Transition metal complexes of a new 15-membered [N5] penta-azamacrocyclic ligand with their spectral and anticancer studies

Article abstract of DOI:10.1016/j.saa.2014.05.018

Novel penta-azamacrocyclic 15-membered [N₅] ligand [L] i.e. 1,5,8,12-tetetraaza-3,4: 9,10-dibenzo-6-ethyl-7-methyl-1,12-(2,6-pyrido) cyclopentadecan-5,7 diene-2,11-dione and its transition metal complexes with Co(II), Ni(II), Cu(II), Ru(III) and Pd(II) have been synthesized and structurally characterized by elemental analysis, spectral, thermal as well as magnetic and molar conductivity measurements. On basis of IR, MS, UV-Vis ¹H NMR and EPR spectral studies an octahedral geometry has been proposed for all complexes except Co(II), Cu(II) nitrate complexes and Pd(II) chloride complex that adopt tetrahedral, square pyramidal and square planar geometries, respectively. The antitumor activity of the synthesized ligand and some complexes against human breast cancer cell lines (MCF-7) and human hepatocarcinoma cell lines (HepG2) has been studied. The complexes (IC ₅₀ = 2.04-9.7, 2.5-3.7 μg/mL) showed potent antitumor activity comparable with their ligand (IC₅₀ = 11.7, 3.45 μg/mL) against the above mentioned cell lines, respectively. The results evidently show that the activity of the ligand becomes more pronounced and significant when coordinated to the metal ion.

Full text of DOI:10.1016/j.saa.2014.05.018

Accepted Manuscript
Transition metal complexes of a new 15-membered [N5] penta-azamacrocyclic
ligand with their spectral and anticancer studies
Hanaa A. El-Boraey, Azza A. Serag El-Din
PII:
S1386-1425(14)00789-6
http://dx.doi.org/10.1016/j.saa.2014.05.018
SAA 12180
DOI:
Reference:
Spectrochimica Acta Part A: Molecular and Biomo-
lecular Spectroscopy
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Revised Date:
Accepted Date:
5 March 2014
1 May 2014
9 May 2014
Please cite this article as: H.A. El-Boraey, A.A. Serag El-Din, Transition metal complexes of a new 15-membered
[N5] penta-azamacrocyclic ligand with their spectral and anticancer studies, Spectrochimica Acta Part A: Molecular
and Biomolecular Spectroscopy (2014), doi: http://dx.doi.org/10.1016/j.saa.2014.05.018
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Transition metal complexes of a new 15-membered [N5] penta-azamacrocyclic
ligand with their spectral and anticancer studies
Hanaa A. El-Boraey∗, Azza A. Serag El-Din
Department of chemistry, Faculty of science, El-Menoufia University, Shebin El- Kom, Egypt
ABSTRACT
Novel penta-azamacrocyclic 15-membered [N5] ligand [L] i.e. 1,5,8,12- tetetraaza -
3,4 : 9,10-dibenzo-6- ethyl-7- methyl-1,12-(2,6-pyrido)cyclopentadecan-5,7 diene-
2,11-dione and its transition metal complexes with Co(II), Ni(II), Cu(II), Ru(III) and
Pd(II) have been synthesized and structurally characterized by elemental analysis,
spectral, thermal as well as magnetic and molar conductivity measurements. On basis
1
of IR, MS, UV-Vis H NMR and EPR spectral studies an octahedral geometry has
been proposed for all complexes except Co(II), Cu(II) nitrate complexes and Pd(II)
chloride complex that adopt tetrahedral, square pyramidal and square planar
geometries, respectively. The antitumor activity of the synthesized ligand and some
complexes against human breast cancer cell lines (MCF-7) and human
hepatocarcinoma cell lines (HepG2) has been studied. The complexes (IC50=2.04-9.7,
2.5-3.7 µg/mL) showed potent antitumor activity comparable with their ligand (IC50 =
11.7, 3.45 µg/mL) against the above mentioned cell lines, respectively. The results
evidently show that the activity of the ligand becomes more pronounced and
significant when coordinated to the metal ion.
Keywords: penta-azamacrocyclic, macrocyclic metal complexes, Spectral studies,
antitumor activity, IC50
Introduction
Chemistry of macrocycles and their metal complexes has attracted much attention and
has become a growing class of research [1-9], largely as a result of their remarkable
applications in biology, supramolecular chemistry and new materials [2-9], etc. To
some extent the interest in macrocyclic complexes especially those with polydentate
ligands stems from the chemical properties that the macrocyclic ligands bring to the
complexes as well as the variety of geometrical forms available and the possible
encapsulation of the metal ion [10,11]. Complexes with aza-macrocyclic ligands have
∗Corresponding author. Tel.: +2- 0111-7532777; Fax: +20 48 2235689.
E-mail address: helboraey@yahoomail.com (Hanaa A.El-Boraey).
1

