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Transition metal complexes of α-aminophosphonates Part I: Synthesis, spectroscopic characterization, and in vitro anticancer activity of copper(II) complexes of α-aminophosphonates

Authors:
  • National Research Centre, Egypt

Abstract

New generation of copper(II) complexes with α-aminophosphonate as tridentate ligands has been synthesized. It is characterized by elemental analyses, spectral (IR, UV-Vis, MS, EPR, and 1H NMR) studies, thermal analysis as well as magnetic and molar conductance measurements. On the basis of spectral studies, a distorted square planar geometry has been assigned for all the complexes. Specific rotation measurements for both ligands and copper(II) complexes showed that they are enantiomerically enriched. The metal-free ligands and their Cu(II) complexes were tested for their in vitro anticancer activity against human colon carcinoma HT-29 cell lines. The results showed that the synthesized copper(II) complexes exhibited significantly higher anticancer activity than their free ligands. Among all the tested compounds in the series, the complex 5g demonstrated the highest anticancer activity at low micromolar inhibitory concentrations (IC50 = 14.2 µM) which is about a half of the reference drug activity, cisplatin (IC50 = 7.0 µM) in the same assay.
ORIGINAL RESEARCH
Transition metal complexes of a-aminophosphonates Part I:
synthesis, spectroscopic characterization, and in vitro anticancer
activity of copper(II) complexes of a-aminophosphonates
Hanaa Abdel Latif El-Boraey Ahmed Abdel Aleem El-Gokha
Ibrahim El Tantawy El-Sayed Mariam Ahmed Azzam
Received: 13 June 2014 / Accepted: 7 October 2014 / Published online: 25 October 2014
ÓSpringer Science+Business Media New York 2014
Abstract New generation of copper(II) complexes with
a-aminophosphonate as tridentate ligands has been syn-
thesized. It is characterized by elemental analyses, spectral
(IR, UV–Vis, MS, EPR, and
1
H NMR) studies, thermal
analysis as well as magnetic and molar conductance mea-
surements. On the basis of spectral studies, a distorted
square planar geometry has been assigned for all the
complexes. Specific rotation measurements for both
ligands and copper(II) complexes showed that they are
enantiomerically enriched. The metal-free ligands and their
Cu(II) complexes were tested for their in vitro anticancer
activity against human colon carcinoma HT-29 cell lines.
The results showed that the synthesized copper(II) com-
plexes exhibited significantly higher anticancer activity
than their free ligands. Among all the tested compounds in
the series, the complex 5g demonstrated the highest anti-
cancer activity at low micromolar inhibitory concentrations
(IC
50
=14.2 lM) which is about a half of the reference
drug activity, cisplatin (IC
50
=7.0 lM) in the same assay.
Keywords a-Aminophosphonates Synthesis
Copper(II) complexes Spectroscopic characterization
Anticancer activity
Introduction
Organophosphorus compounds have a wide range of
applications in the areas of industrial, agricultural, and
medicinal chemistry owing to their biological and physical
properties as well as their utility as synthetic intermediates
(Kafarski and Lejczak, 2001). Aminophosphonic acids
Iand their derivatives II, which are analogs of naturally
occurring amino acids III (Fig. 1), are an important class
of organophosphorous compounds, mostly because of their
occurrence in living organisms and their varied biological
activities (Mucha et al.,2011).
The biological relevance of the phosphonate and
phosphate derivatives with N-heterocyclic system and
their high reactivity toward transition metal ions (Aran-
owska et al., 2006;C
´uric
´et al., 1996; Zurowska et al.,
2004) has prompted researchers to synthesize organo-
phosphorus metal complexes of other phosphonate analogs
such as a-aminophosphonate ester of type II. Thus, the
synthesis of metal complexes of a-aminophosphonate
ligands bearing N-heterocyclic system, such as pyridine
(Lipinski et al., 2001), quinoline (Zurowska et al.,2012),
and imidazole (Zurowska et al.,2013) were recently
realized. However, to the best of our knowledge, the
interaction of transition metal ions with a-aminophosph-
onate ligands, having a carbocyclic ring bearing donor
group, is still unknown. As a part of our ongoing project
on synthetic and biological applications of a-amin-
ophosphonate esters (El Sayed et al., 2011a; Joossens
et al., 2007; Van der Veken et al., 2005), we are interested
in exploring the influence of interaction of metal ions with
a-aminophosphonates on their biological activity. In the
present study, we have chosen Cu(II) ion as an example of
transition metal ions, our interest in Cu(II) complexes
stems from their potential use as anticancer agents (Santini
et al.,2014). Herein, we report the first generation and
in vitro anticancer activity of copper(II) complexes with a-
aminophosphonates bearing phenolic and/or naphtholic
hydroxyl donor group.
