Journal of Molecular Structure 1255 (2022) 132482

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Journal of Molecular Structure

journal homepage: www.elsevier.com/locate/molstr

Synthesis, in vitro anticancer activity and reactions with biomolecule

of gold(I)-NHC carbene complexes
Sughra Gulzar a, Umme Ammara a, Zeeshan Abid a, Munazza Shahid b, Raja Shahid Ashraf a,
Nadeem Baig c, Abdel-Nasser Kawde d, Gaurav Bhatia e, Anvarhusein A. Isab f,∗,
Muhammad Altaf a,∗
a
Department of Chemistry, Government College University Lahore, Pakistan
b
Department of Chemistry, University of Education, Lahore, Pakistan
c
Interdisciplinary Research Center for Membranes and Water Security, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia
d
Department of Chemistry, College of Sciences, Research Institute of Sciences and Engineering, University of Sharjah, P.O. Box 27272, Sharjah, United Arab
Emirates
e
Department of Biochemistry, Pandit Jawarharlal Medical College and Hospital, Chamba, Himachal Pradesh 176310, India
f
Department of Chemistry, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia

a r t i c l e i n f o a b s t r a c t

Article history: Gold(I) N-heterocyclic carbene (NHC) complexes are widely investigated for promising anticancer activ-
Received 20 October 2021 ities. Herein, we present the synthesis, structural elucidation and in vitro cytotoxic profiles of five new
Revised 20 January 2022
gold(I)-NHC complexes containing thione ligands represented as [Au(IPr)(thione)]PF6 (where IPr = 1,3-
Accepted 22 January 2022
Bis(2,6-diisopropylphenyl)imidazol-2-ylidene and thione refers to 1,3-imidazolidine-2-thione (Ims) and its
Available online 24 January 2022
four N-mono- and N,N’-dialkyl (alkyl = -CH3 , -C2 H5 ) derivatives. Structural confirmation of all synthesized
Keywords: compounds has been carried out by elemental analysis, FTIR, 1 H NMR and 13 C NMR spectroscopy. Three
Gold out of five complexes (1, 3, 4) have also been subjected to single-crystal X-ray diffraction studies, which
N-heterocyclic carbene revealed the presence of [Au(IPr)(thione)]+ and PF6 − as counter ions and close to linear coordination
Thione geometry of gold(I) atoms. In vitro antitumor studies of synthesized complexes were examined against
X-ray diffraction analysis human cancer cell lines of colon, lung and breast cancers, namely HCT-15, A549 and MCF7 using MTT
In vitro anticancer activity
assay. The electrochemical reactions were also performed to know the possible mechanism of interaction
Biomolecule
between complexes and biomolecule.
© 2022 Elsevier B.V. All rights reserved.

1. Introduction platinum-containing antitumor medicines like carboplatin and

Transition metal-based complexes have earned a repute as
potential therapeutics against ancient and contemporary ailments
caused by pathogens and biological abnormalities [1–3]. A prime
example of the prevailing medicinal benefits of transition metal
complexes is Cisplatin, a platinum-based complex that currently
stands as the most valued anticancer drugs for chemotherapy
against many types of cancers [4]. Although cisplatin is licensed
for medical use since the 1970s and appears in the WHO’s List
of Essential Medicines, it has a number of side effects including
nephro-, neuro- and ototoxicity [5]. Coupled with the post-
treatment recurrence of the cisplatin-resistant disease in patients,
these side effects hinder the efficiency of cisplatin. Similarly, other
∗
Corresponding authors.
E-mail addresses: aisab@kfupm.edu.sa (A.A. Isab), muhammad.altaf@gcu.edu.pk
(M. Altaf).
oxaliplatin share the same complications [6]. These limitations
tempted researchers to investigate non-platinum metal complexes
that offer good antitumor properties while being safer for cancer
subjects. Therefore, a large number of studies have undertaken
gold, silver, ruthenium, rhodium, iron, copper, cobalt, palladium
and some other metals as an alternative to platinum metal [7–15].
Consequently, several metal complexes comprising palladium,
ruthenium and gold metals have been approved as antibacte-
rial, antifungal, antiinflammatory, antirheumatic and antitumour
agents [16].
The healing power of gold has been valued since early human
history. In conventional Egyptian and Asian medicines, gold com-
plexes have been utilized for treating tuberculosis, inflammation
and infection [17]. In modern history, the initial healing studies
of gold complexes were focused on inflammatory ailments. In the
early 1920s, gold(I)-thiolate and gold(I)-phosphine complex (Aura-
nofin) were utilized to cure rheumatoid arthritis [18,19]. With ad-
vances in the research, it was observed that these gold complexes

