In vitro Anti-atherogenic Properties of N-Heterocyclic Carbene Aurate(I) Compounds

Article abstract of DOI:10.1002/cmdc.201800601

The anti-atherogenic (anti-inflammatory) properties of various aurate(I) salts, of the general formula [NHC?H][AuCl₂] (NHC=N-heterocyclic carbene) were investigated. The aurates were easily synthesized and obtained in analytically pure form. In

Full text of DOI:10.1002/cmdc.201800601

Accepted Article
Title: In Vitro Anti-Atherogenic Properties of N-Heterocyclic Carbene
Aurate(I) Compounds
Authors: Steven Patrick Nolan, Ronan Lordan, Eleni Soriki, Ioannis
Zabetakis, Fady Nahra, and Kristof vanhecke
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To be cited as: ChemMedChem 10.1002/cmdc.201800601
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In Vitro Anti-Atherogenic Properties of N-Heterocyclic Carbene
Aurate(I) Compounds
Eleni Sioriki,[a] Ronan Lordan,[b] Fady Nahra,[a] Kristof Van Hecke,[a] Ioannis Zabetakis,[b]* and Steven P.
Nolan[a][c]
*
Abstract: The anti-atherogenic (anti-inflammatory) properties of
various aurate(I) salts, of the general formula [NHC·H][AuCl2] (NHC
= N-heterocyclic carbene) have been investigated. The aurates are
easily synthesized and obtained in analytically pure form. In addition,
the biological activity of these compounds against atheromatosis via
in vitro inhibition of platelet-activating factor (PAF) induced platelet
aggregation was probed. All complexes were found to possess anti-
aggregatory properties in vitro with [IPr*·H][AuCl2] 6 being the most
potent inhibitor of PAF in micromolar concentration. Based on our
findings, we conclude that these simply assembled aurates are a
very promising class of PAF-inhibitors and anti-inflammatory drugs.
platelets, macrophages and endothelial cells.[13,14] PAF and PAF-
like molecules are specific, structurally-defined ligands that
exclusively bind to PAF-R with exceedingly high affinity.[15–17]
Engagement of the PAF-R by PAF or PAF-like lipids triggers an
assortment of intracellular signalling cascades. This initiates
biochemical mechanisms that induces functional responses of
PAF-R bearing cells that then initiate or amplify inflammatory
and thrombotic events.[18]
With the projected increase in world population and increased
life-expectancy, chronic diseases and especially cardiovascular
diseases (CVD) have become the most important leading
causes of death, worldwide.[1] CVD is likely to reach epidemic
proportions in the coming decades.[2,3] These chronic
multifactorial inflammatory diseases are characterized by the
development of lesions on the intima wall of medium and large-
sized arteries, called atheromata or atherosclerotic plaques.
After decades of lethargic progression, these lesions progress
suddenly and cause stenosis, thus limiting blood-flow or even
arterial rupture causing characteristic clinical manifestations
such as distal ischemia, progressive clot formation, and stroke.[4]
One of the most potent mediators of inflammation that
plays a crucial role in atherosclerosis is platelet-activating factor
(PAF) (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine);[5] which
Figure 1. Chemical structure of PAF (1-O-alkyl-2-acetyl-sn-glycero-3-
phosphocholine)[5]
PAF induced inflammatory processes are intensely
involved in the initiation and progression of atherosclerosis.[6]
PAF is also involved in coronary artery constriction, modulation
of myocardial contractility, and the generation of arrhythmias,
which relate to cardiac disorders such as ischemia, infarction,
and sudden cardiac death.[19,20] Mediators of inflammation play
is
a
well-established biologically active glyceryl-ether
an important role in maintaining
a balance in an acute
phospholipid with 16-18 carbons at sn-1 position of the glycerol
backbone (Figure 1).[5] PAF modulates angiogenesis,
thrombosis, oncogenic transformation, tumor growth, metastasis
and the mechanism of atherogenesis (atheromatosis).[4-6] PAF is
considered to be a primitive and global cellular bio-regulator[5,8,9]
that was initially recognized from its potential cumulative action
to platelets but intense studies have shown a broader potent
biological activity in numerous cell types and tissues.[10–12]
PAF exerts its biological actions through a unique seven-
transmembrane G-protein-coupled receptor known as the PAF-
receptor (PAF-R) located on the plasma membrane of a wide
variety of mammalian cells, such as leukocytes, neutrophils,
inflammatory response. Therefore, many biochemical and
enzymatic markers have been suggested for the determination
of inflammation and cardiovascular disease.[21] Synthetic PAF-
inhibitors, such as Rupatadine[22] and natural dietary sources[7,23]
have demonstrated their ability to inhibit PAF-induced platelet
aggregation in washed rabbit platelets and in human platelets.