H. A. L. El-Boraey A. A. A. El-Gokha
I. E. T. El-Sayed (&)M. A. Azzam
Chemistry Department, Faculty of Science, El-Menoufia
University, Shebin El Koom, Egypt
e-mail: ibrahimtantawy@yahoo.co.uk
123
Med Chem Res (2015) 24:2142–2153
DOI 10.1007/s00044-014-1282-8
MEDICINAL
CHEMISTR
Y
RESEARCH
Results and discussion
Synthesis and characterization of ligands
Reactions of aryl aldehydes 1(1 mmol) with 2-amino-
phenol 2(1.1 mmol) and triphenylphosphite 3(1 mmol) in
the presence of lithium perchlorate (10 mol%), as a Lewis
acid catalyst, were carried out in CH
2
Cl
2
at room temper-
ature for 3–5 h under identical conditions (El Sayed et al.,
2011b; Van der Veken et al., 2005). The crude products
obtained were purified by recrystallization from methanol
to give the corresponding a-aminophosphonates 4(H
2
L
1
&
H
2
L
2
) in 44–57 % yields as depicted in Scheme 1.
Interestingly, a-aminophosphonates 4a and 4b showed a
specific rotation of [a]
D
25
=?4.23°and ?5.78°in
dimethylsulfoxide (DMSO), respectively, as depicted in
Table 3, which indicate that they are optically active
compounds in high enantiomeric excess.
The chemical structures of a-aminophosphonates 4were
confirmed by IR,
1
H NMR, and MS. The IR spectra of 4
(H
2
L
1
&H
2
L
2
) are characterized by the presence of broad
absorption bands at 3,500–3,376 and 3,230–3,180 corre-
sponding to the stretching vibrations of the OH and NH
groups, respectively. The symmetric stretching vibrations
of the P=O group for H
2
L
1
and H
2
L
2
appeared at
1,244–1,242 cm
-1
. On the other hand, the bands at 946 and
993 cm
-1
are attributed to the P–O–C groups, whereas the
band at 744 cm
-1
is due to the P–CH group (Kumar,
2011). The structures of 4were further characterized by
1
H
NMR (DMSO-d
6
), which showed a characteristic
exchangeable singlet at 8.94 and 9.49 ppm due to the NH
proton for H
2
L
1
and H
2
L
2
, respectively. The CH-aliphatic
proton for 4is resonating at 5.28–5.22 ppm. Moreover, the
structures of ligands 4were further confirmed by electron
impact (EI) mass spectrometry and showed either a
molecular or pseudo-molecular (MH
?
) ion peak.
Synthesis and characterization of the metal complexes
The reaction of optically active chiral a-aminophosphonate
ligands 4that contain potential donor sites viz, phospho-
nate nitrogen, phenolic, and/or naphtholic oxygens, with
different copper(II) salts (chloride, nitrate, acetate, per-
chlorate, or bromide) in 1:1 (M:L) molar ratio yielded
Cu(II) complexes 5(Scheme 2).
It is worth mentioning that the specific rotation mea-
surements for the resulting copper(II) complexes indicated
that they are optically active and enantiomerically enriched
products as shown in Table 1.
The new compounds have been characterized by ele-
mental, spectral (IR, UV–Vis, EPR, MS) studies, and
thermal analysis (TG/DTG) technique as well as magnetic
and molar conductance measurements. The elemental
analyses data (Table 2) are consistent with the proposed
molecular formulae that show 1M:1L molar ratio in these
complexes except for complex 5j that adopts dimeric
structure. The novel complexes are powder-like paramag-
netic compounds, colored green to dark brown, and are
stable in the solid state under normal laboratory conditions.
It should be noted that many attempts have failed to
crystallize suitable single crystals for X-ray analysis for
any of complexes 5due to their partial solubility in com-
mon organic or mixed solvents. However, they are soluble
in polar solvents such as DMF or DMSO. The molar
conductance values (X
-1
cm
2
mol
-1
)in10
-3
M DMSO
solution were measured at room temperature and the results
are listed in Table 2.
The relatively low values show that all complexes have
non-electrolytic nature except complexes 5f,5j which are
1:2 electrolytes (Geary, 1971; Shebl et al., 2010).