https://doi.org/10.1016/j.molstruc.2022.132482
0022-2860/© 2022 Elsevier B.V. All rights reserved.
S. Gulzar, U. Ammara, Z. Abid et al.
show low indications of malignancy rates. This observation raised
the assumption that gold complexes might possess antitumour ac-
tivity. In the early 1970s and 1980s, numerous groups of gold(III)
compounds emerged as promising cytotoxic agents [20]. Many gold
complexes evaluated for antitumor activity comparable with plat-
inum(II) complex (cisplatin) have shown better potency for can-
cer treatment through different mechanisms, including inhibition
of thioredoxin reductase or proteasome, direct DNA damage and
alteration of cell cycles [21–24].
In addition, researchers have emphasized the significant role of
the ligands especially because of their ability to tune cytotoxicity,
lipophilicity, stability and specificity of the complexes [25,26]. The
choice and role of ligands are of crucial importance for the effec-
tiveness, selectivity and potency of gold complexes. Several gold(I)
and gold(III) complexes containing thiolate ligands have exhibited
higher anticancer potential than cisplatin [27–32]. Among these,
gold(I)-phosphine thiolate complexes are particularly significant
owing to a higher cytotoxic activity than simple gold(I)-thiolates.
Anticancer efficiency of gold(I)-phosphino-dithiocarbamate com-
plexes proved that P−Au−S moiety contributes to a higher cyto-
toxic potential of complexes. It has also been proven that phos-
phine ligands enhanced the membrane permeability and lipophilic-
ity of the gold(I)-phosphine complexes that contribute to their an-
ticancer character [33,34,35]. The studies have shown that gold(I)-
phosphine imidazolates [36] and pyrazolates complexes have good
solubility and are seventy times more active against lung, human
breast, cervical colon and ovarian cancer cell lines than cisplatin
[37–39]. The studies have also proved that the right choice of lig-
and can take the therapeutic potential of gold(I) complexes beyond
cancer treatment. Additionally, proven activity of gold(I) complexes
against rheumatoid arthritis [40], gold benzimidazole derivatives
have shown antileishmanial and antibacterial activity [41,42]. Like-
wise, gold complexes are anticipated to bear therapeutic activity
against HIV and AIDS [43,44].
Over the last few years, extensive research has been carried out
on imidazole- and benzimidazole like structures because of their
presence in many potent therapeutic agents [45,46]. Some of the
common anticancer drugs containing imidazole moieties include
dacarbazine, zoledronate (Zometa), azathioprine (Imuran) and tipi-
farnib (Zarnestra), all contain imidazole moieties [47–49]. Similarly,
many antihistaminic (cimetidine, imetit and immepip), antihy-
pertensive (eprosartan, losartan, olmesartan), antifungal (micona-
zole, oxiconazole, clotrimazole), antiparasitic (benznidazole, sec-
nidazole, metronidazole) compounds comprising imidazole moi-
eties are commonly used against different diseases with great ther-
apeutic potency [46,50,51].
Recently, NHCs have (Fig. 1) grabbed the attention of re-
searchers as emerging ligands of imidazole and benzimidazole
classes to form promising bioactive inorganic complexes [52–55].
A carbene is a two-coordinate state of carbon that contains a
lone pair of electrons. NHCs attain stability by forming two ni-
trogen atoms and coordinate efficaciously to many metal centers
to form stable metal-NHC complexes [56,57]. In particular, gold-
NHC complexes are valued for their stability, catalytic properties,
controllable steric hindrance, and antitumor potential [52]. Be-
sides, gold-NHCs have also shown antibacterial activity [58], an-
tileishmanial activity [59], thioredoxin reductase (TrxR) inhibition
[60] and antiproliferative properties [61–66]. The captivating ther-
apeutic potential of gold complexes encouraged us to synthesize
and examine gold(I)-NHC complexes (1–5) bearing a soft thione
co-ligand which is likely to impart additional stability to the com-
plexes. The complexes were characterized using advanced analyt-
ical techniques and examined for cytotoxicity against colon (HCT-
15), lung (A549) and breast (MCF7) cancer cell lines. This study
provides first-ever insight into cytotoxic profile of gold(I)-NHCs
with ligands reported herein.
2
Journal of Molecular Structure 1255 (2022) 132482
2. Experimental
2.1. Materials
Common chemicals i.e., ethyl alcohol (C2 H5 OH) and dichloro-
methane (CH2 Cl2 ) were bought from local commercial sources.
1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidenegold(I)chloride)
(Au(IPr)Cl), silver hexafluorophosphate (AgPF6 ) and L-tyrosine
were procured from Sigma-Aldrich, St. Louis, United States. Dul-
becco’s Modified Eagle Medium (DMEM) and HCT-15, A549 and
MCF7 cell lines were obtained from The National centre for Cell
Science, Pune, India. 2H-Imidazole-2-thione (ImS) and its four dif-
ferent alkyl derivatives were synthesized and purified by literature
procedures [67,68]. Double-distilled water (ddH2 O) was acquired
from Aquatron A40 0 0D WaterStill assembly.
2.2. Instrumentation
Elemental analyses data was obtained from Perkin-Elmer 2400
Series II (CHNS/O), Analyzer. Solid-state FTIR analysis was con-
ducted on Perkin-Elmer FTIR 180 spectrophotometer using KBR
pellets of samples over the range 40 0 0–40 0 cm−1 and 4 cm−1 res-
olution. LAMBDA NMR spectrophotometer (500 MHz) was used for
the recording of 13 C (125.65 MHz),1 H (500.01 MHz) NMR analy-
sis. Tetramethylsilane was used as internal standard and chemical
shifts were presented in δ (ppm) relative to it. NMR spectra were
obtained at 297 K using chloroform-d (CDCl3 ) as solvent. The X-ray
data of all complexes were taken from STOE’s IPDS II containing a
two-circle Goniometer and graphite-monochromated MoKα radia-
tion (λ = 0.71073 Å) at 173 K (-100 °C). SHELXS-2014 program was
employed to resolve and refine the structures using direct meth-
ods. A semi-empirical method implemented by MULABS in PLA-
TON was used for absorption correction. Cyclic Voltammetry (CV)
and Square Wave Voltammetry (SWV) calculations were produced
using AutoLab (Netherlands). The electrochemical workstation con-
sisted of working glassy carbon electrode, platinum counter elec-
trode and silver chloride (Ag-AgCl) reference electrode. Accumet®
XL50 meter was utilized to monitor buffer pH. GR-20 0 0 electrical
balance was used for the measurements of the weights of the var-
ious chemicals.
2.3. Synthesis of complexes
2.3.1. Synthesis of [Au(IPr)(ImS)]PF6 (1)
0.500 mmol (0.311 g) of Au(IPr)(Cl) was first solubilized in
15.0 mL of dichloromethane (DCM) and then added to 5.0 mL
ethanolic solution of 0.500 mmol (0.127 g) of AgPF6 . The mix-
ture was magnetically stirred for 5 min at room temperature fol-
lowed by filtration. After filtration, 0.500 mmol (0.051 g) of 1,3-
Imidazolidine-2-thione (ImS) was added to the filtrate. After 1 h
of additional stirring, the mixture was filtered off and placed
in refrigerator for crystal growth. The white crystals were col-
lected after three to four days. Yield 57% (0.237 g). Anal. Calc.
for C30 H42 AuN4 S·PF6 (832.68), C, 43.22; H, 5.20; N, 6.72; S, 4.65.
Found: C, 43.38; H, 5.34; N, 6.61; S, 4.32%. 1 H NMR (CDCl3 , δ ppm):
8.12 (NH, s, 2H), 7.44 (3H, d, 2H), 7.59 (4H, t, 2H), 3.38 (5H, m, 4H),
1.21 (6H, d, 12H), 1.25 (7H, s, 12H), 8.08 (8H, s, 2H), 3.54 (11H, s,
4H). 13 C NMR (CDCl3 , δ ppm):145.4 C1, 133.6 C2, 124.9 C3, 130.7
C4, 28.4 C5, 23.9 C6, 23.6 C7, 124.1 C8, 173.6 C9, 179.0 C10, 44.8
C11.
2.3.2. Synthesis of [Au(IPr)(MeImS)]PF6 (2)
It was synthesized according to the above procedure for (1)
except that 0.500 mmol (0.058 g) of N-methyl-1,3-imidazolidine-
2-thione (MeImS) was added as ligand instead of ImS and prod-
uct was filtered as white powder. Yield: 65% (0.265 g). Anal. Calc.
S. Gulzar, U. Ammara, Z. Abid et al. Journal of Molecular Structure 1255 (2022) 132482