remained a focus of scientific attention [12-15]. Much attention has been paid to
macrocyclic compounds containing amide groups [4,6,12,16]. These compounds not
only can act as hydrogen bonding host molecules but also can form macrocyclic
rotors [17]. The formation of macrocyclic complexes depends significantly on the
dimension of internal cavity, rigidity of macrocycles, nature of its donor atoms, the
selectivity of metal ions and the complexing properties of the anion involved in
coordination, for transition metal ions, features such as the nature and magnitude of
crystal-field effects play also an important role [18-20]. Moreover, macrocyclic Schiff
bases have been widely studied due to their selective chelation to certain metal ions
depending on the number, type and position of their donor atoms, the ionic radius of
metal ion and coordinating properties of counter ions [21]. In view of the interest and
importance of nitrogen macrocycles, we have reported the synthesis, spectroscopic
characterization and anticancer activity of Co(II), Ni(II), Cu(II), Ru(III), Pd(II)
complexes with new penta-azamacrocyclic 15-membered [N5] ligand i.e. 1,5,8,12-
tetraaza -3,4 :9,10-dibenzo-6- ethyl-7- methyl-1,12-(2,6-pyrido)cyclopentadecan-5,7
diene- 2,11-dione. These complexes have been characterized with the help of various
physicochemical techniques. Furthermore, the in vitro antitumor activity against
human breast cancer cell lines (MCF-7) and human hepatocarcinoma cell lines
(HepG2) has been studied.
Experimental
Materials and methods
All the chemicals used were of AnalaR grade and procured from Sigma–
Aldrich and Fluka. Metal salts (E. Merck) were commercially available as
pure samples and solvents were used as received.
Synthesis of start material
The starting material (A) has been synthesized as previously reported for similar
compounds [22, 23]. A mixture of 1H-benzo [d] [1,3]oxazine-2,4-dione (2.0 mmol, 2
gm) with 2,6 diaminopyridine (1.0 mmol, 0.66 gm) in distilled water was stirred at 60
oC for about 3 h, heating on water bath was continued till the effervescence of CO2
gas ceased. The reaction mixture was allowed to stand over night. Light brown
crystals were filtered off and washed several times with cold distilled water.
Recrystallization from ethanol gave 2-amino-N-{2-[(2-amino-benzoylamino)
pyridine]-benzamide (A) {Color: off white, Yield: 50 %, m.p. = 95 oC. Analysis Cal.
(Found) for C19H17N5O2.2H2O (MW: 383) C, 59.53 (59.52); H, 5.48 (5.34); N, 18.27
2

(18.53) %. IR (KBr, υ cm-1): 3293 υ(NH2); 1664 υ(C=O);1617 υ(C=N); 1509 [υ(C-N)
+δ(N-H)] .¹H NMR (DMSO-d6, δ, ppm) δ = 4.00 (H2O), δ = 6.54-8.08 (py, Ar, H), δ =
5.74-5.79 (Ar–NH2), δ = 13.23 (NH- amide). MS (EI+, m/z): Calc. for C19H17N5O2 (M
= 347 Found: 346 [M-H] +.
Synthesis of ligand (L)
The (N5) ligand has been synthesized by refluxing ethanolic (20 ml) of (A) (1.0 mmol,
1gm) with 2,3 pentandione (1.0 mmol, 0.29 gm) in the same solvent for 12 h, the
brown precipitate obtained was filtered and washed several times with cold ethanol
and dried over P4O10 (m.p. 230 oC) (Scheme 1).
General procedure for synthesis of the macrocyclic complexes
All the complexes were prepared using the following general procedure. To
a
suspension of the macrocyclic ligand (L) (1.0 mmol, 0.5 gm) in ethanol (20 ml), a
solution of hydrated metal salt (chloride, perchlorate, nitrate, acetate or bromide) in
20 ml ethanol was added gradually, in molar ratio 1:1 (L: M). The reaction mixture
was heated under reflux for 10 h. The formed solid product was removed by filtration
washed several times with cold ethanol and vacuuo dried over P4O10.
Physical measurements
The elemental analysis (C,H,N) were performed at Microanalytical Center, Cairo
University, Giza, Egypt using CHNS-932 (LECO) Vario Elemental Analyzer. Metals
and halide analyses were estimated using standard methods. The FTIR measurements
were performed (4000-400 cm-1) in KBr discs using Nenexeus-Nicolidite-640-MSA
FT-IR, Thermo-Electronics Co. The UV-visible absorption spectra were measured in
Nujol mull using 4802 UV/vis double beam spectrophotometer. The ¹H NMR
spectrum was recorded in DMSO-d6 using Varian Gemini 200 NMR
spectrophotometer at 300 MHz. The EPR spectra were recorded using a Varian E-
109C model X-band spectrometer. Molar conductivities were measured in DMSO
solution (10-3 M) using a CON 6000 conductivity meter. Magnetic susceptibilities of
the complexes were measured at room temperature by the modified Gouy method
using magnetic susceptibility Johnson Matthey Balance. The effective magnetic
½
moments were calculated using the relation µeff = 2.828 (χmT) B.M., where χm is the
molar susceptibility corrected for diamagnetism of all atoms in the compounds.
Thermal analysis (TGA / DTG) was obtained out by using a Shimadzu DTA / TG -50
o
Thermal Analyzer with heating rate of 10 C/ min in nitrogen atmosphere with a
3

o
following rate 20 ml /min in the temperature range 25-800 C using platinum
crucibles. Electrospray mass spectra (ESI) for the complexes were performed at the
National Research Center, Egypt by the Thermo Electron Corporation. The electron
impact (EI) mass spectrum for the ligand was run on Shimadzu-QP 2010 plus Mass
Spectrometer, Microanalytical Laboratory, Faculty of Science, Cairo University,
Egypt
.
Biological tests
The cytotoxicity of the compounds was tested at the National Cancer
Institute, Cairo University Egypt by SRB assay using the method of Skehan
et al. [24]. Cells were plated in 96-multiwell plate (104 cells/well) for 24 h
before treatment with the compounds to allow attachment of cell to the wall
of the plate. Different concentration of the compound under test (0, 2.5, 5, 10,
20 µg/mL) were added to the cell monolayer triplicate wells were prepared
for each individual dose.
Monolayer cells were incubated with the
o
compounds for 48 h at 37 C and in atmosphere of 5% CO2. After 48 h, cells
were fixed, washed and stained with Sulfo-Rhoda-mine-B stain. Excess stain
was washed with acetic acid and attached stain was recovered with Tris
EDTA buffer. Color intensity was measured in an ELISA reader. The relation
between surviving fraction and drug concentration is plotted to get the
survival curve of each tumor cell line after the specified compound.
Results and discussion
Physical properties
The condensation of 2-amino-N-{2-[(2-amino-benzoylamino) pyridine] - benzamide
(A) with 2, 3 pentanedione afford the macrocyclic ligand (L) (Scheme1). The reaction
of (L) with different transition metal salts resulted in the formation of mononuclear
macrocyclic complexes; the purity of the ligand and complexes has been checked by
TLC. All the metals complexes are colored solids, stable towards air. Analytical data
of the complexes (Table1) suggest that the metal to ligand ratio in all the complexes is
1M: 1L (Scheme 2). All complexes are slightly soluble in alcohols, insoluble in most
common organic solvents, but soluble in DMF/DMSO. Crystals of these complexes
could not be grown therefore X-ray crystal determination is not possible. The molar
conductivity of complexes (2-5,8-10) in DMSO solutions (10-3M) at room
temperature indicates that they are non-electrolytes. Complexes (6,7) show molar
4