Fig. 1 a-Aminophosphonic acids I, their analogs II as structural
mimics of a-amino acids III
R
CHO
OH
NH
2
OH
++
R
OH
NHP
OH
OOPh
PhO
P(OPh)
3
123
CH
2
Cl
2
/ LiClO
4
rt, 3-5 h
R = 0, C
4
H
4
R = 0
R = C
4
H
4
4a (H
2
L
1
)
4b (H
2
L
2
)
4
Scheme 1 Synthesis of a-
aminophosphonate Ligands 4
(H
2
L
1
/H
2
L
2
)
Med Chem Res (2015) 24:2142–2153 2143
123
FTIR spectra
Comparison of the IR spectra of the metal complexes with
that of the free ligands revealed that all complexes showed
broad bands in the range 3,460–3,230 cm
-1
which can be
assigned to t(OH) of the uncoordinated phenolic/
naphtholic–OH group of the ligands, coordinated or non-
coordinated water/solvent molecules associated with the
complexes which are confirmed by elemental and thermal
analyses. Also, absorption of the NH stretching vibrations
in the free ligands is found at about 3,230–3,180 cm
-1
as a
medium band. In the complexes, this band is reduced in
intensity and is shifted to lower frequency (sometimes
overlapped by OH) by up to 20 cm
-1
indicating the par-
ticipation of the phosphonate nitrogen in chelation (Juri-
bas
ˇic
´et al.,2011). Significant differences may be noticed
between 1,627 and 1,530 cm
-1
, where the NH deformation
modes along with the benzene/naphthalene ring stretching
vibrations are found. The t(C–O) phenolic/naphtholic of
the free ligands at 1,315–1,273 cm
-1
was shifted to lower
frequencies (1,226–1,211 cm
-1
) in the complexes, sug-
gesting the participation of the phenolic/naphtholic–OH
group in chelation (Shebl et al., 2010). There are no
remarkable changes in the position of absorption bands of
t(P=O) group as it is not involved in the metal coordination
(Juribas
ˇic
´et al.,2011). The small variation in position of
CuX
2
.nH
2
O
EtOH,10-15 hrs
4 (H
2
L
1
/H
2
L
2
)
NH
Cu
Br
OH
O
H
POPhPhO O
Br
.H
2
O
5e
NH
Cu
O
H
POPhPhO O
Cl
2
.5H
2
O
OH
OH
2
OH
2
5f
NH
Cu O
O
P
PhO OPh
O
OH
2
R
.Z
5b (R=0, X= NO
3-
, Z= 2EtOH)
5c,d (R=0, X= OAc
-
, ClO
4-
, Z= 0)
5g-i (R=C
4
H
4
, X= NO
3-
, OAc
-
, ClO
4-
, Z= 0)
NH
Cu O
O
H
P
PhO OPh
O
NH
Cu
O
H
O
POPh
PhO O
5j
NH
Cu O
O
H
P
PhO OPh
O
Cl
.H
2
O
5a
Br
2
Scheme 2 synthesis of
copper(II) a-aminophosphonate
complexes 5
Table 1 Specific rotation for a-aminophosphonate ligands 4 and
their corresponding copper(II) complexes 5
Compound
no.
Concentration
(mg/1 mL)
Solvent Specific rotation [a]
D
25
(deg dm
-1
g
-1
cm
3
)
4a (Ligand) 11.1 DMSO ?4.23
4b (Ligand) 13.5 DMSO ?5.78
5c (Complex) 11.0 DMSO -1.60
5d (Complex) 10.5 DMSO ?7.62
5e (Complex) 2.2 DMSO ?0.91
5f (Complex) 3.4 DMSO ?1.18
5g (Complex) 11.7 DMSO ?0.60
5i (Complex) 12.2 DMSO ?0.71
2144 Med Chem Res (2015) 24:2142–2153
123
Table 2 Analytical, physical, electronic spectra (cm
-1
), and magnetic moment (B.M.) of Cu(II) complexes
Compound Color (M. Wt) Yield (%) Elemental analysis Calcd. (F) (%) (K
m
)
a
Electronic spectra (cm
-1
)l
eff
(B.M.)
C H N M Halogen d–d
transitions
Other bands
[Cu(HL
1
)Cl]H
2
O(5a) Dark brown (563) 55.6 53.29 (53.27) 4.09 (3.88) 2.49 (2.54) 11.3 (11.3) 6.3 (6.3) 15 14705, 21505 26315, 38461 2.4
[Cu(L
1
)H
2
O]2EtOH (5b) Green (618.5) 47.6 56.27 (55.72) 5.5 (5.61) 2.26 (2.76) 10.3 (10.3) 7 16129, 22471 29411, 38461 2
[Cu(L
1
)H
2
O] (5c) Light green (526.5) 59 56.98 (56.45) 4.18 (4.59) 2.66 (2.07) 12.1 (12.8) 1 16129, 22727 31250, 38461 2
[Cu(L
1
)H
2
O] (5d) Light green (526.5) 75 56.98 (56.21) 4.18 (4.09) 2.66 (2.82) 12.1 (12.8) 2 16129, 22727 31250, 38461 2.4
[Cu(H
2
L
1
)Br
2
]H
2
O(5e) Dark brown (688.5) 45.5 43.57 (43.50) 3.48 (3.53) 2.03 (2.80) 9.2 (9.5) 23.2 (23.5) 25
b
13888, 21978 30769, 38461 1.9
[Cu(H
2
L
2
)(H
2
O)
2
]Cl
2
5H
2
O(5f) Dark brown (757.5) 57.9 45.94 (45.75) 5.02 (4.72) 1.85 (2.03) 8.4 (8.4) 9.4 (9.4) 100, 148
b
13869, 20833 27777, 41666 2.3
[Cu(L
2
)H
2
O] (5g) Brown (576.5) 60.4 60.36 (60.07) 4.16 (4.35) 2.43 (2.5) 11.0 (11.0) 1 16129, 21739 28169, 38461 1.8
[Cu(L
2
)H
2