for C31 H45 AuN4 S·PF6 (847.27), C, 42.92; H, 5.35; N, 6.61; S, 4.56. Table 1
Selective IR bands (cm–1 ) of ligands and complexes.
Found: C, 42.93; H, 5.44; N 6.88; S,4.53%. 1 H NMR (CDCl3 , δ ppm):
8.10 (NH, s, 1H), 7.44 (3H, d, 2H), 7.55 (4H, t, 2H), 2.63 (5H, m, 4H), Compound ν (C=S) ν (N–H) ν (C–H)
1.23 (6H, d, 12H), 1.22 (7H, s, 12H), 8.11 (8H, s, 2H), 3.56 (11H, s, [Au(IPr)Cl] – – 3073, 2960
2H), 3.37 (12H, s, 6H). 13 C NMR (CDCl3 , δ ppm):145.3 C1, 133.6 C2, ImS 510, 1199 3200 –
124.9 C3, 130.7 C4, 28.4 C5, 23.9 C6, 23.4 C7, 130.7 C8, 173.5 C9, (1) 496, 1061 3377 3169, 2964, 2869
178.2 C10, 48.8 C11, 34.3 C12. MeImS 520, 1200 3200 –
(2) 470, 1058 3360 2962, 2873
Me2 ImS 516, 1201 – –
2.3.3. Synthesis of [Au(IPr)(Me2 ImS)]PF6 (3) (3) 496, 1123 – 2963, 2870
It was synthesized according to the above procedure for (1) ex- EtIms 515 3200 –
cept that 0.500 mmol (0.065 g) of N,N’-dimethyl-1,3-imidazolidine- (4) 441, 1060 3398 3120, 2962
Et2 ImS 514, 1199 – –
2-thione (Me2 ImS) was added as ligand instead of ImS. The prod-
(5) 449, 1118 – 3145, 2963
uct was obtained as white crystals. Yield: 63% (0.285 g). Anal. Calc.
for C32 H47 AuN4 S·PF6 ·C2 H6 O, (907.32), C, 44.98; H, 5.88; N, 6.17; S,
4.47. Found: C, 44.82; H, 5.71; N 6.18; S,4.23%. Yield = 0.285 g
(63%). 1 H NMR (CDCl3 , δ ppm): 7.44 (3H, d, 2H), 7.61 (4H, t, 2H), until it appeared purple. The optical density of 96 well-plates was
2.64 (5H, m, 4H), 1.23 (6H, d, 12H), 1.21 (7H, s, 12H), 8.12 (8H, s, found out using LabSystems Multiskan EX ELISA reader at 570 nm.
2H), 3.57 (11H, s, 2H), 3.37 (12H, s, 6H). 13 C NMR (CDCl3 , δ ppm): The outcomes of the study are shown as IC50 value of each com-
145.3 C1, 133.5 C2, 124.1 C3, 124.9 C4, 28.3 C5, 23.9 C6, 23.4 C7, plex which corresponds to micromolar concentration effective for
130.7 C8, 171.3 C9, 178.0 C10, 48.8 C11, 34.4 C12. 50% inhibition of cell growth.

