Synthesis and anticancer activity of novel NHC-gold(I)-sugar complexes

Article abstract of DOI:10.1016/j.tetlet.2018.06.040

Gold(I) complexes containing stabilising ligands such as phosphines or N-heterocyclic carbenes (NHCs) are known to be inhibitors of the enzyme thioredoxin reductase (TrxR) and therefore act as potential apoptosis-inducing anticancer drug candidates. The conjugation of biomolecules overexpressed in cancer cells to the gold complexes makes them semi-targeted metabolites. Auranofin, an anti-arthritis agent, encompasses this property and exhibits anti-tumour activities. The synthesis, characterization and biological evaluation of four novel N-heterocyclic carbene-gold(I)-thiosugar complexes derived from glucose, lactose and galactose is reported. The reactions of 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) chloride (NHC?-Au-Cl) with pre-synthesized glycosyl thiols under mildly basic conditions gave the desired NHC-Au-thiosugar complexes in high to excellent yields (79–91%). The complexes retain the strong and redox-active Au-S bond contained in Auranofin. All complexes showed good solubility in biological media and were tested against the NCI 60 cancer cell panel for cytotoxicity. The synthesized NHC?-Au derivatives showed good activity in the medium to low micromolar region, while complex 2 showed activity in the low micromolar to nanomolar region against the tested cell lines. To provide a theoretical structure of 4, computational calculations were carried out based on the crystal structures of NHC-Au-SCN and NHC-Au-S-C₆H₄OMe.

Full text of DOI:10.1016/j.tetlet.2018.06.040

Tetrahedron Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and anticancer activity of novel NHC-gold(I)-sugar complexes
a,
Oyinlola Dada a, Goar Sánchez-Sanz a,b, Matthias Tacke a, , Xiangming Zhu
⇑
⇑
a School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland
b Irish Centre of High-End Computing, Grand Canal Quay, Dublin 2, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Gold(I) complexes containing stabilising ligands such as phosphines or N-heterocyclic carbenes (NHCs)
are known to be inhibitors of the enzyme thioredoxin reductase (TrxR) and therefore act as potential
apoptosis-inducing anticancer drug candidates. The conjugation of biomolecules overexpressed in cancer
cells to the gold complexes makes them semi-targeted metabolites. Auranofin, an anti-arthritis agent,
encompasses this property and exhibits anti-tumour activities. The synthesis, characterization and bio-
logical evaluation of four novel N-heterocyclic carbene-gold(I)-thiosugar complexes derived from glu-
cose, lactose and galactose is reported. The reactions of 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene
gold(I) chloride (NHC⁄-Au-Cl) with pre-synthesized glycosyl thiols under mildly basic conditions gave
the desired NHC-Au-thiosugar complexes in high to excellent yields (79–91%). The complexes retain
the strong and redox-active Au-S bond contained in Auranofin. All complexes showed good solubility
in biological media and were tested against the NCI 60 cancer cell panel for cytotoxicity. The synthesized
NHC⁄-Au derivatives showed good activity in the medium to low micromolar region, while complex 2
showed activity in the low micromolar to nanomolar region against the tested cell lines. To provide a the-
oretical structure of 4, computational calculations were carried out based on the crystal structures of
NHC-Au-SCN and NHC-Au-S-C6H4OMe.
Received 27 March 2018
Revised 8 June 2018
Accepted 15 June 2018
Available online xxxx
Keywords:
Anticancer activity
Thiosugar
NHC-gold complex
Thioredoxin reductase
Ó 2018 Published by Elsevier Ltd.
Significant attention has been focused in the past decades on
the synthesis and biological study of NHC-metal complexes since
the successful synthesis of the first NHC derivative by Arduengo
and co-workers in 1991 [1]. NHC-metal complexes have emerged
as a research frontier for the development of novel metallodrugs
due to their high stability and ease of modification [2]. Metallo-
drugs such as auranofin which is used in the treatment of rheuma-
toid arthritis could exhibit a wide range of biological activities and
their applications in medicinal chemistry have attracted great
interest [3]. Auranofin consists of a gold(I) center linearly coordi-
nated to triethylphosphine and to the thiosugar 2,3,4,6-tetra-O-
promising anticancer agent, and it could induce cancer cell apopto-
sis via increased levels of reactive oxygen species (ROS) [6].