O] (5h) Brownish yellow (576.5) 43 60.36 (60.03) 4.16 (4.47) 2.43 (2.94) 11.0 (11.0) 1 16129, 21739 29411, 38461 2.38
[Cu[(L
2
)H
2
O] (5i) Greenish brown (576.5) 57.8 60.36 (60.41) 4.16 (3.64) 2.43 (2.83) 11.0 (11.0) 1 16129, 21739 27777, 38461 1.87
[Cu(HL
2
)]
2
Br
2
(5j) Dark brown (1279) 45.5 54.42 (53.79) 3.6 (3.68) 2.19 (2.69) 9.9 (10.0) 12.5 (12.6) 170
b
13888, 21739 27777,40816 0.9
a
X
-1
cm
2
mol
-1
(10
-3
M DMSO)
b
10
-3
M DMF
Med Chem Res (2015) 24:2142–2153 2145
123
the t(P=O) absorptions displayed in the above region is
arising from their sensitivity to the hydrogen bonding
which may change the polarity of the phosphoryl oxygen
atom and brings about the appearance of these bands at
higher or lower frequencies (Juribas
ˇic
´et al.,2011). The
absence of band attributable to anion vibrations; t(NO
3
),
Fig. 2 Mass spectra of complexes [Cu(L
1
)H
2
O](5c), [Cu(H
2
L
2
)(H
2
O)
2
]Cl
2
5H
2
O(5f)
2146 Med Chem Res (2015) 24:2142–2153
123
t(OAc), or t(ClO
4
) indicates that both ligands acted as
dibasic tridentate in these complexes (5bd,5gi).Vibra-
tions at 535–530 cm
-1
(and expected below 500 cm
-1
; out
of our measuring limit) can be attributed to M–O and M–N,
vibrations. Therefore, and according to the IR spectra, the
ligands H
2
L
1
,H
2
L
2
acted as mono- or dibasic tridentate,
bonding to the metal ion through the two phenolic/napht-
holic oxygen atoms and one NH group. Also, they acted as
neutral bidentate in case of the complexes 5e,5f.
Mass spectra
The structure of the complexes was also supported by the (ESI)
mass spectra. The mass spectra of [Cu(L
1
)H
2
O] 5c,
[Cu(H
2
L
2
)(H
2
O)
2
]Cl
2
.5H
2
O5f (Fig. 2) provide good evidence
for their molecular formulae by observing molecular ion peaks
at m/z=526.62(100 %), 757.79(100 %) amu, which coin-
cide with their formulae weight (calculated M =526.5, 757.5,
respectively). Complex 5c shows the presence of the molecular
ion as sodium adduct [M ?Na]
?
at m/z=549.37
(58 %) amu. The mass spectra of the complexes also show
important fragmentions at m/z=447 [M–C
6
H
5
–2H]
?
, 434
[M–C
6
H
5
NH]
?
, 409[(M ?Na)–(C
6
H
5
NHO
2
?H
2
O) ?2H]
?
for complex 5c,andm/z=715[M–2H
2
O?2H]
?
, 666
[M–(5H
2
O?2H)]
?
, 649[M–(Cl
2
?2H
2
O?2H)]
?
, 606
[M–(Cu ?5H
2
O)
?
2H]
?
for complex 5f.
Electronic, EPR spectra, and magnetic measurements
The Nujol mulls electronic absorption spectra (cm
-1
)as
well as room temperature effective magnetic moment
values (l
eff
, B.M.) of the investigated complexes are given
in Table 2. The electronic spectra of the ligands in Nujol
mulls showed three bands at 37174, 28571, 21052 cm
-1
for H
2
L
1
and at 38910, 22271, 21141 cm
-1
for H
2
L
2
. The
first one assigned to the p?p
*
transition of aromatic
rings, the second one assigned to p?p
*
and n?p
*
transitions of chromophore moieties present in the ligands,
while the last one may be assigned to the CT transition,
respectively. Comparison of the spectra of the free ligands
with their metal complexes showed the persistence of the
bands of the ligands in all complexes. The electronic
spectra of Cu(II) complexes exhibit two main transitions.
The moderately intense peak at 20,833–22,727 cm
-1
is
probably due to MLCT transition, whereas the broad band
at 13,869–16,129 (Table 2) can be assigned to the combi-
nation of
2
B
1g
?
2
E
g
and
2
B
1g
?
2
A
1g
transitions in a
distorted square planar copper(II) environment (Daniel
et al., 2008; Rajesh et al., 2012; Tounsi et al., 2008). The
shift of the absorption band of some complexes to lower
energy than that expected for square planar geometry may
be due to the distortion of the square planar geometry
toward tetrahedral (Abou-Melha, 2008). Magnetic moment
of Cu(II) complexes 5aiat room temperature is in the
range 1.75–2.4 B.M. (Table 2). These values clearly sup-
port the monomeric nature of the complexes. For complex
5j the value of magnetic moment is lower than that of the
monomeric one suggesting copper–copper interaction
through phenolic oxygen bridge.