conductivity value (70, 68 Ω‾¹ cm2 mol-1) indicating that they are (1:1) electrolyte.
However, complexes (1,11) show molar conductivity value (100, 87 Ω‾¹ cm2 mol-1)
indicating their (1:2) electrolytic nature [8,25].
¹H NMR and mass spectral studies of ligand
The ¹H NMR spectrum of the ligand (L) was recorded in DMSO-d6 solution. The
spectrum do not show any signal assignable to primary amino protons (at δ= 5.7
ppm). This is strong evidence that proposed macrocyclic is formed by condensation
reaction. The spectrum displays a singlet at ca. δ 1.05 ppm (s, 3H, N=C–CH3)
corresponding to the protons of one methyl group, another signal at ca. δ 2.14-2.46
ppm (m, 3H, – CH2– CH3) due to three protons of the second methyl group, signal at
ca. δ 3.39 ppm (m, 2H, N=C–CH2) due to two protons of one methylene group, signal
at δ (6.50-8.61 ppm) assigned to aromatic and pyridine rings and signal at ca. δ 13.17
ppm (m, 2H, -NH-CO-) assigned to amide proton. Thus, the ¹H NMR result supports
the assigned geometry. The electron impact (EI) mass spectrum of the free ligand
(Fig. 1S) confirms the proposed formula by showing a peak at 412 amu (M+1)
corresponding to the macrocyclic moiety (C24H21N5O2, atomic mass m/z =411). The
series of peaks in the range m/z = 65[C4H3N]+, 77[C5H3N]+, 92[C5H4N2]+, 120
[C6H4N2O]+, 255 [C13H9N4O2+2H]+ may be assigned to various fragments.
O
O
N
C
NH
HN
C
O
CH3
reflux-12 hr
C
C
NH2
H2N
+
Ethanol-70°C
O
C2H5
2-amino-N-{2-[(2-amino-benzoylamino) pyridine]- benzamide
2,3 pentanedione
(A)
O
O
N
C
NH
N
HN
N
C
+
2H2O
C
C
H3C
C2H5
(L)
Scheme1.Synthetic route for the preparation of the macrocyclic ligand.
FT-IR
5

Fundamental IR spectral bands for the ligand and its complexes are given in Table 2.
The IR spectrum of the free ligand is characterized mainly by the strong bands at
3206, 1644, 1618, 1499, 1289, and 754 cm-1 are attributed to the stretching
frequencies of secondary amide υ(NH), amide-I [υ(C=O)], azomethine υ(C=N) group,
amide-II [υ(C-N)+δ(N-H)], amide-III δ(N-H) and amide-IV [φ(C=O)] wagging
vibrations, respectively [16, 26-28]. This supports the macrocyclic nature of the
ligand. The alkyl groups show characteristic stretching absorption bands in the region
2952- 2925 cm-1, deformation band at 1432, 1367 cm-1 and rocking at 695 cm-1,
respectively. The broad band at 3347 cm-1 is assigned to the stretching frequency
υ(OH) of water molecules, which is also confirmed from elemental and thermal
analysis. On complexation, the lowering of υ(C=N) frequency values in all complexes
(1611-1583 cm-1) indicating the coordination of azomethine nitrogen to the metal
center [26,27]. This is consistence with the presence of a new band at (463-400 cm-1)
assignable to υ (M-N) vibration [2,29]. The binding of secondary amide nitrogen in
complexes (3-8,11) is indicated by a shift of amide-I vibration from 1644 cm-1 in the
free ligand to (1626-1607 cm-1) in the complexes [16]. Moreover, the shift to lower or
higher frequencies at (3386-3174 cm-1) of υ(NH) of secondary amide group also
confirms the involvement of amide nitrogen in metal coordination [16]. In case of
complexes (1,2,9,10), the amide-I and υ(NH) of secondary amide group appears
almost at nearly the same frequency, hence the mode of coordination is through
(C=N) of azomethine only. Aquo and hydroxo complexes exhibit a strong as well as
broad band at (3444 - 3317 cm-1) due to υ(OH) vibration. This observation has been
further confirmed by the appearance of new medium intensity band in the (625-529
cm-1) region, assignable to υ(M-O) [27,14]. The IR spectra of the complexes clearly
demonstrate that the amide-II and amide-III are altered compare to the ligand due to
complex formation. The strong band corresponding to the pyridine ring vibration, do
not exhibit a shift in the all complexes [14]. Further, the complexes show the
additional band due to anions (Table 2). Complexes (2,7) show IR bands at (1412-
1380 (ν5), 1301-1269 (ν1), 1046-1041(ν2) cm-1), (ν5−ν1) stretching vibration are
separated by 111 cm-1 suggesting unicoordinated nitrate ion [16,30]. Complex (7) also
shows IR bands at (1380, 708 cm-1) characterizing the ionic nitrate ion; the presence
of ionic nitrate is also supported by conductance measurements (Table 1) [16,31,32].
The acetato complexes display bands at (1587-1583) and (1379-1376 cm-1) due to
unidentate coordination of acetate ions [12,33,34]. It is worth to mention that, the
6

