Silver(I)-N-heterocyclic carbene complexes of nitrile-functionalized imidazol-2-ylidene ligands as anticancer agents

Article abstract of DOI:10.1016/j.inoche.2014.03.016

Reactions of symmetrically and non-symmetrically substituted nitrile-functionalized imidazolium salts (1-3) with silver(I) oxide in methanol at room temperature afforded complexes (4-6) of the type [NHC-Ag-NHC]PF ₆, (NHC: imidazol-2-ylidene). A

Full text of DOI:10.1016/j.inoche.2014.03.016

Inorganic Chemistry Communications 44 (2014) 128–133
Contents lists available at ScienceDirect
Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
Silver(I)-N-heterocyclic carbene complexes of nitrile-functionalized
imidazol-2-ylidene ligands as anticancer agents
a
a
a
Rosenani A. Haque a, , Srinivasa Budagumpi , H. Zetty Zulikha , Noorhafizah Hasanudin ,
⁎
Mohamed B. Khadeer Ahamed b, Amin M.S. Abdul Majid b
The School of Chemical Sciences, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia
a
b
EMAN Research and Testing Laboratory, The School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
Reactions of symmetrically and non-symmetrically substituted nitrile-functionalized imidazolium salts (1–3)
with silver(I) oxide in methanol at room temperature afforded complexes (4–6) of the type [NHC-Ag-NHC]PF6,
(NHC: imidazol-2-ylidene). All reported compounds have been characterized by spectral (1H, 13C NMR and
FTIR) and elemental analysis. The structure of bis-imidazolium salt 3 and silver complex 4 was unambiguously
elucidated by the single-crystal X-ray diffraction method. The effect of substitutions on the anticancer activity
of compounds 1–6 has been investigated by in vitro cytotoxicity studies against human colorectal (HCT 116)
cancer cell line, using the MTT assay method. All three silver complexes (4–6) displayed promising anticancer ac-
Received 13 February 2014
Accepted 19 March 2014
Available online 27 March 2014
Keywords:
Anticancer potential
Imidazolium salts
MTT assay
tivity with IC50 values of 6.0
0.2, 14.0 0.6 and 4.0 0.2 μM, while imidazolium salts, 1–3, showed least
(N200 μM) to moderate (20.3 0.2 and 95.0 2 μM) anticancer potential, respectively. Bis-imidazolium salt
3 and binuclear complex 6 displayed good activity against human breast (MCF-7) cancer line with IC50 values
of 82.4 2.5 and 0.9 0.4 μM, respectively.
N-heterocyclic carbene
Silver(I)–complex
X-ray diffraction
© 2014 Elsevier B.V. All rights reserved.
N-heterocyclic carbenes (NHCs) are formally derived from azolium
salts such as 1,3-disubstituted imidazolium salts by deprotonating the
C2 proton by a strong base. The interest in this area has increased im-
pressively in the last decade due to the potential applicability of
NHC–metal complexes in a large quantity of fields [1]. The study of
the specific properties of NHC–metal complexes continues to spring
many interesting facts ranging from catalysis to medicinal chemistry.
Variety of silver(I)–NHC complexes can be composed by both, func-
tionalized and/or non-functionalized NHCs [2], adopting standard
synthetic pathways suggested by Lin and Wang [3] to afford a plethora
of structural motifs highly dependent on reaction conditions, nature of
metal centre and solvent choice. The most widespread line in progres-
sive expansion in this particular field is the family of N-functionalized
NHC–metal complexes that contain imidazole core [4]. The electronic
tunability of N-functionalized NHCs and variety of established reactivity
make their carbene complexes a promising choice in the expansion of
targeted synthesis of anticancer agents.
