Iridium complexes inhibit tumor necrosis factor-α by utilizing light and mixed ligands

Article abstract of DOI:10.1016/j.jorganchem.2016.02.001

We report herein a large study of the inhibition of tumor necrosis factor-α with 51 iridium(III) complexes, thus highlighting the influence of the nature of the ligands around the metal, their synergic effect and the role of the light.

Full text of DOI:10.1016/j.jorganchem.2016.02.001

Journal of Organometallic Chemistry 808 (2016) 122e127
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Communication
Iridium complexes inhibit tumor necrosis factor-
and mixed ligands
a by utilizing light
,
,
,
d
,
, b
Elodie Sauvageot a b, Pierre Lafite c d, Eric Duverger c e, Ronan Marion a
,
Matthieu Hamel f, Sylvain Gaillard a **, Jean-Luc Renaud a ***, Richard Daniellou c
,
b,
,
b,
, d, *
a
ꢀ
Normandie University, University of Caen Normandie, Laboratoire de Chimie Moleculaire et Thioorganique, 14050 Caen, France
b CNRS, UMR 6507, 14050 Caen, France
c
ꢀ
ꢀ
Univ. Orleans, CNRS, Institut de Chimie Organique et Analytique, 45067 Orleans, France
CNRS, UMR 7311, 45067 Orleans, France
d
e
ꢀ
ꢀ
Glycodiag, rue de Chartres, 45067 Orleans, France
f CEA, LIST, Laboratoire Capteurs et Architectures Electroniques, 91191 Gif-sur-Yvette Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We report herein a large study of the inhibition of tumor necrosis factor-a with 51 iridium(III) complexes,
Received 15 November 2015
Received in revised form
29 January 2016
Accepted 1 February 2016
Available online 18 February 2016
thus highlighting the influence of the nature of the ligands around the metal, their synergic effect and
the role of the light.
© 2016 Elsevier B.V. All rights reserved.
Keywords:
Iridium complexes
Inhibition
TNF-alpha
Light
1. Introduction
diversified roles in the body but all members, without exception,
exhibit pro-inflammatory activity, in part through activation of the
Since the discovery of the well-known cis-platin and its ana-
logues, organometallic complexes have been widely used as anti-
cancer drugs [1] and their biological studies are growing
exponentially. This intense interest has been summarized in many
reviews which nicely depict the state of the art of these researches
in many diseases [2]. The principle advantage of transition metal
complexes is their highly versatility for drug design. Besides vari-
ations in the metal and its oxidation state, metal ions have a range
of geometries and coordination numbers that allow the fine-tuning
for biological activities.
transcription factor NF-
kB [3]. Amongst them, the fascinating and
heavily studied TNF- demonstrated to play roles in inflammation,
a
cellular proliferation, apoptosis and morphogenesis. In addition, its
expression also proved to be linked with a wide variety of diseases,
including cancer, diabetes, obesity, cardiovascular, neurologic,
pulmonary, and autoimmune disorders. Thanks to that, TNF-a has
become a tremendous active target for drug development in the
last years. Novel therapies including anti-TNF antibodies such as
Enbrel®, Humira®, Remicade® or Cimzia®, have significantly
improved disease outcomes in patients suffering from a range of
important inflammatory conditions including rheumatoid arthritis,
psoriasis and Crohn's disease for examples. However and despite
their success in the clinic, such antibodies suffer from important
drawbacks, including poor tissue penetration, high manufacturing
costs and frequent secondary effects like increase of cancer. As a
consequence, there is an urgent need for alternatives. Following the
pioneering work of He et al. with the compound SPD304 (Fig. 1) [4],
small molecule modulation of this specific protein-protein inter-
The tumor necrosis factor (TNF) superfamily plays highly
ꢀ
* Corresponding author. Univ. Orleans, CNRS, Institut de Chimie Organique et
ꢀ
Analytique, 45067 Orleans, France.
** Corresponding author. Normandie University, University of Caen Normandie,
ꢀ
Laboratoire de Chimie Moleculaire et Thioorganique, 14050 Caen, France.
*** Corresponding author. Normandie University, University of Caen Normandie,
ꢀ
Laboratoire de Chimie Moleculaire et Thioorganique, 14050 Caen, France.
action, i.e. able to transform an active TNF-a trimer into an inactive
E-mail addresses: sylvain.gaillard@ensicaen.fr (S. Gaillard), jean-luc.renaud@
ensicaen.fr (J.-L. Renaud), richard.daniellou@univ-orleans.fr (R. Daniellou).
http://dx.doi.org/10.1016/j.jorganchem.2016.02.001
0022-328X/© 2016 Elsevier B.V. All rights reserved.