Transition metal compounds have a wide range of medical
applications. Platinum, palladium, ruthenium, and gold metal
complexes have been synthesised by the pharmaceutical
industry for a number of medicinal applications that include anti-
viral, anti-bacterial, anti-rheumatic and anti-inflammatory
efficacy.[24] Metals were first used 50 years ago, when Cisplatin
(cis-diamminedichloroplatinum(II)) was shown to inhibit cellular
division in Escherichia coli and was later studied for its anti-
tumor activity.[25,26] Cisplatin has since been shown to inhibit
PAF-induced platelet aggregation.[27] Previous research on gold
metal complexes has shown that they also possess putative
bioactivities that may be useful in medicinal applications,
particularly in relation to cancer treatment.[28,29] To date, only two
gold salts have been developed for medicinal purposes,
Au(I)thiolate and auranofin (Au(I)-thiolate triethylphosphine),
which have been used in the treatment of rheumatoid
arthritis.[28,30] Other complexes have not yet entered clinical trial
due to their high cardiotoxicity.[24]
[a]
Dr E. Sioriki, Dr F. Nahra, Dr K. Van Hecke, Prof. Dr S. P. Nolan
Department of Chemistry and Centre for Sustainable Chemistry,
Ghent University,
Krijgslaan 281, 9000 Ghent, Belgium.
E-mail: Steven.Nolan@UGent.be
[b]
[c]
R. Lordan, Dr I. Zabetakis
Department of Biological Sciences
University of Limerick, Limerick, V94 T9PX, Ireland.
Prof. Dr S. P. Nolan
Department of Chemistry, College of Science,
King Saud University,
P. O. Box 2455, Riyadh 11451, Saudi Arabia.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/cmdc.201800601
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COMMUNICATION
Previous studies have shown that metal complexes, such
as square planar rhodium(I) organometallic complexes and a
series of novel octahedral rhodium(III) complexes possess
potent antithrombotic properties.[27] Recently, NHC-based (NHC
= N-heterocyclic carbene) complexes have attracted substantial
interest as these compounds possess broad applications in the
field of medicine.[31] NHC ligands, are neutral 2-electron donors,
that have been extensively used to stabilize organometallic
species due to their strong donating properties and tunable
steric bulk.[32] In the particular case of gold complexes, the use
of NHC ligands has allowed for the isolation of typically unstable
species and for the development of highly active homogeneous
catalysts.[33] As we have significant expertise in the area of
NHCs, of transition-metal bearing NHC ligands and their uses,
we sought to investigate the potential anti-atherogenic properties
of various recently synthesized aurate(I)-NHC salts as well as
evaluate their in vitro biological activities against PAF induced
platelet aggregation.
bearing either alkyl or aryl groups of various size on the
heterocyclic nitrogens.
Figure 2. Thermal ellipsoid representations of complexes 4, 7 and 9 (from left
to right) at 50% probability. Solvent molecules and all hydrogen atoms are
omitted for clarity.
