Effects of up to 48 h exposure to Complexes C1 ([Mn[L]2]), C2 ([Cu(L)2]), C3
([Zn(L)2]) and C4 ([Pt(L)2]) on the viability of HeLa, MRC5-SV2 and MRC5 cells. (A).
Effects of C2 (24 and 48 h) on HeLa cells. (B) Effects of C2 (24 and 48 h) on MRC5-SV2
cells. (C). Effects of C2 (24 and 48 h) on MRC5 cells. (D) Effects of C1, C3 and C4 (48 h) on
HeLa cells. (E). Effects of C1, C3 and C4 (48 h) on MRC5-SV2 cells. (F) Effects of C1, C3
and C4 (48 h) on MRC-5 cells. Each bar represents the mean ± SEM of triplicate viability
values obtained as cellular (cytotoxic) response to treatment with the indicated concentration
of the indicated compound. *P<0.05, **P<0.001 and ***P<0.0001 compared with negative
control. Each data point represents an average of 3 or 4 independent experiments.
Figure 7: Representative photomicrographs showing the effects of the anti-cancer drug,
cisplatin, and Complexes C2 ([Cu(L)2]) and C3 ([Zn(L)2]) on the morphology of HeLa and
MRC5-SV2 cells following 48 h exposure to each compound. Bright-field images were
acquired with a 10x objective on an Olympus CKX41 microscope fitted with an Olympus DP71
U-TVIX-2 camera. Dead or dying cells are indicated by their rounded and/or shrunken
appearance (compared to the control image). Scale bar = 100µm.
2
2

0
0
0
0
0
0
.55
.45
.35
.25
.15
.05
L
C1
C2
C3
C4
2
40
290
340
390
440
490
540
590
-0.05
Wavelength (nm)
Figure 6. Overlay spectra of the ligand (L) and the complexes: (C1) Mn(II), (C2) Cu(II),
C3) Zn(II) and (C4) Pt(II)
(
2
3

Figure 7. The molecular structure of Cu(II) complex with atom numbering thermal
ellipsoids 50% probability displacement
Figure 8. Molecular packing of Cu(II) viewed down crystallographic b-axis of the unit cell
with the supramolecular layer sustained by intra molecular C—H···S and O—H···S
interactions.
2
4

Figure 9. The molecular structure of [Pt(L) ] with atom numbering thermal ellipsoids 50%
2
probability displacement
Figure 10. The unit cell packing of [Pt(L) ] with hydrogen atoms omitted for clarity and
2
hydrogen bonds in dash green lines
2
5

2
6

2
7

Declaration of interests
☒
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐
The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests:
2
8

Graphical Abstract
NH2
OH
CHO
OH
1
. reflux 8h, MeoH
+
2
. NaBH , 20h, MeOH:DCM
4
HN
CH3
CH3
H C
CH3
S
3
KS
N
OH
M(II)
H O
S
S
N
M
N
2
S
S
H C
3
M = Mn, Cu, Pt, Zn
OH
HO
2
9