N-terminals of an azole-based NHC ligand [5]. However, other types of
N-functionalized ligands such as nitrile-functionalized NHCs have dem-
onstrated a great utility to afford structurally divergent motifs. Especial-
ly, the silver(I) complexes derived from the nitrile-functionalized NHCs
have established an excessive utility as anticancer agents, for instance,
1-methyl-3-(4-nitrilebenzyl)-benzimidazol-2-ylidenesilver acetate
displayed promising anticancer potential against the human renal can-
cer cell line, but, failed to show tumor growth inhibition in vivo in a xe-
nograft model [6]. Recently, we have reported [7] that rare structural
motifs can result from nitrile-functionalized NHC precursors, even
from apparently simple and commonly used experimental methods.
One early surprising outcome was the formation of a binuclear sil-
ver–NHC complex formed by the coordination of a carbene carbon
and a nitrile nitrogen atoms to the silver(I) centre in an almost linear
coordination geometry. By analogy, we intend to take benefit of the
nitrile-functionality either in the coordination or in the formation
of supramolecular architectures. Recently, we have reviewed the bi-
ological applications of silver(I)–NHC complexes bearing different
NHCs and found that these are important synthons in anticancer re-
search [8]. The present nitrile-functionalized imidazolium salts are
specifically designed to link one or two metal centres. Imidazolium
salt 2 is a symmetric version of unsymmetric salt 1, while salt 3 is
its dimeric entity. In the present communication, three different
nitrile-functionalized silver(I)–NHC complexes have been prepared,
methodically characterized and studied for their potential as anti-
cancer agents against HCT 116 and MCF-7 cancer cell lines.
Despite their extensive potential as anticancer agents, the supramo-
lecular chemistry and structural diversity in N-functionalized NHC–
metal complexes are of continuous interest. Traditionally, the N-
functionalized complexes involved in both catalysis and pharmacology
possess amides, amines and/or N-heterocyclic systems attached at the
⁎
Corresponding author. Tel.: +60 194118262 (H/P).
E-mail address: rosenani@usm.my (R.A. Haque).
http://dx.doi.org/10.1016/j.inoche.2014.03.016
1387-7003/© 2014 Elsevier B.V. All rights reserved.

R.A. Haque et al. / Inorganic Chemistry Communications 44 (2014) 128–133
129
solvent removal under reduced pressure. The reactions involved in the
preparation of mono- and binuclear silver(I)–NHC complexes 4–6 are
shown in Scheme 2. Both, imidazolium salts and corresponding silver
complexes are non-hygroscopic in nature and readily soluble in com-
mon organic solvents such as methanol, ethanol, acetonitrile, DMF and
DMSO. Elemental analysis data along with spectroscopic data is in
well agreement with the proposed structure of the compounds, which
is further complemented by means of the data obtained by single crystal
X-ray diffraction.
N
N
N
PF6
1
N
(ii) KPF6
MeOH
(i) A, Dioxane
Reflux, 20 h
n = 1
Stir, 3 h
(i)
B, NaOH
EtOH
The 1H NMR spectra of the imidazolium salts show a distinguished
singlet in the range 9.15–9.51 ppm, corresponding to the imidazolium
C2 proton, and a couple of doublet resonances at around 7.9 ppm for
backbone C4 and C5 protons [10]. In the silver complex spectra, the
peak corresponding to the C2 proton of the salt is completely disap-
peared, indicating its deprotonation and coordination of the C2 carbon
to the metal centre [11]. However, resonances for methyl and benzylic
protons were observed at around 3.85 and 5.50 ppm, respectively, in
all spectra. Further, the coordination of C2 carbon to the metal centre
is confirmed by the 13C NMR spectral technique. The silver(I) bound
carbene carbon is identified in the 13C NMR spectra of the complexes
at the typically high-frequency shift at around 180 ppm, indicating the
successful formation of the desired complexes [12]. In the case of com-
plex 6, the most downfield resonance for the carbene carbon nuclei ap-
peared as two doublets centred at 180.1 ppm due to the presence of
13C–107Ag and 13C–109Ag couplings with the average coupling constant
of 190.6 Hz [13]. In addition to this, there is a negligible difference in
the peak position and integration of the resonances for the rest of the
carbon nuclei compared with 13C NMR spectra of the corresponding
salts. Interestingly, the 1H NMR spectrum of complex 6 also shows
two separate broad resonances at 5.30 and 6.46 ppm, ascribed to the
central methylene spacer. This might be due to the endo and exo ar-
rangement of the two protons orienting towards and away from the
metallacycle, respectively [14]. Also, it is speculated that endo protons
that are orienting toward the metallacycle show interaction with the
metal centres.