The putative antithrombotic and anti-inflammatory effects
of novel gold N-heterocyclic carbene complexes were next
assessed. Previous reports have shown that metal complexes
can inhibit PAF-induced platelet aggregation in washed rabbit
platelets (WRP) and rabbit platelet-rich plasma (PRP) in vitro
through the PAF receptor dependent pathway.[27] All of the gold
compounds tested in this study possessed strong antithrombotic
activity as indicated by their IC50 value expressed in µM (Table
1), thus confirming that these simple gold metal complexes can
inhibit PAF-induced platelet aggregation on human platelets in
vitro.
As it is clear that PAF plays a critical role in inflammatory
processes, the promising results of PAF inhibitor studies evoke
the need for the development of more synthetic PAF inhibitors.
In this study, nine gold complexes (1-9) were synthesized and
fully characterized via NMR spectroscopy, elemental analysis
and mass spectroscopy (Scheme 1). Furthermore, single
crystals of complexes 4, 7 and 9 were grown and their molecular
structures were unambiguously elucidated via X-ray diffraction
analysis (Figure 2). All complexes were air and moisture stable,
with the exception of 4, which decomposed upon prolonged
exposure to air. Thus, this complex was excluded from the
present biological assays.
Table 1. Inhibition of PAF-induced platelet aggregation in human PRP by gold
metal complexes (mean ± SD, n = 3).
Metal Complex
Formula
IC50 (µM) (mean ± SD, n =3)
2.01 ± 0.15b
1
2
3
5
6
7
8
9
A
[IPr·H][AuCl2]
[SIPr·H][AuCl2]
[IMes·H][AuCl2]
[IPent·H][AuCl2]
[IPr*·H][AuCl2]
[IPr*OMe·H][AuCl2]
[IDD·H][AuCl2]
[IAd·H][AuCl2]
[IPr·HCl]
[AuCl(SMe2)] (1 equiv.)
acetone, 40 oC, 1-2 h
N
N
N
N
R
R
R
2.96 ± 0.76c
1.67 ± 0.15b
1.62 ± 0.36b
0.98 ± 0.24a
1.66 ± 0.38b
1.58 ± 0.06b
1.69 ± 0.31b
3.52 ± 1.39c
R
Cl
AuCl2
N
N
N
N
N
N
N
N
AuCl2
[IMes·H][AuCl2] (3)
AuCl2
AuCl2
AuCl2
[SIPr·H][AuCl2] (2)
[IPr·H][AuCl2] (1)
[SIMes·H][AuCl2] (4)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
N
N
N
MeO
OMe
AuCl2
Ph
Ph
AuCl2
Ph
Ph
AuCl2
515.49 ± 102.58d
Ph
Ph
B
[AuCl(IPr)]
Ph
a,b,c,d
Values with similar superscripts indicate no significant statistical
difference; different superscripts indicate significant differences among the
different metal complexes (P<0.05) when means are compared using a
Fisher’s LSD multiple comparison test.
[IPr*OMe·H][AuCl2] (7)
[IPent·H][AuCl2] (5)
[IPr*·H][AuCl2] (6)
N
N
N
N
AuCl2
[IDD·H][AuCl2] (9)
12
12
AuCl2
[IAd·H][AuCl2] (8)
The IC50 values reflect the inhibitory strength of each
compound towards PAF induced platelet aggregation (Table 1).
A low IC50 value indicates a strong inhibitory effect against PAF
N
N
N
N
for
a given concentration of the metal complexes. The
Au
Cl
Cl
complexes synthesized in this study have displayed varying
levels of inhibition against the interactions of PAF and the PAF-
R in human platelets. As can be seen in Table 1, complex 6
exhibited the lowest IC50 value (0.98 µM ± 0.24) indicating that
this complex was the most potent against PAF-induced platelet
aggregation. The IC50 value for c 6 was significantly different
from all other complexes. Furthermore, when comparing the IC50
of 1, 3, 5, 7, 8, and 9, no significant difference is noticed. These
similar IC50 values may be due to the fact that there are only
subtle structural and electronic differences between these
complexes that lead to similar antithrombotic activity; it appears
that alkyl or aryl substituents on the nitrogen atoms do not
significantly influence the change in activity. However, when
comparing 6 to the closely related 7, we see a significantly
higher activity in the case of 6, which most likely is due to
IPr·HCl (A)
[Au(IPr)Cl] (B)
Scheme 1. Gold-imidazoli(ni)um, gold-NHC complexes and Imidazolium
evaluated for biological activity against PAF.