Compared to normal cells, the rapid growth and proliferation of
cancer cells demand a drastic increase in glucose uptake and
metabolite flux through glycolysis, which is termed the Warburg
effect [7], and as such, altered glucose intake and glucose trans-
porter (GLUT) overexpression are common in cancers and provide
clinically validated targets for cancer treatment. Therefore, the bio-
conjugation of chemotherapeutics including metal-containing
anticancer agents to glucose-like or glycomimetic substrates
serves as a new method of semi-targeted chemotherapy. The ratio-
nale of designing such a strategy relies on the assumption that the
glucose-like scaffold attached to a bioactive molecule could be rec-
ognized by the glucose transporter and the glycoconjugate inter-
nalized as a whole. Once taken up the cytotoxic metallodrug
could exert its anticancer activity directly inside the tumour cells,
which would greatly increase the drug effectiveness as well as
selectivity [8]. Moreover, such bioconjugation could also poten-
tially improve bioavailability, water solubility, enantiomeric purity
and biocompatibility of the metallodrugs. For example, a series of
glycoconjugates of cisplatin with monsaccharides were synthe-
acetyl-b-D-glucopyranosyl-1-thiolate. Recently, auranofin was also
found to be a potent inhibitor of thioredoxin reductase (TrxR) with
an IC50 value in the low nanomolar region, which is often overex-
pressed in many cancer cells and has been identified as a potential
target for anticancer drugs [4,5]. TrxR is essential in normal cells
for redox homeostasis and protection against oxidative damage
and mutation. Once transformed into malignant cells, TrxR
supports tumour growth and progression. Auranofin is thus a
⇑
Corresponding authors.
E-mail addresses: matthias.tacke@ucd.ie (M. Tacke), xiangming.zhu@ucd.ie
sized and the one with a b-
D-glucose derivative showed promising
activity against human A2780 ovarian carcinoma and MeWo
(X. Zhu).
https://doi.org/10.1016/j.tetlet.2018.06.040
0040-4039/Ó 2018 Published by Elsevier Ltd.
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2
O. Dada et al. / Tetrahedron Letters xxx (2018) xxx–xxx
melanoma cell lines [9]. Also, structure-activity relationship stud-
ies revealed that complexes containing -anomers were overall
more active than the corresponding b-anomers, whereas no differ-
ence was observed between the - and -isomers [9b]. A gold(I)
the in vitro and in vivo activity of NHC-gold(I)-2,3,4,6-tetra-O-
acetyl-b- -glucopyranosyl-1-thiolate (1 Fig. 1) [15]. This complex
a
D
exhibited very good activity against a wide range of human cancer
cell lines carried out on NCI 60 as well as promising growth inhibi-
tory activity against the xenografted renal cancer cell line Caki-1 in
mice. Moreover, inhibitory activity against the mammalian thiore-
doxin reductase enzyme was also observed with IC50 values in the
low micromolar range [15], indicating that apoptosis induction
through elevated oxidative stress could be the main mechanism
for the complex. Encouraged by the promising in vitro and in vivo
anticancer activity of 1, another four complexes with the general
structural formula NHC-Au(I)-SR, as shown in Fig. 1, were designed
and synthesized in this work, in which NHC is the 1,3-dibenzyl-
4,5-diphenyl-imidazole ligand and SR represents the thiosugars.
L
G
complex with thioglucose also exhibited increased stability under
physiological conditions, water solubility, bioavailability and
antiproliferative activity compared with the non-glycosylated
counterpart. Moreover, it proved cytotoxic towards human MCF7
breast adenocarcinoma, NCH89 and NCH82 glioblastoma, and
murine C6 glioma cell lines with IC50 values in the low
micromolar range [10]. A series of ruthenium complexes with
sugar-phosphite ligands were synthesized and the influence of
the different sugar ligands on their in vitro anticancer activity
was evaluated. Such complexes could also have improved water
solubility and showed enhanced selectivity towards cancer cells
with moderate growth inhibition capability against several human
tumour cell lines [11].
Structure 2 containing
a-thioglucose was designed because the
anomeric configuration could have significant impact on the cellu-
lar uptake and activity profiles of metallodrugs as revealed in a
Recently, we reported the synthesis and bioactivity of NHC ana-
logues of auranofin in which the alkyl substituents on the carbene
were specifically modified. Bioactivity studies were very encourag-
ing especially in human MCF7 breast adenocarcinoma and Caki-1
skin carcinoma cells, in particular in comparison to analogues
where either the carbene or the thioglucose ligands are replaced
by chlorides [12]. As an extension of this project, we report herein
the synthesis and cytotoxicity studies of four new NHC-Au(I)-sugar
complexes.
recent report [16]. Also, it is known that other sugars besides D-glu-
cose can be substrates for GLUT transporters, and can thus be con-
sidered as candidates for GLUT-targeting approach as well.
