Synthesis, characterization and antitumor activity of Cu(II), Co(II), Zn(II) and Mn(II) complex compounds with aminothiazole acetate derivative

Article abstract of DOI:10.2478/s11532-010-0022-2

This paper presents the synthesis of complex compounds of type [M(L1)₂], where M(II)= Cu (1), Co (2), Zn (3), L1=2-aminothiazole-4-acetate and [Mn(L1)₂(H₂O)] (4) using ethyl 2-(2-aminothiazole-4-yl) acetate (L), and characterization by elemental analysis, magnetic susceptibilities, IR, 1H-NMR, UV-Vis spectroscopy and for [Mn(L1)₂(H₂O)] also by X-ray diffraction. In vitro cytotoxicity studies were performed on human cervix adenocarcinoma, HeLa cells. The antitumor selectivity was assessed using normal human peripheral blood mononuclear cells, PBMC as control. Versita Sp. z o.o.

Full text of DOI:10.2478/s11532-010-0022-2

Cent. Eur. J. Chem. • 8(3) • 2010 • 639–645
DOI: 10.2478/s11532-010-0022-2
Central European Journal of Chemistry
Synthesis, characterization and antitumor
activity of Cu(II), Co(II), Zn(II) and Mn(II) complex
compounds with aminothiazole acetate derivative
Research Article
1
2
1
Maria-Gabriela Alexandru *, Tanja Cirkovic Velickovic , Ioana Jitaru ,
3
4
Sanja Grguric-Sipka , Constantin Draghici
Inorganic Chemistry Department, University “Politehnica” of Bucharest,
1
0
11061 Bucharest, Romania
2Department of Biochemistry, University of Belgrade, Faculty of Chemistry,
1
1000 Belgrade, Serbia
3Faculty of Chemistry, Department of Inorganic Chemistry, University of
Belgrade, 11000 Belgrade, Serbia
4C.D. Nenitescu Center of Organic Chemistry of the Romanian Academy,
7
1141 Bucharest, Romania
Submitted 28 November 2009; Accepted 10 February 2010
Abstract: This paper presents the synthesis of complex compounds of type [M(L1) ], where M(II)= Cu (1), Co (2), Zn (3), L1=
2
2
-aminothiazole-4-acetate and [Mn(L1) (H O)] (4) using ethyl 2-(2-aminothiazole-4-yl) acetate (L), and characterization by
2 2
elemental analysis, magnetic susceptibilities, IR, 1H-NMR, UV-Vis spectroscopy and for [Mn(L1) (H O)] also by X-ray diffraction.
2
2
In vitro cytotoxicity studies were performed on human cervix adenocarcinoma, HeLa cells. The antitumor selectivity was assessed
using normal human peripheral blood mononuclear cells, PBMC as control.
Keywords: Aminothiazole • Cytotoxicity • HeLa • PBMC
©
Versita Sp. z o.o.
netropsin [16]. The antitumor activity of some thiazole
derivatives for example thiazole nucleoside tiazofurin,
distamycin, netropsin, thia-netropsin- with binding
properties to DNA and the thiazole containing antitumor
agent bleomycin was reported. Ethyl 2-substituted-
aminothiazole-4-carboxylate analogs were tested for
their in vitro antitumor activity against human tumor cell
lines. Ethyl 2-[3(diethylamino)propanamido]-thiazole-4-
carboxylate exhibited remarkable activity against RPMI-
1
. Introduction
Naturally occurring and synthetic thiazole derivatives
find applications as antioxidants [1], antibacterial drugs
[
2-4] and fungicidal treatment [5,6]. Anti-inflammatory,
analgesic and antipyretic activities are known for some
thiazolyl and benzothiazolyl derivatives [7-9]. These
compounds are able to block cartilage destruction during
the inflammatory process and thus are a promising class
of anti-inflammatory compounds [10].
The use of 2-aminothiazole derivatives as inhibitors
of human cancer and Alzheimer’s disease was studied
and developed [11-15]. 2-Aminothiazole-5-carboxylates
are an important class of heterocycles in organic
chemistry, especially in the preparation of biologically
and medicinally useful agents such as angiotensin
II antagonists, DNA minor groove binding analogs of
8226 leukemia cell line [17].
Only few studies have been published related to
complex compounds with 2-aminothiazole derivatives
which presented coordination geometry of the metal ion
of tetrahedral type for Zn(II), Co(II) [18,19], Cd(II) [20],
and octahedral type for Co(II) [21]. The complex of Ru(III)
with
ethyl
2-amino-4-phenyl-5-thiazolecarboxylate
showed significant antileukaemic activity on various
human cells [22] and also Keppler-type ruthenium(III)
E-mail: alexandru.gabriela@gmail.com
6
39