All gold(I) complexes were synthesised according to our
previously reported simple procedure (Scheme 1).[34] X-ray
analysis of complexes 4, 7 and 9 showed that the aurates were
indeed formed with a linear [Cl-Au-Cl]- anion in all cases, along
with the [NHC.H]+ as the counter-cation.[35] The family of
complexes consists of simple anion/cation pairs where the
cation is a saturated or unsaturated imidazole-based heterocycle
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10.1002/cmdc.201800601
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COMMUNICATION
electronic effects and/or solubility issues (since the difference
between 6 and 7 lies mainly in their electronic properties). The
presence of a methoxy group may account for this difference as
the lies at the periphery of the complex and may affect solubility
in the biological medium.[36] In contrast, complex 2 had a much
higher IC50 value than all other aurates in this study; this could
be due to the noticeable change in electronic properties since
this is the only complex bearing a saturated backbone. These
data indicate that major electronic variations, especially on the
NHC backbone, could be key for further developments in future
aurate-NHC drug design. These avenues are presently being
explored in our laboratories.
(Bepafant), BN 52021 (Ginkgolide B), Cedrol and Rupatadine
(0.02 µM, 3.6 µM, 13 µM and 0.26 µM respectively in WRP).[39–
44]
Therefore, these gold complexes may be viable for further
research and development for the purpose of anti-inflammatory
therapeutic agents for non-communicable diseases such as
cardiovascular disease and cancer. Further in vivo, ex vivo, and
clinical research is required in order to establish the efficacy of
these compounds as therapeutic agents.
PAF orchestrates its biological activity through a specific
seven-transmembrane receptor coupled with G-proteins (PAF-
R). Therefore, it is proposed that these gold compounds may
possess anti-inflammatory and anti-atherogenic effects. PAF-R
antagonists have exhibited promising results in vitro and in vivo
as anti-angiogenic molecules in several cancer cells and
tumors.[45] Gold complexes similar to those tested in this study,
have already exhibited anti-inflammatory activity (respiratory
burst assay) and cytotoxicity against HeLa (cervical cancer),
MCF-3 (breast cancer), and 3T3 (mouse fibroblast) cell lines.[29]
Notably, PAF has been implicated in coordinating angiogenesis,
oncogenic transformation, tumour growth, and metastasis in
cancer (AA). Research has shown that PAF plays a significant
metastatic role in difficult to treat cancers such as melanoma,
where it has shown to promote metastasis in vivo. Furthermore,
it has been demonstrated that the PAF-R antagonist PCA4248
has inhibited experimental human melanoma lung metastasis in
nude mice.[46] Therefore, as similar gold complexes to those
synthesized for this study possess anti-cancer activity,[28,29]
further research on the antagonistic actions of the herein
presented aurates against the PAF-R is warranted and currently
ongoing in our group, as they are potentially powerful anti-
metastatic agents.
In summary, the present work has evaluated for the first
time the structural and potent antithrombotic properties of gold
N-heterocyclic carbene complexes towards PAF-induced
aggregation of human PRP, at concentrations comparable with
those of classical PAF-inhibitors. The simple and atom-
economical synthetic route to these aurates renders them
attractive from an accessibility perspective. The inhibitory effect
of all aurate compounds was tested and expressed by their IC50
value in μM. All complexes were found to possess anti-
aggregatory properties in vitro with 6 being the most potent
inhibitor of PAF in micromolar concentration. Based on our
findings, we can conclude that these aurates are indeed a very
promising class of PAF-inhibitors and anti-inflammatory drugs.
Further investigations into molecular design are ongoing with the
aim of reaching even higher levels of efficacy in the in vitro
biological activity detailed in this study.