To further understand the geometry around the metal ion
in copper complexes, the X-band room temperature EPR
spectra of polycrystalline solid samples of the complexes
5a (Fig. 3), 5b,5g,5f are recorded at RT. The spectra of
5a,5b,5g displayed axial type with gvalues of g
//
(2.212,
2.159, 2.16) [g
\
(2.043, 2.027, 2.033) [2.0023(g
e
),
respectively, indicating that the unpaired electron resides in
dx2y2orbital of the copper ion. Further, the values are
consistent with Cu–N and Cu–O bonded copper complexes
(El-Boraey and Serag El-Din, 2014). It is well documented
in the literature that the tetragonally coordinated Cu(II)
complexes show features with g
//
[2.1 [g
\
[2.0 (Munjal
et al.,2011). The fact that g
//
values are less than 2.3 is an
indication of significant covalent bonding. Moreover,
splitting seen in the perpendicular region of the spectra for
-2500
-2000
-1500
-1000
-500
0
500
1000
1500
Intensity
G
5a
2400 2600 2800 3000 3200 3400 3600 3800 4000 4200
2400 2600 2800 3000 3200 3400 3600 3800 4000 4200
-10000
-5000
0
5000
10000
15000
Intensity
G
5f
Fig. 3 Solid state X-band EPR spectra of [Cu(HL
1
)Cl]H
2
O(5a),
[Cu(H
2
L
2
)(H
2
O)
2
]Cl
2
5H
2
O(5f)atRT
Med Chem Res (2015) 24:2142–2153 2147
123
complexes 5b and 5g corresponds to the interaction of
electrons with nuclear spin of nitrogen, which gives an
evidence for the coordination of phosphonate nitrogen. The
geometric parameter G, which is a measure of the
exchange interaction between copper centers in the poly-
crystalline compound, is calculated using the equation:
G=(g
//
-2.0023)/g
\
-2.0023). The Gvalues (4.86, 5.8,
4.8 for 5a,5b,5g, respectively), being greater than 4,
suggesting that the local tetragonal axes are aligned parallel
or only slightly misaligned with unpaired electrons in
dx2y2orbital (Procter et al., 1968) The powder EPR
spectrum of complex 5f (Fig. 3) displays exchange coupled
EPR spectrum with two gvalues g
1
=2.053, g
2
=2.165.
One important factor which affects the line shape of EPR
spectra in magnetically non-diluted systems is exchange
coupled interaction. If this interaction is greater than
thermal energy, partial spin pairing may occur. As the
observed magnetic moment of this complex (2.3B.M.) is
greater than the spin only value, exchange coupling, if it
does occur, must be less than thermal energy. In this case,
it primarily influences the line shape and does not reduce
the magnetic moment below the spin only value (Procter
et al., 1968; Sheeja, 2010). Pattern of gvalues and
appreciable differences between g
//
and g
\
values indicate
strong Jahn–Teller distortion around copper ion, i.e., axial
elongation and effective geometry around copper are
almost square planar.
Thermal properties (TG/DTG)
In order to give more insight into the structure and thermal
stabilities of ligands and their complexes, the thermal
studies have been carried out using thermogravimetry (TG/
DTG) technique. The thermogravimetric studies have been
made in the temperature range RT -800 °C. The nature of
proposed chemical change with temperature and the
Table 3 Thermal data of the investigated copper(II) complexes
Compound Temperature range/(°C) Mass loss % TG Reaction Leaving species
DTG peak Calcd. (F)
[Cu(HL
1
)Cl]H
2
O(5a) 51 34–78 3.2 (3.40) i
a
–H
2
O
281 269–397 75.2 (75.2) ii
b
Decomp.
at 397 21.65 (21.4)
c
:1
=
3(Cu/Cu
2
P
2
0
7
)
[Cu(L
1
)H
2
O]2EtOH (5b) 200 119–322 14.9 (14.20) i
a
–2EtOH
336,401 322–594 60.77 (60.9) ii
b
Decomp.
at 594 24.33 (24.9)
c
:Cu/Cu
2
P
2
0
7
[Cu(L
1
)H
2
O] (5c) 351 310–398 71.4 (72.0) ii
b
Decomp.
at 398 28.6 (28.0) :Cu/Cu
2
P
2
0
7
[Cu(L
1
)(H
2
O)] (5d) 340,375 320–427 71.4 (71.6) Decomp
at 427 28.6 (28.34)
c
ii
b
:Cu/Cu
2
P
2
0
7
[Cu(H
2
L
1
)Br
2
]H
2
O(5e) 70 64–119 2.6 (3.0) i
a
–H
2
O
193 162–295 11.7 (11.8) ii
b
–HBr
428,586 295–627 74.1 73.2 Decomp.
at 627 11.6 (12.0)
c
:CuO
[Cu(H
2
L
2
)(H
2
O)
2
]Cl
2
5H
2
O(5f) 40,62,96 25–151 11.9 (10.8) i
a
–5H
2
O
174,223, 523 151–599 79.7 (80.7) ii
b
Decomp.
at 599 8.4 (8.5)
c
:Cu
[Cu(L
2
)H
2
O] (5g) 321,401,435 299–500 78.9 (80) ii
b
Decomp.