Synthesis, characterization and antitumor activity of Cu(II),
Co(II), Zn(II) and Mn(II) complex compounds with
aminothiazole acetate derivative
complexeslike2-aminothiazolium[trans-tetrachlorobis(2-
aminothiazole)ruthenate(III)] exhibit promising antitumor
properties [23].
In this work, we synthesized and characterized
four new complex compounds of Cu(II), Co(II), Zn(II)
and Mn(II), respectively with thiazole derivative L1
2
. Experimental Procedure
All reagents and solvents (Sigma-Aldrich), were of
analytical grade and used without further purification.
Complete medium for cell growth and the reagents for
cytotoxicity studies were purchased from Sigma-Aldrich
(2-aminothiazole-4-acetate) obtained from ethyl 2-(2-
(Taufkirchen, Germany).
aminothiazole-4-yl)acetate, L which hydrolyzed during
Synthesis of L1: NaOH and L, molar ratio 1,5:1 were
the synthesis. Cytotoxicity of L as well as [Cu(L1) ] (1)
2
mixed in water-ethanol as solvent and kept under reflux
for 5 h. The solvent was evaporated and the precipitate
resulted was recrystallized from water.
and [Mn(L1) (H O)] (4) on HeLa cells and on PBMC
2
2
have also been determined.
Synthesis of complex (1): 0.372 g (2 mmoles) of L
dissolved in EtOH were added to an aqueous solution
of 0.17 g (1 mmole) CuCl •2H O. The solution was kept
2
2
0
under stirring at 50 C for 2 h. The brown precipitate was
filtered off, washed with EtOH and dried under vacuum.
Yield: 55%. Anal Found (%): Cu, 16.52; C, 32.10; H,
2
.60; N, 15.06. Calculated for CuC H N O S (%): Cu,
10 10 4 4 2
-1
16.82; C, 31.78; H, 2.65; N, 14.83. σ (µS cm ): 34, non-
electrolyte.
Synthesis of complex (2) and complex (3): The
complexes were prepared as described for complex (1),
using 0.372 g L and 0.238, and 0.24 g of CoCl •6H O
2
2
and ZnCl , respectively.
2
The complex (2) was obtained as a light pink solid.
Yield: 60%. Anal Found (%): Co, 15.14; C, 32.31; H,
3
.02; N, 15.12. Calculated for CoC H N O S (%): Co,
10 10 4 4 2
-1
15.81; C, 32.17; H, 2.68; N, 15.01. σ (µS cm ): 42, non-
electrolyte.
The complex (3) was isolated as a white solid.
Yield: 56%. Anal Found (%): Zn, 17.06; C, 31.50; H,
Figure 1. X-ray structure of [Mn(L1) (H O)]
2
2
Figure 2. UV-VIS spectra for L, (1), (2), (3) and (4)
640