region of νasym(COO–) overlapped with ν(C=N) [35]. The presence of uncoordinated
perchlorate anion in complex (6) is inferred from the bands around 1087 and 630 cm-1
[15,36,37]. Therefore, and according to the IR spectra, it is concluded that the ligand
behaves as neutral quatridentate one in complexes (3-8,11) with the lone electron
pairs of two amide nitrogen atoms and the lone electron pairs of two azomethine
groups. While in complexes (1,2,9,10) the ligand behaves as neutral bidentate one
with the lone electron pairs of azomethine groups.
Mass spectra of complexes
Mass spectra provided additional structural information about the analyzed species.
ESI-MS of the [Cu(L)Cl2].5½H2O complex (5) (Fig.1) and [Ru(L)(H2O)Cl3].5H2O
complex (10) show a molecular ions peak at m/z 642, 725 amu (calculated M=644.5,
726.5 amu, respectively) which coincide with their formulae weight. The spectra of
the complexes also show structurally important fragment ion at m/z 52 [C4H4]+, 67
[C5H6+H]+, 76 [C6H4]+, 119 [C7H5NO]+, 238 [M-(C11H23N2O5.5+CuCl2+H)]+, 370.5
[M-(C11H23N2O5.5+3H)]+, 516.5 [M-C2H16O5.5]+ for complex (5) and fragment ion at
m/z 52 [C4H4]+, 76 [C6H4]+, 119 [C7H5NO]+, 196 [C12H8N2O]+, 239 [M-
(C11H24N2O6+RuCl3)]+, 315 [M-(C5H20N2O6+RuCl3)]+, 502 [M-C5H19NO6Cl]+ for
complex (10). The observed data confirmed the proposed formulae for the complexes.
Electronic spectra and magnetic measurements
Nujol mull electronic absorption spectral data (λ max, nm), room temperature
effective magnetic moment values (µeff B.M.) are given in Table 3. The ligand and its
complexes show the high energy bands in the range 250-224, 326-270 and 393-347
nm due to π→π* transitions within the aromatic and pyridine rings, n→π* transition of
chromophore moieties present in the ligand, and CT transitions, respectively.
Cobalt (II) complexes
The electronic spectrum of the Co(II) complex (1) exhibits three d-d transition bands
4
at 700, 640 and 450 nm, respectively. These bands can be assigned to T1g (F)→4T2g
(F)(v1); 4T1g(F)→4E2g(F)(v2); 4T1g(F) →4T2g (P) (v3) transition, respectively suggesting
an octahedral geometry around Co(II) ion [38,39]. The electronic spectrum of Co(II)
4
complex (2) displays only one band in the visible region at 648 nm due to A2(F)
→4T1 (P) transition, which indicates tetrahedral geometry [40,41]. The value of the
room temperature magnetic moment of complex (1) is 5.12 B.M., is well within the
7

range usually observed for high-spin octahedral Co(II) (4.8-5.6 B.M.) with 4T1g (F)
ground state. The magnetic moment of complex (2) is 4.51 B.M., is well within the
reported range (4.2–4.7 B.M.) for tetrahedral complexes of cobalt(II) [41,42].
Nickel complexes
The electronic absorption spectra of Ni(II) complexes (3,4) display three d-d
transition bands at 633-632, 535-495, 427-420 nm, are attributable to the
3
3A2g→3T2g(v1);3A2g→3T1g(v2); A2g→3T1g (P)(v3) transitions, respectively. These
observations together with the magnetic moment value of the nickel(II) complexes
(Table 3) give adequate support to an octahedral environment around the Ni(II) ions
[42-44].
Copper (II) complexes
The electronic absorption spectra of all Cu(II) complexes (except 7) show three d-d
transition bands at 644 - 632, 532-500 and 476-400 nm assigned to 2B1g→ 2A1g (v1);
2
2B1g→2B2g (v2); B1g→2Eg (v3) transitions, respectively. Suggesting tetragonally
distorted octahedral geometry around Cu(II) ions [45,46]. Complex (7) shows bands
around 770, 600 nm which are indicative of tetragonally distorted square pyramidal
2
2
2
geometry. These bands may be assigned to transitions B1g→ A1g; B1g→2Eg [47].
Their room temperature magnetic moment is in the range 2.49-1.80 BM,
corresponding to one unpaired electron. These values clearly support the monomeric
nature of the complexes and also show the absence of metal-metal interaction.
Ruthenium(III) complex
Electronic spectra of Ru(III) complex (10) in Nujol mulls shows moderately intense
band in the visible region at 632 nm due to d–d transition and an absorption band at
490 nm probably due to MLCT transition [48,49]. Its magnetic moment at room
temperature is 2.21 B.M., corresponding to one unpaired electron.
Palladium(II) complex.
The electronic spectrum of Pd(II) complex (11) displays three d-d transition bands at
640, 520 and 420 nm which may be assigned to 1A1g→1A2g, 1A1g→1B1g and 1A1g→1Eg
transitions, respectively indicating square-planar geometry around the Pd(II) ion
[16,50]. The magnetic susceptibility studies show that Pd(II) complex (11) is
diamagnetic with spin-paired d8 system. Electrolytic nature of the complex indicates
that, the chloride ion does not take part in coordination.
8