at 500 21.10 (20)
c
:1
=
3(Cu/Cu
2
P
2
0
7
)
[Cu(L
2
)H
2
O] (5h) 351 330–522 74.00 (73.12) ii
b
Decomp.
at 522 26.00 (26.88)
c
:Cu/Cu
2
P
2
0
7
[Cu(L
2
)(H
2
O)] (5i) 271,354,500 241–730 85.5 84.3 Decomp.
at730 13.8 (14.4)
c
:CuO
[Cu(HL
2
)]
2
Br
2
(5j) 176 130–302 12.5 (12.3) ii
b
–2HBr
323,414,503 302–599 74.9 (75.4) Decomp.
at 599 12.4 (12.3)
c
ii
b
:2CuO
a
Desolvation
b
Decomposition
c
Final product percent
2148 Med Chem Res (2015) 24:2142–2153
123
percent of final product obtained are given in Table 3. The
results obtained from thermogravimetric analysis (El-Bo-
raey and Serag El-Din, 2014) were in agreement with the
suggested theoretical formulae from the elemental
analyses.
Ligands
The absence of weight loss in the TG/DTG curves up to
155 °C for H
2
L
1
and 200 °C for H
2
L
2
reveals that they do
not contain adsorbed water/solvent molecules. Beyond this
Fig. 4 TG/DTG curves of the complexes [Cu(L
1
)H
2
O](5c), [Cu(H
2
L
2
)(H
2
O)
2
]Cl
2
5H
2
O(5f) *weight of sample (mg)
Med Chem Res (2015) 24:2142–2153 2149
123
temperature, the ligands simultaneously melt and
decompose.
Complexes
The TG curve of compounds 5a,5e, and 5f show weight
loss in the region from 34 to 151 °C, corresponding to loss
of lattice water molecules that coincides with DTG curves
which show well-defined one or more (5f, Fig. 4)
peak(s) maximum in the same temperature range (Table 3).
The TG curve of compound 5b shows a weight loss of
14.2 % in the temperature range 119–322 °C which is
equivalent to two ethanol molecules (Calcd. 14.9 %). The
higher temperature of desolvation (higher than its boiling
point) indicated that the ethanol molecules are stabilized in
the structure (Yeh et al., 2012;Huet al., 2013) and played
an important role in holding the crystal together through
hydrogen bonding network between the ethanol and host
molecule.
The TG/DTG curves of complexes 5c (Fig. 4), 5d,
5giexhibit thermal stability up to 241–330 °C, since their
decomposition started above 241 °C. The presence of any
solvent/water molecules may be ruled out. This is in
agreement with their analytical and spectroscopic data.
However, the TG curve of 5j shows no weight loss up to
130 °C, the decomposition of 5j begins beyond 130 °C.The
TG curve of 5j also shows a weight loss 12.3 % in the
temperature range 130–302 °C, which is equivalent to
2HBr (Calcd. 12.5 %). The TG curves of the desolvated
complexes 5a,5b and the complexes 5c,5gishow that
they display higher thermal stability (241–330 °C), prob-
ably due to the structure-strengthening chelate rings
(Hiltunen et al.,2010) It is worth mentioning that the lower
thermal stability of complexes 5e,5f, and 5j (130–162 °C)
compared to that of the desolvated complexes 5a,5b
(269–322 °C) and the complexes 5c,5gi(241–330 °C)
may be due to the presence of only one six-membered
chelate ring in 5e,5f, while the di-l-oxo four-membered
chelate ring present in the dimeric structure 5j may
decrease its stability (130 °C). Also, the presence or
absences of counter anions plays an important role in the
thermal stability of the complexes. At higher temperature,
the organic part decomposed, the remaining weight corre-
sponds to the formation of Cu/Cu
2
P
2
0
7
as final end product
for complexes 5a,5g,Cu
2
P
2
0
7
for complexes 5bd,5h
(Dehghanpour et al., 2012; Maniam and Stock, 2011) while
complexes 5e,5j, and 5i give CuO and complex 5f gives
Cu as final end product. The percentage ratio of the metal
residue fits well with the formulae proposed. Based on
analyses and spectral studies, tentative structures of the
complexes are shown in Scheme 2.
Anticancer activity
All copper(II) complexes and the corresponding free ligands
H
2
L
1
and H
2
L
2
were examined for their in vitro anticancer
activity against human colon carcinoma (HT-29) cell line.
Screening for anticancer activity included measurement of
% of the in vitro cell inhibition using MTT colorimetric
assay at 10 lM concentration (Mosmann, 1983) using cis-
platin, as the reference drug, using a colorimetric method.