Two other compounds were tested to quantify any
background activity for ligand and neutral complexes.
Compound A, [IPr•HCl], was examined to study the activity, if
any, of the imidazolium ligand and compound B, [AuCl(IPr)], to
model the neutral Au(I) system.[28,29,34] Compound A contains the
IPr core without the gold moiety (only Cl- as counterion; this will
serve as a blank and will thus allow us to confirm the need for
the gold moiety when compared to its close counterpart complex
1) and compound B represents another class of gold complexes
that have shown potential in previous biological studies, though
having lower activity than the aurate-class showcased herein. It
is clear from Table 1 that compound B was far less potent than
the other complexes (515.49 µM ± 102.58), however this
compound possessed a relatively low IC50 in comparison to
those tested on WRP in the literature. In contrast compound A
demonstrated a lower IC50 (3.52 µM ± 1.39) than compound B;
however, this is still higher than all the other aurate complexes.
These data highlight the important difference between the
various classes of NHC compounds studied herein (NHC-
aurates 1-9 vs gold-NHC compound B vs gold-free imidazolium
compound A), where the combination of the gold moiety and
NHC salt present in the aurates seems to be crucial for higher
activity. To the best of our knowledge, metal complexes have
not been tested in human PRP; therefore, for the first time, this
study has confirmed that these gold complexes possess anti-
aggregatory
properties
against
PAF-induced
platelet
aggregation in vitro.
In previous research, WRP were the preferred method of
platelet aggregometry studies, due to their stability and longevity
while testing. Rabbit platelets also exhibit similar physiological
modes of platelet activation and aggregation to human platelets,
and thus is one of the main experimental models of choice to
replicate human platelets.[37,38] Therefore, the observed IC50
values of the studied gold complexes against PAF-induced
platelet aggregation can cautiously be compared with the IC50
values of metal complexes determined using rabbit PRP and
WRP in previous studies. The obtained IC50 values of the
aurates are within range of the IC50 values determined in studies
of rhodium and ruthenium metal complexes by PAF-induced
platelet aggregation in WRP. Rhodium complexes possessed
IC50 values of 0.015 - 2.6 µM in WRP, and IC50 values of 18 -
582 µM in rabbit PRP, whereas ruthenium complexes had IC50
values ranging from 0.18 – 11.8 µM in WRP and 10.5 – 900 µM
in rabbit PRP.[27,38] Of note, the iridium and ruthenium complexes
are obtained through multistep synthetic routes whereas the
present gold complexes are obtained after simply mixing a gold
Acknowledgements
This work was supported in part by the Department of Biological
Sciences, University of Limerick, Limerick, Ireland. We thank
King Saud University (Distinguished Scientist Fellowship
Program) and King Abdullah University of Science and
Technology (Award No.OSR-2015-CCF-1974-03) for their
support.
precursor and
a commercially available (or synthetically
Keywords: Platelet-activating factor • N-heterocyclic carbene •
Aurate • atheromatosis • Anti-atherogenic
straightforwardly obtained) imidazolium salt. Interestingly, the
NHC-aurates presented here inhibit PAF-induced platelet
aggregation to the same order of magnitude of known natural
and pharmaceutical PAF antagonists, namely Web 2170
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10.1002/cmdc.201800601
ChemMedChem
COMMUNICATION
Entry for the Table of Contents
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COMMUNICATION
A series of NHC-aurates
E. Sioriki, R. Lordan, F.
were
synthesised
and
Nahra, K. Van Hecke, I.
evaluated for the first time
for their anti-atherogenic
properties towards PAF-
induced aggregation of
human PRP. Both the gold
and NHC moieties were
shown to be crucial for
achieving good activity. All
complexes were found to
possess in vitro anti-
aggregatory properties.
Zabetakis*, and S. P. Nolan*
Page No. – Page No.
In Vitro Anti-Atherogenic
Properties of N-
Heterocyclic Carbene
Aurate(I) Compounds
This article is protected by copyright. All rights reserved.