EPR spectroscopic studies
The solid state EPR spectra of the copper(II) complexes (5-9) were recorded at
room temperature on the X-band frequency 9.719 GHz. The EPR parameters are
listed in (Table 4). All complexes (except 7) give axial spectra. Analysis of
spectra gives
= 2.20 - 2.15 and g┴ = 2.06 - 2.03. The trend
>
g// g⊥
> 2.0023
g//
suggests dx²-y² ground state for the Cu(II) ion and also indicates that the unpaired
electron is localized in the dx²-y² orbital of the Cu(II) ion [51-53]. The greater value
of g// compared to g⊥ indicates a tetragonal distortion around the Cu(II) ions
[54,55]. Also the observed g// values are less than 2.3 provide evidence for
appreciable covalent character for Cu-L bond [56]. The exchange interaction
between the copper centers in polycrystalline sample is explained by Hathaway
expression G = g// -2.0023/ g⊥ -2.0023 [57]. The exchange interaction is negligible
if G > 4, whereas a considerable interaction occurs for G < 4. As shown in (Table
4), the calculated G value for complex (5) (Fig. 2) is less than 4 suggesting some
interaction between Cu(II) ions in the solid state. For complexes (6,8,9) G value is
higher than 4 indicating no exchange interaction. The EPR of complex (7) (Fig. 2)
displays rhombic features with three g-values (
= 2.048, g2 = 2.087,
=
g 3
g 1
2.161) the lowest
value is > 2.04 indicating a rhombic distorted square based
g 1
pyramidal geometry in the spectra with
> g2
>
the rhombic spectral
g 1
g 3
parameter R=(
-
)/(
-
g2
g 3
) may be significant, if R > 1, a predominant
g2
g 1
dz² ground state is present. If R<1, a predominant dx²-y² ground state. Here R
<1=0.524. Also for rhombic spectra G =( - 2.0023)/( g⊥ - 2.0023) where g⊥ =
g 3
(
+ g )/2 = 2.45. In view of the fact that G < 4.4 and R<1, dx²-y² ground state is
2
g 1
assigned to this complex.
1H NMR spectra of Palladium(II) chelate
The [Pd(L)]Cl2.5H2O complex (11) was selected as it is diamagnetic. Its 1H NMR
spectrum was recorded in DMSO-d6 (Fig.2S). 1H NMR spectrum showed similar
signals as for the ligand, but the position of the amide proton signal in the complex is
downfield (11.97 ppm) in comparison with the free ligand (13.17 ppm), indicating the
involvement of the amide group in chelation [58]. This observation furthermore
confirmed the conclusion drawn on the basis of infrared spectra regarding the
coordination of amide nitrogen atom.
9

Thermal studies
TG/DTG measurements have yielded much insight in the composition and the thermal
stability of compounds. The thermal properties of ligand and its metal complexes
were investigated by thermogravimetric analysis (TG/DTG), under nitrogen
o
atmosphere from 25 to 800 C; important data are summarized in Table 1S. The
results obtained from thermogravimetric analysis [59-61] were in agreement with the
suggested
theoretical
formulae
from
the
elemental
analyses.
Ligand
The TGA curve of the ligand shows weight loss of 8.04% (calc. 8.06%) in the
temperature range of 28-253 oC. The DTG peaks recorded at 56,182oC reflect the loss
of two water molecules (in two separate steps) per ligand molecule. Also the TG
o
curve shows two decomposition steps (Fig.3) in the temperature range 253-676 C,
with total weight loss of 100% (Found 100%).
Cobalt(II) chelates
The TG curves of cobalt(II) complexes (1,2) show weight loss in the temperature
range 28-221oC (Calc./Found% 10.5 /10.46; 10.42/10.43%), respectively associated
with DTG peaks at 55, 114 and 48, 172 oC, that are assigned to release of four water
molecules (complex 1, Fig. 3), one molecule of water of crystallization along with
one ethanol molecule (complex 2). The TG thermograms also show that the
complexes gradually decomposed at 235 and 221oC, ended with formation of metal
oxide or metal for complexes 1,2, respectively.
Nickel(II) chelates
The TG curves of nickel(II) complexes (3,4) show weight loss in the temperature
o
range 33-164 C (Calc./Found % 14.22/14.27; 9.00/8.98 %), respectively associated
with two DTG peak at 32, 156 and at 54, 151oC, that are assigned to release of solvent
of crystallization in two steps. The TG thermograms also show that the complexes
gradually decomposed at 254 and at 265oC ended with formation of metal or metal
oxide, respectively.
Copper(II) chelates
The TG curves of copper(II) complexes (5, 7 -9) show weight loss in the temperature
o
range 25-226 C (Calc./Found% 15.35/15.37; 5.67/5.66; 9.68/9.67; 11.83/11.85%),
respectively associated with two endothermic DTG peak at 42,59 oC, that are assigned
to release of five and half water molecules (complex 5), peak at 53 oC, that is assigned
10

to release of two water molecules (complex 7, Fig. 3), peaks at 56, 156 oC that are
assigned to release of half ethanol together with two water molecules in two steps
o
(complex 8) and peak at 61 C that is assigned to release of five water molecules
(complex 9) (Table 1S). The TG thermograms also show that the complexes gradually
decomposed in more than one stage, ended with the formation of CuO for all
complexes [39]. It is worth to note that, the higher temperature of dehydration of the
ligand, complexes (2,5,9,11) may be due to strong interaction of water molecules in
the crystal lattice [62]. Due to the explosive nature of perchlorate complexes, the
thermal behavior of copper perchlorate complex (6) has not been investigated.
Ruthenium(III) chelate
The TG curve of ruthenium(III) complex (10) shows weight loss in the
o
temperature range 25-157 C (Calc./Found% 12.38 /12.39) associated with a
broad DTG peak at 61 oC, that is assigned to release of five molecules of
water crystallization in one step (Fig. 3). The TG thermogram also shows that
the complex starts decomposition at 157 °C ended with the formation of
RuO2 as final decomposition product.
Palladium(II) chelate
The TG curve of Palladium(II) complex (11) shows weight loss in the temperature
range 26-95 oC (Calc./Found %7.96/7.98) associated with one endothermic DTG
peak at 55 oC, that is assigned to release of three molecules of water crystallization.
The TG thermogram also shows that the complex starts decomposition at 246 oC
given Palladium(II) oxide as final decomposition product [63]. The slight higher
value found for the percentage of the residue when compared with the theoretical
value for pure metal oxides shows that the residue is contaminated with carbon [64].
The nature of the remaining residues was reported and identified by IR
spectroscopy.
Kinetic and thermodynamic parameters for complexes (1,2,4,7)
The kinetic and thermodynamic parameters of the decomposition stages of the
desolvated complexes (1,2,4,7) were determined from TGA thermogram using the
Coats–Redfern equation [65]. The Horowitz and Metzger [66] equation
(n )1
=
1 − n
was used for the determination of the value of the reaction order, and
Cs
m s − m ∞
m 0 − m ∞
given by
,where
is the weight fraction of the substance present
Cs
C s
=
11

m
m
at DTG peak temperature Ts, ms is the remaining weight at Ts, 0 and ∞ are the
C
initial and final weights of the substance, respectively. The estimated values of
for
s
the thermal decomposition of the desolvated complexes were found in the range of
0.30–0.34 (Table 5). This indicated that the decomposition follows first order kinetic
E*
[67]. So the values of the activation energy
, Arrhenius constant A, the activation
are
S*
, the activation enthalpy * and the free energy of activation
G*
entropy
H
calculated by applying Coats–Redfern equation for n = 1
− log
(
1− x
)
AR
θE*
2RT
E*
E*