E. Sauvageot et al. / Journal of Organometallic Chemistry 808 (2016) 122e127
123
OH
CH3
CH3
O
O
S
N
H
O
OH
O
HN
O
HN
NH
N
N
O
NH
HN
OH
H
H
O
N
NH2
N
N
H2N
N
O
O
H
O
O
O
OH
S
F3C
SPD304
WP9QY
OH
Fig. 1. Chemical structures of SPD304 and WP9QY.
dimer, has also been recognized as a promising approach in drug
discovery [5]. For example, the antagonist cyclic peptide WP9QY
(Fig. 1) demonstrated its efficiency in preventing both inflamma-
tory bone destruction and systemic bone loss in rheumatoid
arthritis [6]. Structured-based screening of chemical library of
natural products has also led to the discovery of two potent small
inhibitors, namely quinuclidine and indoloquinolizidine [7].
Moreover the screening of the SPECS database allowed the identi-
fication of original scaffolds with promising biological properties
[8]. Besides, group 9 organometallic compounds have recently
received an increased attention for their therapeutic and bio-
analytical applications, mainly due to their ease of preparation,
their stability in water and air, and their high solubility [9].
Amongst them, the team of Leung recently reported that the
racemic (or even each enantiomer) iridium(III) complex, [Ir(p-
py)2(biq)][PF6], was able to prevent the active trimer association
2.2. General procedure GP2 for the synthesis of neutral
[Ir(C^N)2(acac)] complexes
In a flamed-dried Schlenk tube under argon atmosphere,
iridium dimers (1 eq.) and acac ligands (5 eq.) were introduced in a
degassed solution of ethoxyethanol with K2CO3 (10 eq.). The reac-
tion mixture was stirred at 100 ꢀC for 24 h. After cooling down the
solution to room temperature, water was added affording a pre-
cipitate. The resulting precipitate was collected on a frit and
washed with water (5 mL) and diethyl ether (5 mL) and finally dried
under vacuum to afford pure complexes.
2.3. TNF-aeTNFR-1 binding ELISA procedure
This assay was carried following a known protocol [10]. Briefly,
microtiter plates were coated overnight with TNF- (0.625 g/mL)
in 100
L PBS at 4 ꢀC. The wells were washed three times with
200 L PBS/0.05% Tween 20 (PBST), blocked with 200 L PBST
containing 1% BSA for 60 min and washed as before. Dilutions of the
test compounds (100 M) in 50 L PBS containing 2% DMSO were
added to the wells and the microtiter plates were incubated with
shaking for 20 min. TNFR-1 (0.2 g/mL) in 50 L PBS was added to
a
m
through its interaction with
exhibited an IC50 of 22 M in ELISA experiments against the TNF-
TNFR1 interaction, comparable with SPD304 [10].
b-strands of the TNF-a dimer, and
m
m
a/
m
m
Since several years, we have developed a research program
devoted to the synthesis [11], the coordination [12], and the reac-
tivity of metal complexes coordinated to dipyridylamine de-
rivatives. We have recently reported the synthesis and the
characterization of a series of neutral and cationic cyclometalated
iridium(III) complexes bearing both C^N ligands and a dipyridyl-
amine motif as N^N ligand [13,14]. They proved to be efficient cat-
alysts under photoredox conditions in a model aza-Henry reaction
m
m
m
m
the wells and the plates were incubated for a further 120 min. The
plates were washed as before and incubated for 120 min with
TNFR-1 antibody (1:1000) in 100 mL PBST containing 1% BSA. The
plates were washed three times with PBST and incubated for
90 min with anti-rabbit cross adsorbed-peroxidase secondary
[13]. Herein, we wish to report the inhibition properties of TNF-
with 51 iridium(III) heteroleptic organometallic complexes.
a
antibody (8
and incubated with 100
chlorhydric acid and the absorbance was measured at
m
g/mL) in 100
m
L PBS. The plates were washed as before
L 2 N
¼ 450 nm.
m
L TMB solution, quenched with 100
m
l
2.4. Influence of light on ELISA procedure
2. Material and methods
Microtiter plates were coated overnight with TNF-
a
(0.625
m
g/
mL) in 100
200 L PBS/0.05% Tween 20 (PBST), blocked with 200
containing 1% BSA for 60 min and washed as before. Test com-
pounds (100 M) in 50 L PBS containing 2% DMSO were added to
m
L PBS at 4 ꢀC. The wells were washed three times with
2.1. General procedure GP1 for the synthesis of [Ir(C^N)2(N^N)][PF6]
complexes
m
mL PBST
m
m
In a dry flamed Schlenk tube under argon atmosphere, iridium
dimers (1 eq.) and N^N ligands (2.2 eq.) were introduced in
degassed 2:1 mixture of dichloromethane/methanol (8 mL). The
reaction mixture was stirred at 50 ꢀC for 6 h. After cooling down the
solution to room temperature, excess of KPF6 (10 eq.) was added
affording a precipitate. The inorganic solid was filtered off and the
filtrate was evaporated. The solid was washed on a frit with diethyl
ether (3 ꢁ 5 mL) and dried under vacuum to afford pure cationic
iridium [Ir(C^N)2(N^N)][PF6] complexes.
the wells and the microtitre plates were incubated with shaking for
20 min, under blue LED strip (FlexLed inspire®, 2.4 W/m) or
obscurity. TNFR-1 (0.2 mg/mL) in 50 mL PBS was added to the wells
and the plates were incubated for a further 120 min under blue LED
strip or obscurity. The plates were washed as before and incubated
for 120 min under blue LED strip or obscurity with TNFR-1 antibody
(1:1000) in 100 mL PBST containing 1% BSA. The plates were washed
three times with PBST and incubated for 90 min under blue LED
strip or obscurity with anti-rabbit cross adsorbed-peroxidase