Conventional FTIR spectroscopy was effectively used to understand
the possibility of nitrile nitrogen involvement in the coordination with
the metal centre. In the spectra of the imidazolium salts, a sharp band
with medium intensity was observed at around 2230 cm−1, corre-
sponding to the stretching vibrational modes of nitrile functionality.
Interestingly, in the complex spectra this band was not affected, attrib-
uting to the non-involvement of the nitrile nitrogen in the coordination
[15]. This is further confirmed by single crystal X-ray analysis. On the
other hand, imidazole ring vibrations shifted to a lesser energy region
in the complexes, indicating the successful formation of silver(I)–NHC
complexes. C–H vibrations of imidazole ring and benzyl frameworks
were observed at around 2860 and 2940 cm−1 in all the compounds.
N
N
Reflux, 24 h
n
PF6
(ii)
KPF6
N
Br
MeOH
Stir, 3 h
n = 2
(ii) KPF6
MeOH
(i) C, Dioxane
Reflux, 24 h
n = 1
2
N
Stir, 3 h
N
N
N
N
N
N
A: 1-methylimidazole
B: 1H-imidazole
2PF6
3
C: di(1H-imidazol-1-yl)methane
Scheme 1. Synthesis of nitrile-functionalized mono- and bis-imidazolium salts.
Nitrile-functionalized imidazolium salts, 1–3, are accessible in two
steps starting from N-alkyl/aryl imidazole as shown in Scheme 1. Treat-
ment of 1-methylimidazole with 3-bromomethylbenzonitrile in diox-
ane at refluxing conditions, followed by the salt metathesis with
potassium hexafluorophosphate yields the imidazolium salt 1 in quan-
titative yield. Symmetrically substituted imidazolium salt 2 and the
corresponding silver(I)–NHC complex 5 were synthesized according
to the reported procedure [9] via the reaction of 1H-imidazole with 3-
bromomethylbenzonitrile in ethanol at basic conditions and metallation
with silver(I) oxide, respectively. Finally, bidentate NHC proligand 3
was prepared via the reaction of 3-bromomethylbenzonitrile with
di(1H-imidazol-1-yl)methane in dioxane at refluxing conditions,
followed by the salt metathesis with potassium hexafluorophosphate.
NHC transition metal complexes are often prepared via reaction of an
(benz)imidazolium salt with a basic metal source such as Ag2O or
Pd(OAc)2 to afford the desired complex. Thus, the imidazolium salts
1–3 were treated with Ag2O in acetonitrile at room temperature for
12–48 h under exclusion of light. The target mono- or binuclear
silver(I)–NHC complexes 4–6 can then be isolated in good yield by
1
N
N
N
N
N
N
N
N
2
N
CH3CN, RT
CH3CN, RT
Ag2O
Ag+
Ag+
PF6
Stir, 12 h
N
Stir, 12 h
PF6
N
N
N
N
3
Stir, 48 h
4
5
CH3CN, RT
N
N
N
N
N
N
N
Ag+
N
N
N
Ag+
2PF6
N
N
6
Scheme 2. Synthesis of nitrile-functionalized mono- and binuclear silver–NHC complexes.