The results shown in Table 4indicate that these complexes
exhibit much higher anticancer activity when compared to
the corresponding ligands. The a-aminophosphonate ligand
(H
2
L
1
) exhibited a mild anticancer activity while the ligand
(H
2
L
2
) showed no activity on the examined carcinoma cell
line (Table 4). This indicates that the anticancer activity of
a-aminophosphonate enhanced remarkably upon coordina-
tion with copper(II) ion. Among all the tested compounds in
the series, the complex 5g demonstrated the highest anti-
cancer activity at low micromolar inhibitory concentrations
(IC
50
=14.2 lM)) which is lower than the reference anti-
cancer drug cisplatin (IC
50
=7.0 lM) in the same assay. It
is worth mentioning that although complexes 5bc,5gihave
the same structure, they display a remarkable difference in
anticancer activity. As a result of the chirality of the a-
aminophosphonate ligands or the rotation around the C–N
bond, this remarkable difference in the anticancer activity
between these complexes might be attributed to the pre-
sence of either different stereoisomers (Dufrasne and
Galanski, 2007) or conformers (Yeh et al.,2012).
Further confirmation for the difference in stereochem-
istry as well as anticancer activity was provided by the
Table 4 The percentages of cell inhibition induced by Ligands and
their corresponding copper(II) complexes in HT-29 cell line after
72 h
Compound no Structure % of cell inhibition
a
4a H
2
L
1
10.2
5a [Cu(HL
1
)Cl]H
2
0 47.8
5b [Cu(L
1
)H
2
O]2EtOH 89.7
5c [Cu(L
1
)H
2
O] 87
5d [Cu(L
1
)H
2
O] 82.4
5e [Cu(H
2
L
1
)Br
2
]H
2
O 14.6
4b H
2
L
2
0
5f [Cu(H
2
L
2
)(H
2
O)
2
]Cl
2
5H
2
O 66.2
5g [Cu(L
2
)H
2
O] 94.8
5h [Cu(L
2
)H
2
O] 55.5
5i [Cu(L
2
)H
2
O] 19.5
5j [Cu(HL
2
)]
2
Br
2
82.4
a
Inhibition rate (%) was calculated at 0.01 mM concentration using
MTT assay, DMSO was used as solvent which is widely used in cell-
culture studies
2150 Med Chem Res (2015) 24:2142–2153
123
differences in the TG/DTG profile as well as their initial
temperature of decomposition.
Conclusions
In conclusion, new series of copper(II) complexes con-
taining a-aminophosphonate ligands have been synthe-
sized. The analytical, spectral, and thermal data supported
the structure and the geometry of complexes. The evalua-
tion of anticancer activity against HT-29 cell lines proved
that the copper(II) complexes are promising anticancer
active agents. Of all the studied copper(II) complexes,
compound 5g exhibited higher activity with an IC
50
of
14.2 lM. The results also proved that the complexes are
significantly more potent than the free ligands against the
tested cell line. Further variation in transition metal type to
obtain more anticancer active complexes is currently
underway in our laboratory.
Experimental
Materials and physical measurements
All chemicals and solvents were of analytical grade and were
used as received without further purification. The metal salts
CuCl
2
2H
2
O (BDH), CuBr
2
(BDH), Cu(OAc)
2
H
2
O(Sigma),
and Cu(ClO
4
)
2
6H
2
Owereusedassupplied.
Elemental microanalyses (C, H, N) were performed at the
Micro Analytical unit, Cairo University, Giza, Egypt. Cop-
per(II) content in the complexes was determined via com-
plex metric method, while halide ions were determined by
Mohr’s method. IR spectra have been recorded on Nenexeus
Nicolidite–640MSAFT-IR, Thermo Electronic CO. using
KBr pellets. The electronic spectra have been measured in
Nujol mull using 4802 UV–Vis spectrophotometer. The
1
H
NMR spectrum was recorded in DMSO-d
6
on a Varian
Gemini 200 NMR spectrometer at 400 MHz. The electro-
spray mass spectra (ESI) for the complexes were performed
at the National Research Center, Egypt, by the Thermo
Electron Corporation. The electron impact mass spectra (EI)
for the ligands were run on Shimadzu-QP 2010 plus Mass
Spectrometer, Microanalytical Laboratory, Faculty of Sci-
ence, Cairo University, Egypt. The electron paramagnetic
resonance (EPR) spectra were recorded on a Varian E-109 c
spectrometer equipped with a field modulation unit at
100 kHz. Measurements were effected in the X-band on a
microcrystalline powder at room temperature; the micro-
wave power was around 10 mW. The molar conductivity
has been measured at room temperature with approximately
10
-3
M in DMSO solution using a CON6000 conductom-
eter, Cyberscan, Eutech instruments. Magnetic susceptibility
of metal complexes was measured using the modified Gouy
method at room temperature on Magnetic susceptibility
Johnson Matthey balance. Diamagnetic corrections were
made using Pascal
s constant. The thermal analysis (TG/
DTG) was carried out by a Shimadzu DAT/TG-50 thermal
analyzer with a heating rate of 10 °C/min under N
2
atmo-
sphere with a flowing rate of 20 ml/min in the temperature
range RT-800 °C using platinum crucibles. Optical rotations
were measured at the University of Tu
¨bingen,Germanyon
a Perkin Elmer-Mode1 241 Polarimeter-using the sodium D
line (589 nm) with Spectrophotometric Grade Dimethyl
Sulfoxide (DMSO).