2.3.4. Synthesis of [Au(IPr)(EtImS)]PF6 (4) 2.5. Electrochemical measurements

It was synthesized according to the above procedure for (1)
except that 0.500 mmol (0.079 g) of N-ethyl-1,3-imidazolidine-2-
thione (EtImS) was added as ligand instead of ImS. The product
was obtained as white crystals. Yield: 61% (0.244 g). Anal. Calc.
for C32 H46 AuN4 S·PF6 (860.72), C, 44.60; H, 5.50; N, 6.50; S, 4.47.
Found: C, 44.82; H, 5.47; N 6.43; S, 4.67%. 1 H NMR (CDCl3 , δ ppm):
8.13 (NH, s, 1H), 7.10 (3H, d, 2H), 6.95 (4H, t, 2H), 2.00 (5H, m, 4H),
0.75 (6H, d, 12H), 0.73 (7H, s, 12H), 7.62 (8H, s, 2H), 2.86 (11H, m,
2H), 3.69 (12H, m, 2H), 3.56 (13H, 2H), 0.30 (14H, m, 3H). 13 C NMR
(CDCl3 , δ ppm): 145.3 C1, 133.5 C2, 123.7 C3, 130.6 C4, 28.3 C5,
23.9 C6, 23.5 C7, 124.1 C8, 182.0 C9, 178.4 C10, 41.1 C11, 48.1 C12,
41.6 C13, 11.6 C14.
Ethanolic solutions of synthesized complexes were subjected to
electrochemical analysis owing to their greater solubility in ethanol
compared with water. Before each analysis, bare GCE was cleaned
with alumina slurry using a polishing clothe till the mirror-like re-
flection was achieved. The SWV and CV were range was set from
0.2 to 1.0 V for numerous analyses of the anticancer complexes and
the L-tyrosine interaction.
3. Results and discussion
3.1. Synthesis and spectroscopic characterization

2.3.5. Synthesis of [Au(IPr)(Et2 ImS)]PF6 (5)
It was synthesized according to the above procedure for (1) ex-
cept that 0.500 mmol (0.079 g) of N,N’-diethyl-1,3-imidazolidine-
2-thione (Et2 ImS) was used as ligand instead of ImS and product
was filtered as white powder. Yield = 61% (0.244). Anal. Calc. for
C34 H51 AuN4 S·PF6 (889.31), C, 45.98; H, 5.78; N, 6.30; S,4.30. Found:
C, 45.88; H, 6.28; N, 4.13; S, 4.51%. 1 H NMR (CDCl3 , δ ppm): 7.44
(3H, d, 2H); 7.73 (4H, t, 2H), 3.13 (5H, m, 4H), 1.21 (6H, d, 12H),
1.05 (7H, d,12H), 7.59 (8H, s, 2H), 3.44 (11H, d, 2H); 3.59 (12H, t,
2H), 0.89 (13H, dd, 2H). 13 C NMR (CDCl3 , δ ppm): 145.3 C1, 133.5
C2, 123.7 C3, 130.7 C4, 28.6 C5, 24.0 C6, 23.9 C7, 124.9 C8, 182.1
C9, 177.0 C10, 45.9 C11, 42.2 C12, 11.5C13.
2.4. In vitro anticancer activity evaluation
The cytotoxicity of synthesized complexes was evaluated
against colon, lung and breast cancer cell lines employing MTT as-
say. HCT-15, A549 and MCF7 cells were seeded and maintained
in triplicate onto 96-well plates at 3 × 103 cells/well density in
DMEM (100 μL) comprising 10% fetal bovine serum (FBS) and in-
cubated for growth in CO2 incubator for 72 h (37 °C, 5% CO2
and 90% relative humidity). This was followed by addition of 100
μL solution of cisplatin standard and synthesized complexes in
DMEM and further incubation for 24 h (37 °C, 5% CO2 ). The cul-
ture medium was removed followed by addition of 100 μL DMEM
having 0.5 mg/ml MTT. Further incubation for 4 h (37 °C, 5% CO2 )
in dark resulted in the formation of purple-formazan crystals at
the base of wells. After careful removal of the medium without
disrupting the monolayer of MTT metabolic product, DMSO (100
μL) was introduced to each well and the well-plates was shaken at
150 rpm for 5 min for thorough dissolution of formazan crystals
The elemental analysis and spectroscopic data confirmed the
formation of complexes. The synthetic scheme and molecular
structures of ligands are illustrated in Scheme 1.
The IR frequencies absorbed by functional groups present in
complexes are presented in Table 1. The IR band of ν (C=S)
in thiones was noticed between 1191–1217 cm−1 in complexes,
which justifies the successful complexation. The stretching band of
ν (N–H) shifted to a higher frequency in complexes. Likewise, high
frequency shift of C-N bond indicated an increase in its π char-
acter. Overall, the results conform with existing reports of gold(I)-
thione complexes [69–71].
1 H NMR spectral data (δ , ppm) of complexes is presented in
Table 2. The chemical shifts for Au(IPr)Cl are similar to the pre-
vious reports [72]. The N-H signals of thiones in 1 H NMR shifted
downfield (higher ppm) compared with their chemical shifts in the
free state. Upon coordination of thione with metal, transmission
of electron density from N to S increase π character of C-N bond
which in turn deshielded the thiones and increased the chemi-
cal shift value (downfield). Table 3 presents the selected 13 C NMR
shifts of thiones. In complexes, C-C resonance shifted to a higher
chemical shift value of >6 ppm in comparison with Au(IPr)Cl. The
downfield shift results from transfer of electron density towards
the metal from C-N bond as the complexation takes place. The C=S
chemical shift of [Au(IPr)(thiones)]PF6 complexes is observed up-
field compared with free thiones. This upfield shift conforms with
the literature data [73,74].
3.2. Crystal structure determination
The structural represention of [Au(IPr)(ImS)]PF6 (1),
[Au(IPr)(Me2 ImS)]PF6 ·C2 H6 O (3) and [Au(IPr)(EtImS)]PF6 (4) is