M. G. Alexandru et al.
-
1
2
.87; N, 14.23. Calculated for ZnC H N O S (%): Zn, 14.47. σ (µS cm ): 46, non-electrolyte.
10 10 4 4 2
-1
17.15; C, 31.66; H, 2.64; N, 14.77. σ (µS cm ): 28, non-
The elemental analysis was performed on a Perkin-
Elmer Series II CHNS/ O Analyser 2400. H-NMR
1
electrolyte.
Synthesis of complex (4): 0.372 g (2 mmoles) of L spectra were recorded on a Gemini 300 BB operating
dissolved in EtOH was added to an aqueous solution of at 300 MHz in DMSO-d6 using TMS as internal
0
.24 g (1 mmole) of Mn(CH COO) •2H O. The solution standard. UV-Vis reflectance spectra were recorded
3 2 2
0
was kept under stirring at 50 C for 2 h. The light on Jasco V-560 spectrophotometer and IR spectra on
brown precipitate was filtered off, washed with EtOH a FT-IR Bruker VERTEX 70 equipped with a diamond
and dried under vacuum. Yield: 53%. Anal Found (%): ATR. Electrical molar conductivities were measured
Mn, 14.15; C, 30.93; H, 3.41; N, 14.65. Calculated for in N,N-dimethylformamide (10 M solution) on OK-
MnC H N O S (%): Mn, 14.21; C, 31.01; H, 3.10; N,
-3
0
114 RADELKIS Conductometer at 25 C. Magnetic
measurements were carried out with a Faraday balance
at room temperature using Mohr salt as standard. X-ray
diffraction measurements were performed on a STOE-
IPDS II diffractometer. The structures were solved
10
12
4
5
2
(SHELXS-97) by direct methods and refined (SHELXL-
97) by full matrix least-square procedures on F2 [25].
Crystallographic data for the structural analysis have
been deposited with the Cambridge Crystallographic
Data Centre, CCDC No. 755831.
2
.1. Cytotoxicity assays on HeLa cells
(HeLa cells (human cervical carcinoma cell line) were
cultured in triplicate in a 96-well plate at 37°C under 5%
CO in 100 μL of growth medium, RPMI 1640 (Sigma-
Aldrich, Taufkirchen, Germany) supplemented with
2
Figure 3. 1H-NMR spectra of L, [Zn(L1) ] and L1
2
1
0 % fetal calf serum (FCS) (Sigma-Aldrich), 2 mM
Table 1. Crystal data and structure refinement for [Mn(L1) (H O)]
2
2
-1
glutamine (Sigma-Aldrich), 100 IU mL penicillin and
Formula weight
Temperature
386.31
297(2) K
-1
100 IU mL streptomycin (Sigma-Aldrich). The Hela
cells were seeded as 2000 cells/well and after 24 h,
serial dilutions of the compounds are added. The ligand
and the complex compounds (1) and (4) were dissolved
in DMSO and the solutions were diluted by nutrient
medium, RPMI 1640, containing 10% FCS.
After allowing cells to adhere to the plate for 24 h,
the medium was removed and the compounds were
added to the wells at different concentrations in the
range 0,01-100 μM for the ligand and 0,001-10 μM
for compound (1) and 0,5-500 μM for compound (4).
For the compounds to take effect freshly prepared
compounds solutions were incubated for 24 h at 37°C
under 5% CO . Cytotoxicity was evaluated using MTT
assay (Sigma-Aldrich). A solution of MTT 5mg ml in
phosphate buffered saline (PBS) was added to each well
and mixed with the suspensions followed by incubation
to allow the metabolization of MTT. After the incubation,
Wavelength
Crystal system, space group
0.71073 Å
Monoclinic, C2/c
Unit cell dimensions
a = 12.1567(17) Å alpha = 90 deg.
b = 9.4915(13) Åbeta = 94.556(2)deg.
c = 12.7295(18) Å gamma = 90 deg.
3
Volume
1464.2(4) Å
-3
Z, Calculated density
Absorption coefficient
F(000)
4, 1.752 g cm
1.215 mm-1
784
Crystal size
Theta range for data collection
Limiting indices
0.52×0.16×0.15 mm
2.73 to 24.99 deg.
-14<=h<=14, -11<=k<=11, -15<=l<=15
6785 / 1285 [R(int) = 0.0471]
99.9%
Semi-empirical from equivalents
0.8388 and 0.5707
Full-matrix least-squares on F
1285 / 2 / 110
1.272
Reflections collected / unique
Completeness to theta = 24.99
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I>2sigma(I)]
R indices (all data)
2
2
-1
R1 = 0.0630, wR2 = 0.1135
R1 = 0.0695, wR2 = 0.1163
Table 2. Hydrogen bonds for (4) (Åand deg.)
D–H...
A
d(D–H)
d(H...A)
d(D...A)
∠∠(DHA
Symmetry transformations
.
..
O(3)–H(3) O(2)
0.82
1.88
2.654 (5)
2.849 (6)
2.916(6)
157
½+x, ½+y, z
.
..
N(2)–H(10) O(2)
0.85 (4)
0.85 (5)
2.02 (4)
2.13 (4)
168 (4)
153 (6)
3/2-x, 1/2-y,1-z
.
..
N(2)–H(11) O(1)
6
41