130
R.A. Haque et al. / Inorganic Chemistry Communications 44 (2014) 128–133
Fig. 3. MTT assay results of imidazolium salt 2 and silver–NHC complexes (4 and 5) versus
HCT 116 cell lines.
respectively. The asymmetric unit of compounds 3 and 4 contains one
half of a molecule of imidazolium salt 3 with one hexafluorophosphate
anion and one half of a molecule of complex cation with one half of a
molecule of hexafluorophosphate anion, respectively. Both, imidazolium
salt 3 and silver complex 4, crystallize in the monoclinic space group C2/
c. Molecular structures of compound 3 and 4 along with the pertinent
bond angles and bond distances are shown in Figs. 1 and 2, respectively.
Salt 3 is a well ordered bis-imidazolium salt having two
hexafluorophosphate counter ions. The molecule possesses a zig-zag
structure having each imidazole ring and the attached benzonitrile
planes are perpendicular to each other. The internal bond angles at
N2\C11\N3 (and N2A\C11A\N3A) and nitrile module N1\C1\C2
(and N1A\C1A\C2A) are 108.22(7) and 179.77(13)°, respectively
Fig. 1. Molecular structure of bis-imidazolium hexaflurophosphate salt 3. Selected bond
distances (Å): C1\N1: 1.1522(13), C1\C2: 1.4414(12), C8\N2: 1.4831(11), N2\C11:
1.3254(11), C11\N3: 1.3406(10) and N3\C12: 1.4567(11). Selected bond angles (°):
N1\C1\C2: 179.77(13), C6\C8\N2: 111.28(7), N2\C11\N3: 108.22(7) and
N3\C12\N3A: 109.08(11).
The structure of bidentate NHC proligand 3 and silver(I)–NHC com-
plex 4 has been unambiguously determined by single-crystal X-ray
diffraction studies. The crystal structure of salt 1 has been reported in
our earlier article [16]. Single crystals of 3 and 4 suitable for X-ray crys-
tallographic studies were grown by slow evaporation of salt solution in
acetonitrile and slow diffusion of diethyl ether into the complex solu-
tion in methanol, respectively at room temperature. Pertinent bond pa-
rameters of the NHC proligand 3 and silver(I)–NHC complex 4 are
presented along with the captions of their molecular structures,
Fig. 2. Molecular structure of silver–NHC complex 4. Hexafluorophosphate anion has been
omitted for clarity. Selected bond distances (Å): Ag1\C1: 2.090(8), C1\N1: 1.347(11),
C1\N2: 1.363(9), N1\C11: 1.450(11), N2\C4: 1.459(10) and C12\N3: 1.46(2). Selected
bond angles (°): C1\Ag1\C1A: 179.7(4), N1\C1\N2: 103.6(7), C1\N1\C11: 124.8(7),
C1\N2\C4: 123.5(7) and C9\C12\N3: 173.9(18).
Fig. 4. Images of the control HCT116 cells (A), cells treated with the standard 5-fluorouracil (B)
and cells treated with imidazolium salts 1 (C) and 2 (D) and silver–NHC complexes 4 (E) and 5
(F).

R.A. Haque et al. / Inorganic Chemistry Communications 44 (2014) 128–133
131
Fig. 5. MTT assay results of imidazolium salt 3 and silver–NHC complex 6 versus HCT 116 (a) and MCF-7 cell lines (b).
which are in agreement with the previous reports [17]. In addition,
a weak π–π stacking interactions are observed between the two
benzonitrile rings of two adjacent molecules with the interaction dis-
tances in the range 3.845–3.862 Å. Note that nitrile-functionality is
pointing away from the carbene carbon moiety, and is apart by
3.819(3) Å with the neighboring nitrile module of adjacent molecule.
This separation is short enough to accommodate another metal centre
in between two terminal nitriles of adjacent molecules. Thus, the possi-
bility of polymeric silver complex formation is overlooked. Finally, in
the crystal packing, C\H—F (2.538(6) Å) and C\H—N (2.561(2) Å) hy-
drogen bonding interactions were observed. These hydrogen bonding
interactions along with the aforementioned stacking interactions
formed the 3-dimensional architecture.