(I)
log
= log
1−
−
T 2
2.303RT






Where: x is the fraction decomposed, R: is the gas constant and θ is the heating rate.
Since (1-2RT/E*) 1, a plot of the left-hand side of Eq. (I) against 1/T gives a
E*
straight line from its slope and intercept,
and A were calculated (Table. 5). The
H*
entropy of activation S* , enthalpy of activation
and the free energy change of
activationG* were
calculated
using
the
following
equations.
*
G = H −TS
*
, H * = E* − RT and
* . The calculated kinetic and
S* = R
[ln
(
Ah kT
)
]
R
thermodynamic values are summarized in Table 5. The High values of *reveals high
E
H* ꢀ o
stabilities of the chelates. Since
for which
the reactions are endothermic. The reaction
G*
is positive and * is negative considered as non-spontaneous reactions.
S
The entropy of activation was found to have negative values in the complexes, which
indicates that the activated complex has a more ordered structure than the
corresponding reactant [59]. The correlation coefficients of the Arrhenius plots of the
thermal decomposition steps were found to lie in the range 0.9987 to 0.9988 showing
a good fit with linear function.
Based on analyses and spectral, thermal studies, tentative structures of the complexes
are shown in Scheme 2.
O
O
N
x
C NH
N
NH C
N
M
y
.n
C
C
H C
3
C H
2 5
No.
M
x
y
n
12

(3)
(4)
(5)
(6)
Ni(II) Cl
Ni(II) OAc OH 3H2O
Cu(II) Cl Cl 5½H2O
Cu(II) H2O OH ClO4.4H2O
Cu(II) NO3 nil NO3.2H2O
Cu(II) OAc OH ½EtOH.2H2O
OH 1½EtOH.H2O
(7)
(8)
(11) Pd(II) nil
nil Cl2.5H2O
O
O
N
x
C
NH
H2O
HN
Z
C
M
y
.n
N
N
C
C
H C
3
C H
2
5
No.
1
M
x
y
z
n
Co(II) H2O H2O H2O Cl2.4H2O
9
Cu(II) Br
Ru(III) Cl
Br
Cl
H2O 5H2O
Cl 5H2O
10
O
O
N
OH
C
NH
N
HN
C
Co
NO3
.EtOH.H2O
N
C
C
H3C
C2H5
(2)
Scheme 2. Suggested structures of complexes (1-11).
Biological activity
The results of the cytotoxic activity in vitro were expressed as IC50 (the concentration of the
compound in µg/mL that inhibits proliferation of the cells by 50% as compared to the untreated
control cells) are given in Table 6. The ligand shows IC50 value of 11.7 and 3.45
µg/mL toward human breast cancer cell lines (MCF-7) and human hepatocarcinoma
cells (HepG2), respectively and that for some selected complexes (1,3,5,10,11) were
in the range of 2.04 - 9.7 µg/mL toward the former cells and 2.5-3.7 µg/mL toward
the latter one, respectively. Shier [68] suggested that compounds exhibiting IC50
values more than 10–25 µg/mL indicate weak cytotoxic activities while compounds
13

with IC50 values less than 5µg/mL are considered to be very active. Those having
intermediate values ranging from 5 to 10 µg/mL are classified as moderately active.
Accordingly, the tested complexes (IC50 = 2.04 - 2.7 µg/mL) (except L, complex 3) are
consider to be very active toward human breast cancer cell lines. Also the ligand and
its tested compounds (IC50 = 2.5-3.7 µg/mL) are considered to be very active toward
hepatocarcinoma cells. The results also show that Co(II) complex (1) showed highest
cytotoxic activity on human breast cancer cell lines, IC50 value = 2.04 µg/mL.
Whereas Cu(II), Ni(II) and Ru(III) complexes (5,3,10) showed highest cytotoxic
activity IC50 value = 2.5,2.7, 2.73 µg/mL toward human hepatocarcinoma cells. The
enhanced activity of the investigated complexes agrees well with and better than the
documented activity of similar metal complexes as antitumor agents [12,16,69-
71].The enhanced activity may be attributed to the increase in conjugation in the
ligand moiety on complexation [72]. The type of metal ions may be another reason for
their different anticancer activity. The active sequence of the ligand and its complexes
follows the trend:
Co(II) > Ru(III) > Pd(II) > Cu(II) > Ni(II) > L for MCF-7cells,
Cu(II) Ni(II) > Ru(III) > Pd(II) > L > Co(II) for HepG2 cells
These compounds seem to be promising as an anticancer agent because of their high
cytotoxic activity.
Acknowledgements
The authors would like to thank Dr. Mahmoud Moawad, Pathology Department,
National Cancer Institute, Cairo University, Cairo, Egypt, for his help with the in vitro
anticancer activity.
Conclusion
In this work the synthesis and spectroscopic characterization and anticancer activity
of new eleven new transition metal complexes of (N5) ligand, are reported. The
analytical and physicochemical data confirmed the composition and structure of the
newly obtained compounds. The results obtained can be summarized as follows:
1. The ligand shows interesting coordinating ability to metal ions, behaves as
neutral quatridentate or bidentate one.
2. All the metal complexes are mononuclear, adopt octahedral geometry except,
cobalt(II)(2), copper(II) (7) and palladium(II) (11) complexes in which the
14

metal ions prefer tetrahedral, square pyramidal or square planar geometry,
respectively.
3. In vitro antitumor activity of the synthesized compounds suggests that the
ligand and its tested complexes are potent anticancer agents. Besides, the
complexes are more active as compared to their free ligand. This implies an
increase in the antitumor activity with coordination.
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17

Spectrum Type : Normal Ion (MF-Linear)
RT : 0.85 min Scan# : (16.21)-k((18.25)) [k=1.0]
BP : m/z 46.000 Int. :0.01
Output m/z range : 40.0000 to 700.0000
Cut Level : 0.00 %
46
100
90
80
70
60
50
40
30
20
10
0
163
201
137
99
278
212
440
569
323
370
516
472
435
642
632
600
50
100
150
200
250
300
350
400
450
500
550
650
700
m/z
Fig.1. The ESI mass spectrum of [Cu(L)Cl2].5½H2O (5).
18

(5)
(7)
800
600
400
200
0
-200
-400
-600
-800
-1000
-1200
-1400
2000
2500
3000
3500
4000
4500
G
Fig.2. EPR spectra of complexes (5,7) as polycrystalline sample at RT.