Synthesis, characterization and antitumor activity of Cu(II),
Co(II), Zn(II) and Mn(II) complex compounds with
aminothiazole acetate derivative
the medium was removed and the formazan (MTT
metabolic product) resuspended and thoroughly mixed
in 100 μL DMSO. The optical densities were read at
3
. Results and Discussion
The complex compound was synthesized from aqueous
solutions of metal salts MCl •xH O, where M(II)= Cu,
540 nm and the background substracted at 670 nm using
2
2
an Elisa microreader. The measure of the cytotoxicity of
the compounds both in PHA/PBMC and HeLa cells is an
IC50 value (calculated as the concentration of the tested
compound needed to reduce cell viability for 50% when
compared to the control cells).
Co, Zn, x= 2, 6, 0 and Mn(CH COO) •4H O which was
mixed with methanol solutions of L (1: 2, metal: ligand
ratio).
Ethyl 2-(2-aminothiazole-4-yl)acetate, L, hydrolyzed
in the aqueous solutions and in the presence of metal
ions, conditions in which ligand L1 was generated. Thus
thecomplexcompoundscontainL1thatwassynthesized
and characterized independently. The hydrolysis of the
ester group from L was recently noticed by Zhang et al.
3
2
2
2
.2. Preparation and treatment of PBMC
Peripheral blood mononuclear cells (PBMCs) were
isolated from a healthy donor by Ficoll (Amersham
[
24].
Biosciences) density gradient centrifugation. PBMCs
5
(
2×10 ) were cultured in duplicates in 96-well Nunclone
3
.1. X-ray crystallography
plates in 200 µL of RPMI 1640 medium supplemented
with 10% fetal calf serum (FCS) (Sigma-Aldrich), 2 mM
glutamine (Sigma-Aldrich), 50 µM β-mercaptoethanol
X-ray structure was determined for complex compound
-
1
-1
(4), [Mn(L1) (H O)], (Fig. 1) which crystallizes in the
(
Sigma-Aldrich), 25 µg mL gentamicin, 100 IU mL
2
2
-1
centrosymmetric space group C2/c with a R value of
0.06. Crystal data and structure refinement details
are given in Table 1. Mn atom has distorted square
pyramidal coordination geometry water molecule in
axial position and two ligand molecules in equatorial
plane coordinating through N1, N1a, O1, O1a atoms.
Interatomic distances are Mn(1)–N(1) 2.175(4), Mn(1)–
О(1) 2.106(3) and Mn(1)-O(3) 2.081(5) Å. The packing
of the structure is based on intermolecular hydrogen
bonding between the unit cells. Hydrogen bond lengths
and angles are presented in Table 2. Also, the distance
penicillin and 100 IU mL streptomycin (Sigma-Aldrich)
at 37 C and 5% CO in a humidified atmosphere. Cells
o
2
were stimulated with a mitogen, phytohaemaglutinin
(
PHA) (0.5 µg/mL). The final concentrations of the
compounds in cell suspension ranged between 0,001-
00 μM (L) 0,0001-10 μM (1), 0,5-500 μM for (4). Cell
1
survival was determined by MTT test [26-28].
PHA/PBMC cultures with serial dilutions of the
compounds were incubated for 76 h in a humidified
o
atmosphere at 37 C, before addition of the MTT reagent.
The MTT metabolic product, formazan, solubilizes in
DMSO and absorbs at 540 nm. Optical density was read
at 540 nm and background subtracted at 670 nm using
an Elisa microplate reader.
(3,566(3) Å) between the mean planes suggests the
existence of π-π stacking interactions between the
neighboring thiazole rings.
Table 3. FTIR bands and assignments
L
L1
(1)
(2)
(3)
(4)
Assignment
3
3
2
2
1
277
115
990
903
711
3256
3079
3294
3096
3291
3095
3289
3094
3289
3094
νsimNH2
νsimCH (thiazole)
νasimCH3
νsimCH3
νC=O
νasimCOO-
νC=N
δthiazole
νsimCOO-
δC-H
1591
1574
1634
1511
1398
1358
1289
1127
940
1578
1632
1511
1410
1364
1290
1129
943
1579
1634
1514
1411
1365
1288
1130
940
1578
1634
1514
1399
1365
1288
1130
941
1
1
621
521
1619
1515
1391
1312
1245
1126
1323
1291
1119
973
νC-O
νC-N
νS-C
9
77
4
31
434
435
436
νM-N, M (II)= Cu, Co, Zn, Mn
642