The silver(I) of complex 4 is in a dicoordinate environment, which is
best described as almost linear coordination geometry, with the carbene
carbon atoms of two NHC ligands. The C1\Ag\C1A coordination angle
of 179.7(4)° is in well agreement with those of the other similar
silver(I)–NHC complexes reported by us [18] as well as many others
[19]. Both the nitrile entities are however, pointing away from the
metal centre, showing their non-involvement in the coordination. The
bond distances of C1\Ag (2.090(8) Å) and C1A\Ag (2.090(8) Å) and
internal bond angles at carbene carbon centre N1\C1\N2 (103.6(7)°)
and N1A\C1A\N2A (103.6(7)°) are well within the range for a linear
silver(I)–NHC complex. The planes of imidazole and benzonitrile rings
are almost perpendicular to each other with the dihedral angle of
108.7(7)°. Both the benzonitrile substitutions are located on one side
of the imidazole planes with anti- arrangement of the NHC ligands
around the metal centre. Interestingly, weak π–π stacking interactions
of 3.569(6) Å are observed between the imidazole rings parallel to the
bc plane. In the extended structure, complex cations are connected
with hexafluorophosphate anions via intra and intermolecular hydro-
gen bonds of C\H—F (2.629(2) Å) and C\H—N (2.474(7) Å), leading
to the 3-dimensional arrangement.
Since metal-based pharmaceuticals of groups 10 and 11 play a sub-
stantial role as therapeutic medicine for the treatment of cancer, the
development of novel related entities remains an interesting and exten-
sively studied area of research in medicinal chemistry [20]. Displaying
structural features very similar to that of trademarked methylcaffeine
derived silver-based NHC complex Silvamist® and also exhibiting con-
siderable antimicrobial and cytotoxicity [21], the reported silver(I)–
NHC complexes naturally qualify for screening against human derived
cancer cell lines. In light of our recent information on the promising
anticancer potentials of silver(I)–NHC complexes against HCT 116
and MCF-7 cancer cell lines, the reported imidazolium salts and
corresponding silver complexes have been studied for their antican-
cer abilities using MTT assay [22,23]. The surviving cells were deter-
mined by measuring their ability to reduce the yellow dye 3-(4,5-
dimethyl-2-thiozolyl)-2,5-diphenyl-2H-tetrazolium
bromide
(MTT) to a purple formazan product. Though the unsymmetrically
substituted salt 1 exhibited least activity (IC50 value of N200 μM) to-
wards HCT 116 cells, its symmetric version, salt 2, displayed moder-
ate activity with the IC50 value of 20.3 0.2 μM. However, treatment
of salt 1 with HCT 116 cells showed an insignificant inhibitory effect
on proliferation as the growth and morphology of the cells were un-
altered with respect to that of the negative control. In the case of salt
2, the viability of the HCT 116 cells was severely affected, showing a
moderate anti-proliferative effect. The silver(I) complexes 4 and 5
exhibited significant anticancer potential against HCT 116 cells
with the IC50 values of 6.0
0.2 and 14.0
0.6 μM, respectively.
Specifically, complex 4 displayed a strong anti-proliferative activity
in culture, which is nearly equal to the potential of the standard
used (5-fluorouracil IC50 = 5.2 1.0 μM). The treatment of complex
4 reduced the doubling time of HCT 116 cells drastically so that the
population of cells decreased significantly when compared to the
negative control. While the photomicrograph of the cells treated
with complex 5 illustrated a significant anti-proliferative effect of
the complex. The cells showed marked signs of cytotoxicity caused
by affecting the cellular morphology and viability. MTT assay results
imidazolium salts and corresponding silver complexes are shown in
Fig. 3. Images of control HCT 116 cells and the cells treated with the
test compounds are shown in Fig. 4.
Quite significantly, the binuclear silver(I)–NHC complexes exhibit
remarkable anti-cancer properties due to the fact that, these complexes
are more stable than their mononuclear counterparts and the existence
of possible cooperative effects between metal centres [7,8,22,23].