3
S. Gulzar, U. Ammara, Z. Abid et al. Journal of Molecular Structure 1255 (2022) 132482

Scheme 1. Synthetic scheme of gold(I)-NHC thione complexes and structures of ligands.

Table 2
1
H NMR spectral data (δ , ppm) of complexes.

Compound NH 3H 4H 5H 6H 7H 8H 11H 12H 13H 14H

ImS 7.90 – – – – – – 3.59 – – –

(1) 8.12 7.44 7.59 2.49 1.21 1.25 8.08 3.54 – – –
MeImS 7.93 – – – – – – 3.63 3.4 2.9 –
(2) 8.10 7.44 7.55 2.63 1.23 1.22 8.11 3.56 3.37 – –
Me2 ImS – – – – – – – 3.48 2.91 – –
(3) – 7.44 7.59 2.64 1.23 1.21 8.12 3.57 3.37 – –
EtImS 5.67 – – – – – – 3.70 3.58 3.67 1.20
(4) 8.13 7.10 6.95 2.00 0.75 0.73 7.62 2.86 3.69 3.56 0.71
Et2 ImS – – – – – – – 3.48 3.37 0.97 –
(5) – 7.44 7.73 2.44 1.21 1.05 7.59 3.44 3.59 0.89 –

Table 3
13
C NMR spectral data (δ , ppm) of complexes.

Compound C=S (C10) Au-C (C9) C1 C2 C3 C4 C5 C6 C7 C8 C11 C12 C13 C14

ImS 182.11 – – – – – – – – – 45.38 – – –

(1) 179.0 173.6 145.4 133.6 124.9 130.7 28.4 23.9 23.6 124.1 44.8 _ – –
MeImS 181.38 – – – – – – – – – 42.00 51.82 34.35 –
(2) 178.2 173.5 145.3 133.6 124.9 130.7 28.4 23.9 23.4 130.7 48.8 34.3 – –
Me2 ImS 180.46 – – – – – – – – – 48.77 48.77 34.91 –
(3) 178.0 171.9 145.3 133.5 124.1 124.9 28.3 23.9 23.4 130.7 48.8 34.4 – –
EtImS 182.90 – – – – – – – – – 40.68 47.03 40.41 11.80
(4) 178.4 178.4 145.3 133.5 123.7 130.6 28.3 23.9 23.5 124.1 41.1 48.1 41.6 11.6
Et2 ImS 178.74 – – – – – – – – – 46.13 42.69 11.92 –
(5) 177.1 182.1 145.3 133.5 123.7 130.4 28.3 24.0 23.4 124.6 45.9 42.2 11.5 _

shown in Figs. 2, 3 and 4 respectively, whereas PF6 − and C2 H6 O
groups are removed for clarity. Some particular bond angles [°]
and bond distances [Å] are also enlisted in Table 5. The crystal
structures showing [Au(IPr)(thiones)]+ and PF6 − ions confirmed
that crystals comprised ionic species connected by electrostatic
interactions. The cationic part bearing gold(I) ion showed almost
linear coordination geometry owing bond angles of 177.1(1),
172.9(1) and 176.6(1)° (C—Au—S) for (1), (3) and (4) respectively.
The close values of bonds suggest isostructural nature of (1)
and (4). The bond distances between Au—C and Au—S in (1)
and (4) are in agreement with literature of similar complexes
[74–77]. ligands. In particular, the Au—C bond lengths are 2.003(4),