Different sugars have been conjugated to anticancer agents to take
advantage of GLUT-mediated cellular entry [17], for instance,
D-galactose, the C4 epimer of glucose, has been found to possess
an equivalent affinity and uptake rate by GLUT-1 compared to
glucose [18]. Hence, galactose was also chosen as a sugar ligand
leading to structure 3.
The success of auranofin as a treatment for arthritis as well as in
a currently ongoing preclinical trial for the treatment of chronic
lymphocytic leukaemia makes auranofin-like molecules potential
anticancer agents [13]. The incorporation of tumour-targeting
ligands such as sugars into metal complexes would thus be a
promising approach for targeted anticancer chemotherapy. This
could boost the impact on cancer cells and minimize the occur-
rence of adverse side effects [14]. Our previous work focused on
Our recent work on glycolipids disclosed structural extension
with an extra sugar could sometimes be beneficial to bioactive
molecules [19]. Lactose-containing complex 4 was thus designed
as another target structure. Finally, in order to explore the impact
of a spacer on the bioactivity profile, a three-carbon spacer was
inserted between the sugar and the metal core to give complex 5.
Based on our previous work [12], the synthesis of the above four
complexes 2–5 was relatively straightforward. Commercially
OAc
O
OAc
N
N
N
AcO
AcO
O
AcO
S
Au
Au
AcO
AcO
S
N
OAc
1
2
OAc
AcO
AcO
OAc
AcO
AcO
OAc
N
O
O
N
N
O
S
Au
O
S
Au
AcO
N
OAc
OAc
OAc
4
3
OAc
AcO
AcO
OAc
N
O
O
O
O
S
Au
AcO
OAc
N
OAc
5
Fig. 1. Structures of NHC-Au(I)-SR complexes 1–5.
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O. Dada et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
available 4,5-diphenylimidazole 6 (Scheme 1) was first di-benzy-
lated with BnCl in the presence of K2CO3 to give imidazolium chlo-
ride 7 in 35% yield following the literature procedure [20]. Chloride
7 was then treated with Ag2O in CH2Cl2 under the exclusion of light
at room temperature to generate the NHC-Ag(I) chloride complex,
which was in situ subjected to metal exchange with chloro
(dimethylsulfide)gold(I) to give NHC-Au(I) chloride 8 [12] in 83%
yield. Chloride 8 then served as the precursor to all four target
molecules 2–5. Meanwhile, as needed, four different thio-contain-
ing sugars 9–12 were prepared following different procedures
The a-anomeric configuration of thioglucose 9 was readily deter-
3
mined by the coupling constant JH1-H2 value, which is about 5.7
Hz, whereas analogous b-thiosugars, such as 10 and 11, have
3JH1-H2 value of 7–10 Hz. Thiol 12 [25] was synthesized from b-allyl
per-acetyllactoside in two steps: thiol-ene addition of thioacetic
acid to the double bond followed by selective S-deacetylation.
All the above thiols were then coupled with NHC-Au(I) chloride
8 to form the desired complexes (Scheme 1). The acetyl protecting
groups were retained in the target molecules 2–5 as they could be
labile under physiological conditions and easily hydrolysed to give
[21–24].
a
-Thioglucose 9 [21b] was prepared from tribenzyl
the true active form of the NHC-Au(I) complexes.
was first coupled with chloride 8 in the presence of Et3N in CH2Cl2
to produce compound 2 in very good yield. Notably, the -anome-
ric thiol, which is known to be less nucleophilic than its corre-
sponding b-counterpart [26], exhibited fairly good reactivity
towards the NHC-Au(I) chloride. The coupling between b-thiol 10
and chloride 8 were conducted under the same conditions, but
surprisingly, the reaction failed to give the desired product even
after prolonged reaction times. Hence, we turned to the biphasic
conditions, which has been successfully applied to the synthesis
a-Thioglucose 9
levoglucosan in four steps in very good yield involving a highly
stereoselective ring-opening procedure developed in our
laboratory [21a]. It is worth mentioning that the procedure was a
significant advance in glycosyl thiol chemistry because there had
not been any reports on the direct stereoselective preparation of
a
a-glycosyl thiols prior to our work. b-Glycosyl thiols 10 [22] and
11 [23] were prepared from the corresponding -bromides follow-
ing a standard two-step procedure [24], i.e. treatment with
thiourea followed by hydrolysis with an alkali metal disulfite.