*Mass of sample (mg)
Fig.3. TG/DTA curves of ligand (L) and complexes (1,7,10)

Table 1 Analytical and physical data for the ligand and its complexes.
Elemental analysis Calc. (F) (%)
(Λm)a
Yield
Decomp.
Temp./°C
No.
Compound
Color
Empirical formula
(%)
C
H
N
M
halogen
-
-
-
L=(C24H21N5O2.2H2O)
[Co(L)(H2O)4]Cl2.4H2O
Brown
Green
C24H25N5O4
65 253
64.42(63.69)
42.01(41.58)
5.59(5.69)
5.39(5.18)
15.65(15.12)
10.21(10.19)
1
C24H37N5O10Cl2Co
64
235
8.67(9.15)
10.35(9.93)
100
2
3
[Co(L)OH(NO3)].EtOH.H2O
[Ni(L)(OH)Cl]1½EtOH.H2O
Brown
C26H30N6O8Co
76
60
221
254
50.85(50.14)
53.15(54.54)
4.88(4.53)
5.41(5.44)
13.69(13. 42)
11.48(11.59)
9.69(10.9)
9.68(10.8)
-
39
25
Pale grey
C27H33N5O5.5ClNi
5.82(5.80)
4
5
6
7
8
[Ni(L)OH(OAc)].3H2O
[Cu(L)Cl2].5½H2O
Pale brown
Dark brown
Dark brown
C26H31N5O8Ni
90
60
76
74
98
265
226
250
153
180
52.0(51.6)
5.16(4.91)
4.96(4.99)
4.69(4.69)
3.94(4.34)
5.25(4.49)
11.66(11.73)
10.86(10.83)
10.27(10.5)
15.44(15.45)
11.48(11.89)
9.83(10.3)
9.85(10.7)
9.32(10.5)
10.0(10..9)
10.41(10.70)
20
10
70
68
2
-
C24H32N5O7.5Cl 2Cu
C24H32N5O12ClCu
C24H25N7O10Cu
C27H32N5O7.5Cu
44.68(44.14)
42.29(41.27)
45.39(45.51)
53.15(53.97)
11.01(10.65)
[Cu(L)OH(H2O)]ClO4.4H2O
[Cu(L)NO3]NO3.2H2O
5.21(5.5)
Dark Green
Dark Green
-
-
[Cu(L)OH(OAc)].½EtOH.2H2O
[Cu(L)(H2O)2Br2].5H2O
9
8.35(8.3)
Dark brown
C24H35N5O9Br2Cu
77
202
37.86 (37.48)
4.6 (4.77)
9.2(10.0)
21.03(21.4)
22
12
13.90(13.71)
9.63 (9.98)
14.65(14.65)
39.64 (39.25)
42.47(42.55)
4.54 (4.03)
4.57(4.52)
10
11
[Ru(L)(H2O)Cl3].5H2O
[Pd(L)]Cl2.5H2O
Black
C24H33N5O8Cl3Ru
C24H31N5O7Cl2Pd
98
90
157
246
10.32 (10.03)
15.63(15.50)
Pale brown
10.47(10.50)
87
a: Ω-1 cm2 mol-1 DMSO solutions (10-3M)

Table 2 Fundamental IR spectral bands (cm-1)a of Ligand and its metal complexes.
-
-
No. Compound
ν(OH /H2O)
ν(NH)
ν(C=N)
Amide bands
III
ν(M-O) ν(M- N) Anion (NO3 ,OAc-,ClO4 )
Azomethi
-ne
I
II
IV
L.2H2O
3347(b)
3206(b)
1618(b)
1644(w) 1499(sh) 1289(m)
754(sh)
-
-
-
[Co(L)(H2O)4]Cl2.4H2O
3334-3365(b)
3422-3331(m)
3206(m) 1587(m)
3206(b) 1590(w)
1640(b)
1639(b)
1612(b)
1626(b)
1607(b)
1626(b)
1617(b)
1505(sh) 1295(m)
1505(sh) 1303(w)
1508(sh) 1301(w)
1506(sh) 1306(m)
758(m)
757(m)
753(w)
754(m)
764(m)
760(w)
762(w)
593(w) 418(sh)
594(w) 400(m)
606(w) 400(m)
598(w) 424(w)
-
1
2
3
4
5
6
7
[Co(L)OH(NO3)].EtOH.H2O
[Ni(L)(OH)Cl]1½EtOH.H2O
[Ni(L)OH(OAc)].3H2O
[Cu(L)Cl2].5½H2O
1380(sh),1269(w)b ,1046(m)
3413-3335(m)
3444-3331(m)
3331(b)
3269(w) 1591(m)
3262(w) 1583(m)
3174(w) 1607(b)
-
{1583 (sh)1379(sh)}b
1505(m)
1503(w)
1504(m)
1301(w)
1301(w)
1301(w)
-
463(w)
-
[Cu(L)OH(H2O)]ClO4.4H2O
[Cu(L)NO3]NO3.2H2O
3386(b)
3386(b)
3190(b)
1590(b)
1587(b)
533(w) 462(w)
576(w) 416(w)
{1087(sh) ,630(sh )c
3333(b)
{1412(w),1301(w),1041(w)]
b,1380(sh),708(w)}c
[Cu(L)OH(OAc)]
½EtOH.2H2O
3409(b)
3393(b)
3222(b)
3206(b)
1587(b)
1611(b)
1619(b)
1611(b)
1505(sh) 1297(m)
756(sh) 597(w) 424(w)
{1587 (b),1376(m)}b
8
9
[Cu(L)(H2O)2Br2].5H2O
1504(m)
1293(w)
1295(m)
764(m)
766(m)
564(w) 459(w)
625(w) 438(m)
-
[Ru(L)(H2O)Cl3].5H2O
[Pd(L)]Cl2.5H2O
3396(b),3343(m)
3317(b),3246(b)
3202(b)
3205(b)
1603(b)
1644(b)
1626(b)
1505(m)
1525(m)
-
-
10
11
1611(sh)
1309(sh) 759(sh) 529(sh 419(sh)
a: s, strong; sh, shoulder; m, medium; w, weak; b, broad; ν, stretching
b:Monodentate ion, c :ionic