4
S. Gulzar, U. Ammara, Z. Abid et al.
Fig. 1. Schematic representation of metal NHC complexes.
1.996(3) and 1.982(4) Å for (1), (3) and (4). The bond connection
around the sulfur atom is V-shaped with (Au−S−C) bond angles
103.05(16), 115.12(11), and 102.14(16)° in complexes (1), (3) and
(4) respectively. A trigonal planar geometry was observed by bond
angles surrounding >C=S and carbene C atoms. The absense of
aurophilic interactions in (1), (3) and (4) could result from bulky
groups of the IPr and thiones ligands as in the case of Au(IPr)-
based selenones [76]. A summary of crystal of above mentioned
complexes is given in Table 4.
3.3. In vitro anticancer properties
The complexes (1–5) were investigated for in vitro cytotoxic ac-
tivities against HCT-15, A549 and MCF7 cancer cells. Cisplatin, a
classical chemotherapy agent, was employed as a reference to com-
Fig. 2. X-ray structure of complex (1).
5
Journal of Molecular Structure 1255 (2022) 132482
pare the cytotoxic potential of these complexes. The concentrations
of complexes (1–5) were precisely and gradually raised along with
the cisplatin standard while keeping the number of cells fixed to
measure the dose-dependent activity of complexes. The IC50 val-
ues (μM) thus obtained are summarized in Fig. 5 and Table 6. The
studies indicated that attachment of thione ligands had no positive
influence on the antiproliferation properties of gold(I)-NHC thione
complexes. Therefore, all synthesized complexes possess low effec-
tiveness than cisplatin in terms of antiproliferative properties. The
lower cytotoxic potential of complexes may resulted from steric
hindrance arising from binding of IPr and thiones. Nevertheless,
the results were overall similar or in some cases better than the
platinum(II) complexes of thiones [78]. The results are also com-
parable with the previous reports where selenone was used as a
co-ligand for gold(I)-NHC complexes [61].
3.4. Interaction of complexes with biomolecules
For designing effective pharmaceutical drugs, the mechanism of
drug-cell interaction has a great significant interest. For instance,
several methods have been used to evaluate the interaction of
the drug with the cell components, such as mass spectrometry,
UV spectrophotometry, and fluorescence spectrometry. The elec-
trochemical investigation is another powerful tool to study the
interaction between biomolecules and drugs. For instance, DNA-
modified electrodes have been frequently utilized to investigate the
electrochemical interaction between drug molecules and DNA [79].
Electrochemistry is helpful to extract the thermodynamic and the
kinetic information of the drug [80].
Moreover, the drug-protein interaction has been investigated
where the binding number and association constant between drug
and protein was determined by electrochemical methods [81]. The
assessment of the interaction between small molecules and pro-
teins not only helps elaborate the complex biological mechanisms
but is also one of the most significant phases of drug discov-
ery. Disposable electrochemical cells were used to examine small-
molecule-protein interaction [82]. The tyrosine-derived nanosphere
has been used to investigate their interaction with the drugs, the
S. Gulzar, U. Ammara, Z. Abid et al. Journal of Molecular Structure 1255 (2022) 132482

Fig. 3. X-ray structure of Complex (3).

Fig. 4. X-ray structure of Complex (4).

most prominent interaction was π −π interactions and hydrogen
bonding [83]. The proteins are being used to analyze the electro-
chemical drug resistance in cancer cells. Several electrochemical
approaches, including CV and impedance spectroscopy, have been
employed for electrochemical investigation of the drugs [84]. In
this work, we have used CV and SWV to investigate the interac-
tion of the complexes with L-tyrosine.
The interaction of the synthesized gold(I)-NHC thione com-
plexes (1–5) with model amino acid was investigated. As all these
complexes were found electrically inactive, a highly electroactive
amino acid L-tyrosine was chosen to observe the interaction of the
complexes. Electrochemical investigation of these complexes was
done by using CV and SWV, both of which revealed sufficient in-
formation about complexes interaction with the L- tyrosine by de-

6
S. Gulzar, U. Ammara, Z. Abid et al. Journal of Molecular Structure 1255 (2022) 132482

Table 4
Summary of XRD data for complexes (1), (3) and (4).

Parameters Complex (1) Complex (3) Complex (4)