a
BnCl
N+
1.Ag2O,CH2Cl2
2.(Me2S)AuCl
N
K2CO3
N
H
Cl
H
Au Cl
CH3CN
35%
N
H
N
N
83%
6
7
8
OAc
8, Et3N
OAc
O
O
CH2Cl2
N
N
AcO
AcO
AcO
AcO
Au
AcO
rt, 6h
79%
AcO
S
SH
9
2
8, K2CO3
EtOAc/H2O
1:1
OAc
AcO
AcO
O
OAc
AcO
AcO
SH
N
N
O
OAc
rt, 24 h
83%
S
Au
10
OAc
3
OAc
OAc
AcO
AcO
AcO
8, Et3N
OAc
OAc
O
O
N
N
CH2Cl2
O
O
O
AcO
O
SH
AcO
S
Au
AcO
OAc
OAc
rt, 3h
91%
OAc
OAc
11
4
8, K2CO3
CH2Cl2/H2O
SH
1:1
OAc
AcO
AcO
OAc
OAc
AcO
AcO
O
OAc
O
N
O
O
O
O
AcO
O
O
S
Au
OAc
OAc
AcO
rt, 4h
86%
OAc
N
12
OAc
5
Scheme 1. Synthesis of NHC-Au(I)-SR complexes 2–5.
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4
O. Dada et al. / Tetrahedron Letters xxx (2018) xxx–xxx
of S-glycopeptides and lanthionine derivatives [27]. A mixture of
10 and 8 in EtOAc was treated with an aqueous solution of
K2CO3, and as expected, the desired complex 3 was produced in
very high yield (Scheme 1). Both conditions were thus applied to
the formation of compounds 4 and 5, and fortunately, all reactions
worked well with the highest-yielding shown in Scheme 1. Thio-
glycosylation of 8 with thiol 11 under the action of Et3N gave com-
pound 4 in 91% yield, while with thiol 12 the reaction provided
compound 5 in 86% yield under the biphasic conditions. All of
the NHC-Au(I) complexes 2–5 were isolated as off-white solids
and fully characterized by spectroscopic techniques and micro-
analysis. The formation of complexes 2–4 could be readily deter-
mined by comparing the 1H NMR spectra of the complexes and
their corresponding glycosyl thiols 9–11. A triplet peak corre-
sponding to the anomeric protons of the thiols disappeared and
was replaced with a doublet peak in the complexes. The chemical
shifts of these protons were also clearly shifted. Also, the benzylic
protons observed as a singlet peak in the precursor chloride 8,
became diastereotopic and showed doublet of doublet peaks in
complexes 3 and 4, which was in accordance with the previous
report [12]. Interestingly, the benzylic protons remain a singlet
It is worth noting that the aim of this study was not to perform
a thorough investigation on the relative stability of all the possible
conformations but to evaluate the C-Au and Au-S distances and
benchmark the different functionals against the crystal structure
in order to select the best computational level to be used in larger
systems. All the functionals utilised provided reliable parameters
when compared with the crystal structure (see ESI for details).
The calculated C-Au distances range between 2.012 and 2.030 Å.
The worst case corresponds to B3LYP while MN15 and WB97XD
presented a good agreement with respect to the actual crystal
structure. Similar results are found for the Au-S distances in which
MN15 and WB97XD provided the closest values with respect to the
crystal structure in both conformers 1 and 2. Values of the Au-S-C
angle are very close to the crystal structure with deviations of 1°.
Fig. 4 shows the overlap between the calculated models and the
crystal structure (blue). As observed, all the functionals present a
good overlap with no significant deviations. As previously
observed, B3LYP presented the largest variations (Fig. 3, red) with
a total overall RMSD of the position of each atom with respect to
the crystal structure of 0.674 Å. The total overall RMSD for the rest
of the functionals were 0.428 (M06-2X, orange), 0.501 (MN15,
green) and 0.381 Å (WB97XD, cyan). Considering these results,
MN15 and WB97XD provided the most reliable results (less total
RMSD and distance deviation), and reproduce the crystal structure
more accurately. However, M06-2X could also describe the struc-
ture within a reasonably good accuracy.