Melting points were measured by device with accuracy -
(?)1°C. Biological tests were measured at Okayama
University, Japan.
Synthesis of ligands
Reactions of salicylaldehyde (1 mmol, 0.11 ml) or 2-hy-
droxynaphthaldehyde (1 mmol, 172 mg) with 2-aminophenol
2(1.1 mmol, 120 mg) and triphenylphosphite 3(1 mmol,
0.26 ml) in the presence of lithium perchlorate (10 mol%,
11 mg) as a Lewis acid, were carried out in CH
2
Cl
2
at room
temperature for 3–5 h under identical conditions until all the
starting materials were consumed as monitored by TLC.
After completion of the reaction, the precipitated product was
filtered off, recrystallized from methanol, and dried.
Diphenyl(2-hydroxyphenyl)(2-
hydroxyphenylamino)methylphosphonateH
2
L
1
(4a)
Light orange solid, Yield (44 %), m.p. 155–160 °C,
IR(KBr) cm
-1
: 3,500 (OH), 3,230 (NH), 1244 (P=O), 946
(P–O–C), 744(P–CH).
1
HNMR (DMSO-d
6
, 400 MHz):
5.88 (br. s, 1H, CH-aliphatic, exchangeable), 6.85–7.59 (m,
18H, Ar–H), 8.94 (br. s, 1H,NH). MS (70 eV, EI): m/
z=447 (M
?
, 65 %), 448 (M ?1, 19 %).
Diphenyl(3-hydroxynaphthalen-2-yl)(2-
hydroxyphenylamino) methylphosphonate H
2
L
2
(4b)
Light orange solid, Yield (57 %), m.p. 230–240 °C, IR
(KBr) cm
-1
: 3,367 (OH), 3,180 (NH), 1242 (P=O), 993
(P–O–C), 744(P–CH).
1
H NMR (DMSO-d
6
, 400 MHz):
5.22(br. s, 1H, CH-aliphatic, exchangeable), 6.76–8.38 (m,
2OH, Ar–H), 9.49 (br.s,1H, NH) 10.4 (br. s,1H, OH). MS
(70 eV, EI): m/z=498 (M ?1, 73 %), 497 (M
?
, 12 %).
Synthesis of the complexes
To a solution of the ligand H
2
L
1
or H
2
L
2
(1 mmol) in
20 mL ethanol, hydrated copper(II) salt (1 mmol) chloride
Med Chem Res (2015) 24:2142–2153 2151
123
5a,5f, nitrate 5b,5g, acetate 5c,5h perchlorate 5d,5i or
bromide 5e,5j in the same solvent was added slowly with
constant stirring over a period of 10 min in the molar ratio
1:1 (ligand: metal). The reaction mixture was heated under
reflux for 5 h, concentrated to a small volume. The formed
solid product was precipitated from petroleum ether-ace-
tonitrile mixture, filtered off, and dried over P
4
O
10
. Com-
plexes 5b–d were formed on cold.
Acknowledgments The authors would like to thank Professor
Masaharu Seno research team, Division of Biochemistry, Graduate
School of Natural Science and Technology, Okayama University,
Japan, for their help with the in vitro anticancer activity. The authors
also thank Prof. Dr. Pierre Koch, Pharmazeutisches Institut at the
University of Tu
¨bingen, Germany for assisting with specific rotation
measurements.
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... Moreover, electron impact (EI) mass spectrometry confirmed the probable formulae of the ligands HL 1 and HL 2 . [20,21] The melting point of HL 1 is about 140-145 C and that of HL 2 is about 225-230 C. ...
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Different metal catalysts have been tested for the one-pot transformation of carbonyl compounds, amines and phosphites to α-aminophosphonates. The influence of catalyst type, amount, solvent and the substrate electronic factor have been investigated. The results revealed that the carbonyl compounds could be smoothly converted into α-aminophosphonates at room temperature in good to excellent yields, with or without solvent in a reasonable reaction time. These results suggested that among others, lithium perchlorate and metal triflates were proven to be effective catalysts in 10 moles % catalysts. Polar aprotic solvents proved to be the best for the synthesis of α-aminophosphonates. The synthesized compounds' structure characterizations were elucidated by different spectroscopic tools and showed results consistent with the expected structures.
... Heterocyclic structures are found in nature -they built amino acids, neurotransmitters, nitrogen bases, nucleotides and vitamins (Quin and Tyrell, 2010). So, they exhibit complex biological activities, also making them important for medical chemistry (Nasir et al., 2012;El-Boraey et al., 2015). Therefore, the combination of phosphonic functionality with heterocyclic systems creates the possibility of obtaining compounds of better biological properties (Kmiecik et al., 2018). ...
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... These organometallic compounds are phosphorus analogues of naturally occurring α-amino acids II (cf. Figure 1). The biological activity of α -aminophosphonates was reported in literatures as anticancer [3,4] and antibacterial [5]. Furthermore, these compounds are used as antifungal, anticancer, antiviral agents [6,7] and herbicides [8,9]. ...
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