Fig. 6. Images of the HCT 116 cells treated with the imidazolium salt 3 (A) and silver–NHC
complex 6 (B).

132
R.A. Haque et al. / Inorganic Chemistry Communications 44 (2014) 128–133
1. Further, bis-imidazolium salt 3 and corresponding silver complex 6
displayed promising anti-cancer potential against MCF-7 cancer cell line.
Acknowledgements
R. A. Haque thanks Universiti Sains Malaysia (USM) for the Research
University (RU) grant 1001/PKIMIA/811217 and the short term grant
304/PKIMIA/6311123. H. Z. Zulikha and N. Hasanudin thank USM for
the RU Grants 1001/PKIMIA/834086 and 1001/PKIMIA/834080, respec-
tively. S. Budagumpi thanks USM for a postdoctoral research fellowship.
Appendix A. Supplementary material
CCDC 985183 and 985184 contain the supplementary crystallo-
graphic data for the imidazolium salt 3 and the silver complex 4, respec-
tively. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif. Experimental and characterization details of all new compounds,
crystal data and packing diagrams of the imidazolium salt 3 and the
silver complex 4 and effects of increasing amounts of imidazolium
salts and silver–NHC complexes on the percentage inhibition of Q9
HCT 116/MCF-7 cell proliferation are also available as supplementary
material. Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.inoche.
2014.03.016.
Fig. 7. Images of the control MCF-7 cells (A), cells treated with the standard drug tamox-
ifen (B), cells treated with imidazolium salt 3 (C) and silver–NHC complex 6 (D).
Therefore, the inhibition of cell proliferation using bis-imidazolium salt
3 and corresponding silver complex 6 was examined against two cancer
cell lines, viz., HCT 116 and MCF-7. MTT assay results of compounds 3
and 6 against HCT 116 and MCF-7 are shown in Fig. 5. HCT 116 and
MCF-7 cells treated with bis-imidazolium salt 3 showed moderate cyto-
toxic effects with the IC50 values of 95.0 2 and 82.4 2.5 μM, respec-
tively by affecting the normal morphology of the cells. Binuclear
complex 6 seems to be more stable compared with its mononuclear
counterparts 4 and 5, and is expected to be more active against both
the cancer cell lines. This complex displayed 1.5–3.5 orders of magni-
tude higher activity against HCT cells as compared to the mononuclear
counterparts with an IC50 value of 4.0 0.2 μM. Cells treated with com-
plex 6 showed a significant inhibitory effect on proliferation of cells,
which can be compared with that of standard reference drug. Similarly,
against MCF-7 cells, complex 6 displayed promising activity which is
many fold higher than the corresponding bis-imidazolium salt with an
IC50 value of 0.9 0.4 μM that is nearly three-fold higher potential com-
pared with the standard used (tamoxifen IC50 = 2.4 0.5 μM). The MCF-
7 cells displayed severe toxic signs as all the cells converted into round
shaped morphology after losing the normal pseudopodial cellular projec-
tions. Figs. 6 and 7 depict the images of HCT 116 and MCF-7 cells treated
with bis-imidazolium salt 3 and corresponding silver complex 6,
respectively.
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symmetrically substituted complex 4, which might be due to decreased
lipophilic character as this is bearing symmetrically substituted NHCs.
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In conclusion, this study reported a series of imidazolium salts 1–3
and the corresponding silver(I)–NHC complexes 4–6. All synthesized
compounds were characterized by spectral and analytical techniques.
Additionally, the molecular structure of bis-imidazolium salt 3 and
silver complex 4 was unambiguously elucidated by the single crystal
X-ray diffraction method. Along with hydrogen bonding interactions, a
weak π–π stacking interactions were observed in both the cases that
is leading to the formation of 3-dimensional architectures. Compounds
1–6 were tested for anti-cancer activity against HCT 116 cancer cell line.
All the tested compounds displayed moderate to good anti-cancer prop-
erty with the IC50 values in the range 6–20 μM, except imidazolium salt
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