Empirical formula C30 H42 AuN4 S·PF6 C32 H46 AuN4 S·PF6 ·C2 H6 O C32 H46 AuN4 S·PF6
Mw 832.68 906.79 860.72
Lattice system, Space group Monoclinic, P21 /c Triclinic, P Monoclinic, P21 /c
Temperature (K) 173 173 173
a, b, c [Å] 13.1809(7), 16.4724(7), 15.9454(9) 8.9194(5), 13.5483(7), 16.2561(9) 13.2508(7), 17.4343(7), 16.0079(7)
β [°] 102.399(4) 97.657(4) 102.053(4)
V (Å3 ) 3381.3(3) 1926.85(18) 3616.6(3)
Z 4 2 4
Radiation type Mo Kα Mo Kα Mo Kα
μ (mm−1 ) 4.52 3.97 4.23
Crystal size (mm) 0.45 × 0.32 × 0.19 0.41 × 0.32 × 0.20 0.40 × 0.33 × 0.20
Instrument STOE IPDS 2 diffractometer STOE IPDS 2 diffractometer STOE IPDS 2 diffractometer
Absorption correction Multi-scan(MULABS; Spek, 2009) Multi-scan(MULABS; Spek, 2009) Multi-scan(MULABS; Spek, 2009)
Tmin , Tmax 0.526, 1.000 0.573, 1.000 0.660, 1.000
No. of measured, independent and 46,000, 6393, 4675 26,727, 7266, 6345 49,233, 6847, 4996
observed [I > 2σ (I)] reflections
Rint 0.081 0.052 0.093
(sin θ /λ)max (Å−1) 0.610 0.609 0.610
R[F2 > 2σ (F2 )], wR(F2 ), S 0.026, 0.053, 0.86 0.022, 0.048, 0.94 0.030, 0.064, 0.86
No. of reflections 6393 7266 6847
No. of parameters 432 476 479
No. of restraints 2 6 1

ρ max,
ρ min (e Å−3) 0.99, −0.82 0.94, −1.50 1.70, −0.97

Fig. 5. IC50 values of complexes (1–5) and cisplatin.

creasing the current and peak shift of the L-tyrosine after interac-
tion with complexes. The oxidation peak potential for 0.5 mM L-
tyrosine solution (0.1 M PB, pH 7.0) appeared at 0.598 and 0.620 V
for SWV and CV. The high-level interaction of the L-tyrosine was
observed with complex (1), (2) and (4). The maximum interac-
tion was observed with complex (1). The current was decreased
sharply and a continuous peak shift was observed from 0.620 to
0.674 V using cyclic voltammetry for 0.5 mM L-tyrosine by succes-
sive addition of the complex (1) from 0 μM to 90 μM and simi-
lar trends was observed for SWV (Fig. 6A, A’). Similarly, for com-
plexes (2) and (4). The interaction of the drug with L-tyrosine was
observed a little less compared to complex (1) and the peak shift
(CVs) was observed almost the same for two complexes from 0.620
to 0.660 V (Fig. 6B, B’ and D, D’). The complexes (3) and (5) have
shown very weak interaction with L-tyrosine. A small decline in
current and peak shift was observed for complexes (3) and (5)
from 0.620 to 0.629 V and 0.620 to 0.638 V, respectively (Fig. 6C,
C’ and E, E’). As a controlled experiment, the CV and SWV re-
sponses of 0.5 mM L-tyrosine, as shown in Fig. 6(F, F’), almost re-
tained the same peak current intensity and peak potential even af-
ter spiking the same volume of the reagent solvent was used for
the preparation of the anticancer complexes. The controlled ex-
periment further confirmed the interaction of synthesized com-
plexes and the L-tyrosine. Further investigation of the complexes
was done by studying the effect of these complexes on the diffu-
sion coefficient of the L-tyrosine. The scan rate was varied from
20 to 120 mVs-1 to consider the scan rate effect for 0.5 mM L-
tyrosine in the absence or presence of 100 μM complexes. This ex-
periment indicated that the raising scan rate increased the current.
Linear relations have been observed between the square root of
scan rate and the oxidation peak current of the L-tyrosine with or
without complexes. Linear equations yielded for 0.5 mM L-tyrosine
with or without 100 μM complex (1) were y = 31.784x+0.128 and
y = 23.364x+1.068, respectively (Fig. 7). The diffusion coefficients
were found by using Randles–Sevcik equation
Ip = 2.69 × 105C γ 1/2 D1/2 n3/2 A (1)

7
S. Gulzar, U. Ammara, Z. Abid et al. Journal of Molecular Structure 1255 (2022) 132482

Fig. 6. Cyclic and square wave voltammograms of the gold(I)-NHC thione complexes (1) (A, A ), (2) (B, B ), (3) (C, C ), (4) (D, D ), and (5) (E, E ) in phosphate buffer (pH
7.0, 0.1 M) containing 0.5 mM L-tyrosine at various concentrations of the gold(I) complexes (a) blank, and with concentrations of (b) 0, (c) 10, (d) 30, (e) 50, (f) 60, and (g)
90 μM. The effect on 0.5 mM L-tyrosine solution (F, F ) by adding solvent blank in concentrations of (b) 0, (c) 15, (d) 45, (e) 95, (f) 110 and (g) 155 μL.