Table 3 Nujol mull electronic absorption spectra λ max (nm), room temperature effective
magnetic moment values (μeff, B.M.) of complexes.
No.
Complexes
λmax (Nujol mulls, nm)
(d-d)Transition
μeff(B.M.)
Intraligand and charge transfer
bands
-
353,270 ,224
-
Ligand.2H2O
700,640,450
648
380 ,326 ,230
385 ,323 ,240
398 ,323 ,229
380 ,323 ,250
356 ,290,240
380,323,240
380,323,240
347,293,240
5.12
4.51
3.78
3.5
[Co(L)(H2O)4]Cl2.4H2O
[Co(L)OH(NO3)].EtOH.H2O
[Ni(L)(OH)Cl]1½EtOH.H2O
[Ni(L)OH(OAc)].3H2O
1
2
3
4
5
6
7
8
632 ,495,427
633 ,535 ,420
644,512,400
632,520,420
770,600
1.95
2.49
1.97
2.3
[Cu(L)Cl2].5½H2O
[Cu(L)OH(H2O)]ClO4.4H2O
[Cu(L)NO3]NO3.2H2O
640,500,400
[Cu(L)OH(OAc)].½EtOH.2H2O
632,532, 476
632, 490
365 ,300,240
393,323,240
380 ,326,250
1.8
[Cu(L)(H2O)2Br2].5H2O
[Ru(L)(H2O)Cl3].5H2O
9
2.21
(Dia)a
10
11
640,520,420
[Pd(L)]Cl2.5H2O
a:diamagnetic

Table 4 EPR parameters for the Cu(II) complexes as polycrystalline sample at RT.
No. Compound
[Cu(L)Cl2].5½H2O
G
g
g
g
av
//

2.19
2.16
2.06
2.04
2.10
2.08
3.25
5
6
7
[Cu(L)OH(H2O)]ClO4.4H2O
[Cu(L)NO3]NO3.2H2O
4.02
R=0.524<1
=2.048
=2.161
g 1
g
2 =2.087
g
3
2.15
2.20
2.03
2.04
2.07
2.10
4.02
4.93
8
9
[Cu(L)OH(OAc)].½EtOH.2H2O
[Cu(L)(H2O)2Br2].5H2O
Table 5 Kinetic and thermodynamic data of the complexes (1,2,4,7).
*
*
*
*
No.
Complex
Decomposition
Temp. (K)
A
Cs
S
G
E
H
( S-1)
(J mol -1K-1)
-16.45
(kJ mol -1)
aR2
508-658
11.456E5
42.575
36.23
48.76
39.36
0.33 0.9987
0.34 0.9987
1
[Co(L)(H2O)4]Cl2.4H2O
494-726
538-665
426-647
6.713E5
2.798E11
2.7785E5
-16.837
-3.837
33.646
146.88
14.926
28.168
146.87
10.724
2
4
7
[Co(L)OH(NO3)].EtOH.H2O
[Ni(L)OH(OAc)].3H2O
[Cu(L)(NO3)]NO3.2H2O
149.24 0.32 0.9988
23.82 0.30 0.9988
-17.459
aR2: correlation coefficient

Table 6 Lethal concentration (IC50) of the ligand and its metal complexes on MCF-7 and HepG2.
No.
Compound
IC50 (μg/mL)a
MCF-7
HepG2
3.45
L.2H2O
11.7
2.04
3.7
[Co(L)(H2O)4]Cl2.4H2O
[Ni(L)(OH)Cl].1½EtOH.H2O
[Cu(L)Cl2].5½H2O
1
3
5
9.7
2.7
2.7
2.5
[Ru(L)(H2O)Cl3].5H2O
[Pd(L)]Cl2.5H2O
2.2
2.39
2.73
3.4
10
11
a: (IC50) is the concentration of compound (μg/mL ) that inhibits a proliferation rate
of the tumor cells by 50% as compared to control untreated cells.

Transition metal complexes of a new 15-membered [N5] penta-azamacrocyclic
ligand with their spectral and anticancer studies
Hanaa A. El-Boraey∗, Azza A. Serag El-Din
Department of chemistry, Faculty of science, El-Menoufia University, Shebin El-
Kom, Egypt
O
O
N
C
NH
HN
C
O
CH
3
reflux-12 hr
C
C
NH2
H2N
+
Ethanol-70°C
O
C2H5
2-amino-N-{2-[(2-amino-benzoylamino) pyridine]- benzamide
2,3 pentanedione
O
O
N
C
NH
N
HN
N
C
C
C
H3C
C2H5
(L)
∗Corresponding author. Tel.: +2- 0111-7532777; Fax: +20 48 2235689.
E-mail address: helboraey@yahoomail.com (Hanaa A.El -Boraey).
23

HIGHLIGHTS
• Novel [N5] quatridentate, bis-amide bis -imine macrocyclic ligand and its transition
metal complexes have been synthesized and characterized. • Analytical, spectral and
thermal data confirm the structure of the compounds. • The ligand shows interesting
coordinating ability to metal ions. • In vitro antitumor activity of the synthesized
compounds shows that the obtained complexes are potent anticancer agents.
24