M. G. Alexandru et al.
Figure 4. Representative graphs showing survival of tumor cells HeLa grown for 48 h in the presence of increasing concentrations of the complexes
(1) and (4) determined by MTT test
Table 4. Magnetic moments of the compounds
Compound
Magnetic susceptibility
Magnetic moment, μB
Theoretical magnetic moment, μB
0 *∠ , cm3 g-1
6
1
Xg
(1)
(2)
(3)
(4)
2,6
16
<0
32
1,92
4,39
≈0
1,73
3,87
0
6,42
5,92
3
.2. UV-Vis spectroscopy
-
1
group present in the IR spectrum of L1 at 1591 cm ,
UV-Vis spectra of the solid powders of L and complex
compounds (1), (2), (3), (4) are shown in Fig. 2. UV-
Vis spectrum of compound (1) shows a wide LMCT
type band at 470 nm. The bands at 450 nm and
-1
1
391 cm respectively, and in the IR spectra of the
complex compounds at 1574, 1398 cm (1), 1578,
410 cm (2), 1579, 1411 cm (3) and 1578, 1399 cm
4) demonstrates the hydrolysis of L1. A significant
difference between IR spectra of the ligand L1 and the
coordination compounds is the position of C=N vibration
band which is shifted from 1619 cm (L1) to higher
frequencies 1634 cm (1), 1632 cm (2), 1634 cm (3),
634 cm (4), due to the coordination of the endo-N
-1
-1
-1
-1
1
(
5
50 nm of compound (2) can be assigned to 4T1g
4
T (P) (ν2) and 4T1g ← A (ν3) d-d transitions,
4
←
1
g
2
g
characteristic for Co(II) in tetrahedral symmetry.
The UV-Vis spectrum for compound (4) contains a
large band at 370 nm assigned to LMCT process.
-1
-1
-1
-1
-1
1
atom to the metal ions.
3
.3. IR spectroscopy
1
3
.4. H- NMR spectroscopy
IR spectra were recorded for the ligand and the
complexes in order to determine the coordination
manner. The assignments of the IR bands are presented
in Table 3. Disappearance of vibration band C=O
Aliphatic proton signals from the ester group are
shown only in the H-NMR spectrum of L as opposed
to H-NMR spectra of L1 and (3) due to ethyl 2-(2-
1
1
(
ester group) from the IR spectra of L1 and of complex
aminothiazole-4-yl)acetate, L, hydrolysis. Another
important difference between H-NMR spectra of L, L1
and the complex compound is the shift of amino protons
-1
compounds (1)- (4) which appeared at 1711 cm in the
IR spectrum of L, confirm the hydrolysis of L. Also the
asymmetric and symmetric vibration bands of carboxyl
1
6
43

Synthesis, characterization and antitumor activity of Cu(II),
Co(II), Zn(II) and Mn(II) complex compounds with
aminothiazole acetate derivative
Table 5. EC50 values for L, (1) and (4)
The values obtained for compounds (1) and (4) in the
assayperformedonhumanPBMCshowlesstoxiceffects
than those obtained in human cervix adenocarcinoma
cell lines. The selectivity in cytotoxic effect on HeLa and
PBMC is especially pronounced for complex compound
EC50 (μM)
L
[Cu(L1)2]
[Mn(H O)(L1) ]
2
2
HeLa
PBMC
84
>100
0,67
22
9,85
51
signals from 7,21 ppm (L), 6,90 ppm (L1) to 8,44 ppm
3). Also the signal of aromatic proton from the thiazole
ring from L1 suffers a small displacement from 6,19 ppm
(
4) that exhibited high selectivity on HeLa cells and a
(
very low EC50 value.
(L1) to 6,28 ppm for the complex compound [Zn(L1)2],
Fig. 3.
4
. Conclusions
Four new coordination compounds of type [M(L1)2],
3
.5. Magnetic measurements
where M(II)= Cu(II), Co(II), Zn(II) and [Mn(L1) (H O)]
2
2
were synthesized starting from ethyl 2-(2-aminothiazole-
-yl)acetate which hydrolyzed leading to coordinated
ligand L1, 2-aminothiazole-4-acetate. The complexes
were characterized by UV-Vis, IR, NMR spectroscopy
and magnetic susceptibilities. The structure of complex
The values of the experimental magnetic moments are
very close to theoretical values (Table 4). The values
of the magnetic moments of the (2) and (4) support the
high spin tetrahedral distorted configurations which are
in accordance with the appearance of UV-Vis spectra.
Compound (3) displays diamagnetic behaviour.
4
(
4) was solved by X-ray structure analysis. The cytotoxic
activity of L and of complex compounds (1) and (4) on
HeLa and PBMC was evaluated. The results of the
cytotoxicity tests indicate that L exhibits high viability on
PBMC and HeLa cells, but when involved in coordination
bonding with 3d metals the cytotoxicity increases
3
.6.Viability assessments
The EC50 values were determined by extrapolation from consistently. Coordination compounds (1) and (4)
cell viability curves. Fig. 4 contains two representative exhibit promising antitumor activity against cancerous
graphs for cytotoxic activity of (1) and (4) on HeLa cella. cells (HeLa) and moderate to low toxicity on PBMC.
The EC50 values are presented in Table 5.
The viability increases along with the
decrease
Acknowledgement
of the concentration of the compounds. The ligand (L)
does not show high cytotoxicity in any of the cultures
tested. The presence of the metal ions in coordination
compounds (1) and (4) greatly increased its cytotoxicity
in comparison with the ligand, especially on HeLa cells.
The authors acknowledge the support of ID 1043
project, CNCSIS, Romania and grant number 142020
of the Republic of Serbia.
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