In Eq. (1), γ represents the scan rate (V/s), C is the concentration 3.304 × 10−6 for 0.5 mM L-tyrosine compared to the diffusion co-
of the L-tyrosine (mol/L), D is diffusion coefficient (cm2 /s), n rep- efficient in the presence of 100 μM complexes. The complexes (1),
resents the number of electrons, A describes the surface area of (2) and (4) have shown a significant effect on the diffusion co-
the electrode (cm2 ) and Ip is the current (A). In the absence of efficient of the L-tyrosine and it was decreased to 1.786 × 10−6 ,
gold(I) complexes, the diffusion coefficient has a greater value of 2.138 × 10−6 and 2.425 × 10−6 cm2 /s, respectively. The gold(I)

8
S. Gulzar, U. Ammara, Z. Abid et al. Journal of Molecular Structure 1255 (2022) 132482

Fig. 7. Cyclic Voltammograms (A and B) obtained from solution comprising (0.5 mM) L-tyrosine in the absence of (a) and presence of (b) (100 μM) complex (1) using GCE
at scan rates of (a) 20 mV/s (b) 40 mV/s, (c) 60 mV/s, (d) 80 mV/s, (e) 100 mV/s, (f) 120 mV/s. The graphical representation (C) has shown the linear relationship between
current and the square root of the scan rates for (0.5 mM) L-tyrosine in the absence (a) and the presence (b) of (100 μM) complex (1).

Table 5
Selected bond length [Å] and bond angles [°] of (1), (3) and (4).

(1) (3) (4)

Bond length [Å]

Au1−C4 2.003(4) – –
Au1—C6 – 1.996(3) 1.982(4)
Au1—S1 2.299(1) 2.295(1) 2.298(1)
S1—C1 1.707(4) 1.715(3) 1.710(5)
N1—Cl 1.315(6) 1.320(4) 1.318(6)
N1—C2 1.461(6) 1.469(5) 1.471(7)
Bond angles [°]
C4—Au1—S1 177.1(1) – –
C6—Au1—S1 – 172.9(1) 176.6(1)
complexes (3) and (5) also showed an effect on the diffusion coef- C1—S1—Au1 103.1(2) 115.1(1) 102.1(2)
N3—C4—Au1 124.8(3) – –
ficient of L-tyrosine but that effect was not so prominent compared
N3—C6—Au1 – 128.3(2) 131.3(3)
to the rest of the gold(I) complexes (Table 7). N3—C6—N4 105.5(2) 104.2(3) –
The electrochemical study has revealed how the gold(I)-NHC N3—C4—N4 104.8(3) – –
thione complexes affect peak current, oxidation peak potential N1—C1— N2 – 110.1(3) 110.4(4)
and the diffusion coefficient of the L-tyrosine. These substantial N1—C1—S1 127.9(3) 130.3(3) 123.0(4)
N2—C1—S1 122.0(4) 119.5(2) 126.7(4)
changes have confirmed the interaction between L-tyrosine and C1—N1—C2 112.6(4) 111.4(3) 111.0(4)
gold(I)-NHC thione complexes, especially complexes (1), (2) and N4—C6—N3 – – 104.0(4)
(4). This considerable interaction could be attributed to the struc-
ture of the complexes. These three complexes have a secondary
amino group in their structure, thus allowing the electrostatic in-
teraction (hydrogen bonding) between these complexes and the L-
tyrosine through the hydrogen of the secondary amino group. The and the diffusion coefficient was observed. These complexes have
diffusion of L-tyrosine was decreased due to the attachment of tertiary amino groups allowing a weak interaction and further hin-
the bulky gold(I)-NHC thione complex. This effect was found more drance may be created by the presence of methyl in complex (3)
prominent for complex (1) and this effect resulted from the pres- and the ethyl in complex (5) instead of hydrogen. This behavior of
ence of two secondary amino groups in the complexes. The inter- the complex (3) and complex (5) further supported the evidence
action of the complexes (3) and (5) was very weak with L-tyrosine that amino groups facilitate the enhancement of the interaction
and a small decrease in current, peak shift (Fig. 6 C, C’ and E, E’) with the L-tyrosine.

9
S. Gulzar, U. Ammara, Z. Abid et al. Journal of Molecular Structure 1255 (2022) 132482

Table 6 Emeritus Helen Stoeckli-Evans, University of Neuchâtel, Switzer-

IC50 values (μM) of complexes (1–5) and cisplatin against carcinoma cell lines.
land for X-ray diffraction analysis.
Compound HCT-15 A549 MCF7
IC50 values Supplementary materials
(1) 90.68 ± 1.84 102.17 ± 2.57 92.8 ± 0.34
(2) 88.08 ± 0.91 89.98 ± 2.41 94.93 ± 1.68 X-ray crystal data of 3, 4 and 1 have been submitted to the
(3) 74.26 ± 0.59 90.25 ± 1.78 79.76 ± 1.9
Cambridge Crystallographic Data Center via the CCDC Number
(4) 93.90 ± 1.58 83.36 ± 0.71 91.33 ± 2.07
(5) 90.92 ± 1.91 77.90 ± 1.58 71.90 ± 1.58 2,090,806–2,090,808. The data files can be accessed free of cost
Cisplatin 32.04 ± 2.12 42.2 ± 2.01 23.25 ± 3.79 with application at CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
e-mail: deposit@ccdc.cam.ac.uk or www.ccdc.cam.ac.uk.
Table 7 Supplementary material associated with this article can be
Comparison of the diffusion coefficient of the L-tyrosine in the absence and pres- found, in the online version, at doi:10.1016/j.molstruc.2022.132482.
ence of 100 μM synthesized complexes (1–5).

Complex Concentration of Concentration of Diffusion

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