A similar benchmark study was also carried out using the crys-
tal structure for p-methoxythiophenolate conjugated to the NHC⁄-
Au complex [28]. As observed in the case of NHC-Au-SCN, WB97XD
and MN15 functional provide the most accurate results, i.e. struc-
tural parameters such as bonding distances and angles from those
functionals are the closest to the crystal structure (see ESI). Once
the functionals are benchmarked and the computational level
selected, we obtained a model structure for compound 4. Fig. 4
shows the optimised structure and all the selected structural
parameters were gathered in Table 3 (see ESI). It is shown that
the Au-S bond distance ranges from 2.404 to 2.339 Å with an aver-
age Au-S bond distance of 2.372 0.027 Å. The C-Au distance is less
sensitive to the method with an average distance across the
method of 2.027 0.007 Å. Finally, the Au-S-C angle is very stable
showing an average value of 94.5 0.4°. Of course, there is a wide
range of different conformers to be considered since the OH groups
can have free rotation. But based on the previous crystal structures
and the benchmarks, we believe that this can be a very reliable and
possible structure.
peak for complexes 2 and 5 which is likely due to the a-anomeric
configuration of the sugar in 2 and the extra three-carbon linker in
5. The most conspicuous change in the 13C NMR spectra was the
migration of the chemical shift of the carbene carbon (NCN). The
peak, observed at around 170 ppm for chloride 8, was shifted
downfield to around 180 ppm for the NHC-Au(I) complexes 2–5,
indicating the different chemical environment of the carbon before
and after the reaction.
The in vitro cytotoxicity of the four synthesized complexes 2–5
were subsequently carried out at the National Cancer Institute
(NCI), and the results are given in the ESI. In all tested cell lines,
complex 2 had better activity in comparison with the other tested
compounds and is therefore a potential new anticancer drug candidate.
Computational results
Computational calculations were carried out in order to provide
a theoretical structure of 4.
Structures were optimized by DFT using different functionals
(B3LYP, M06-2X, WB97XD and MN15) with the 6–31 + G(d) basis
set for all the atoms and pseudopotentials LANL2DZ on the heavy
Au atom as described in the computational methods. Firstly, the
performance of each functional was benchmarked on the crystal
structure of NHC-Au-SCN [28]. For such purpose, the crystal struc-
ture was used as an input (Isomer 1) and optimised without any
constraints. Additionally, a second isomer was considered to
explore the possible influence of the different arrangements on
the structural parameters, i.e., Au-S distances, angles, etc, within
both isomers (Fig. 2).
In summary, as an extension of our previous project, four new
monomeric NHC-Au(I)-sugar complexes 2–5 were synthesized in
very high to excellent yields by reacting the appropriate pre-syn-
thesized acetylated thiosugars with NHC-Au(I) chloride. Two
different conditions were attempted for the reaction and the
Fig. 2. Two different conformers evaluated using DFT. Conformer
1
(Conf.1)
Fig. 3. Overlap between the crystal structure (blue), and those calculated using
corresponds to the crystal structure.
B3LYP (red), M06-2X (orange), MN15 (green) and WB97XD (cyan) functionals.
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O. Dada et al. / Tetrahedron Letters xxx (2018) xxx–xxx
5
associated with this article can be found, in the online version, at
https://doi.org/10.1016/j.tetlet.2018.06.040.
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Fig. 4. Structure of compound 4 at the WB97XD/6–31 + G(d)/Lanl2dz.
biphasic conditions were found to be more reliable and gave the
complexes in invariably high yields. The preliminary cytotoxic
activity of the complexes was tested using the NCI60 cancer cell
line panel. All compounds showed good activity against a wide
range of the tested human cancer cell lines. Among them, complex
2 showed the best overall activity in the series and exhibited better
activity than its b-counterpart 1 on all cell lines. Complex 4 exhib-
ited better activity than 3 by a factor of four and better activity
than 5 by a factor of six or seven on specific cell lines. Complex 4
also showed better activity than previously reported complex 1.
This finding indicates that appropriate substitution of the sugar
moiety on the NHC-gold(I) complex can improve the activity
against certain cancer cells. Therefore, there is potential for more
gold(I) complexes in therapy in the future from the rational design
of NHC-gold(I) complexes that are slightly more targeted. With the
use of computational calculations, we were also able to predict the
potential crystal structure of compound 4.
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Acknowledgements
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The authors greatly acknowledge financial support from the
UCD School of Chemistry and the National Cancer Institute (NCI)
at Maryland USA.
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A. Supplementary data
Supplementary data (experimental procedure, characterization
data, as well as copies of the 1H and 13C NMR of new compounds)
Please cite this article in press as: O. Dada et al., Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.06.040