124
E. Sauvageot et al. / Journal of Organometallic Chemistry 808 (2016) 122e127
secondary antibody (8
m
g/mL) in 100
m
L PBS. The plates were
L TMB solution,
L 2 N chlorhydric acid and the absorbance was
¼ 450 nm.
used to facilitate the comparison [10]. Briefly microtiter plates
coated with TNF- were incubated with TNFR-1 together with
racemic complexes. TNFR-1 binding was detected using anti-TNFR-
1 antibody and horseradish peroxidase-conjugated secondary
antibody, by measuring the absorbance at 450 nm.
washed as before and incubated with 100
quenched with 100
measured at
m
a
m
l
2.5. Synergic tests procedure
Unsurprisingly, all the complexes demonstrated to be inhibitors,
going from really poor to highly potent ones (Table 2). Amongst
them, 10 complexes were able to inhibit the interaction at more
Microtiter plates were coated overnight with TNF-a (0.625 mg/
mL) in 100
200 L PBS/0.05% Tween 20 (PBST), blocked with 200
containing 1% BSA for 60 min and washed as before. Two of the test
compounds (100 M) in 25 L PBS containing 2% DMSO were
combined and added to the wells, following the same procedure,
4a, 1c, 3c (100 M) in 16.66 L PBS containing 2% DMSO were
combined and added to the wells. The microtiter plates were
incubated with shaking for 20 min. TNFR-1 (0.2 g/mL) in 50 L PBS
m
L PBS at 4 ꢀC. The wells were washed three times with
than 50% at a concentration of 50 mM, three complexes were even
m
m
L PBST
more potent and only let less than 40% residual binding. Indeed,
like protein-protein interactions were mostly occurring through
hydrophobic interactions, and as reported by Leung et al. [10], ar-
m
m
omatic ligands were expected to be able to interact with the
strands of the binding site of the dimeric form of TNF- . Such re-
sults suggested that the size of the complex and the nature of the
ancillary ligands are of utmost importance for the TNF- inhibitory
b-
m
m
a
m
m
a
was added to the wells and the plates were incubated for a further
120 min. The plates were washed as before and incubated for
120 min with TNFR-1 antibody (1:1000) in 100 mL PBST containing
1% BSA. The plates were washed three times with PBST and incu-
bated for 90 min with anti-rabbit cross adsorbed-peroxidase sec-
activity. More precisely, series a and c demonstrated to be more
potent than b and d, with average residual binding values of 56.2%
and 47.2% against 61.7% and 71.0% respectively. Lower inhibitory
activities were observed with the piq ligands compared to the ppy
ones. Such result might be explained by the steric hindrance of the
isoquinoline moiety. Therefore, in our study, the best C^N ligand
was bzq, slightly better than ppy ligand previously reported by
Leung et al. [10] N^N ligands were also crucial for the interactions
and small changes could have terrible impact. For example, the
addition of methyl substituents could greatly increase the biolog-
ical properties, as shown by going from complex 3a to 4a or 5a. In
an overall manner, polyaromatic substituents are more effective
(phen > bpy and dpa). This trend might be also correlated with the
planarity of the N^N ligands. A negative charge on the N^N ligand
appeared to be unfavourable (dpa compared to dpa-). It is note-
worthy that acac ligands displayed interesting biological proper-
ondary antibody (8
as before and incubated with 100
100 L 2 N chlorhydric acid and the absorbance was measured at
¼ 450 nm.
mg/mL) in 100
mL PBS. The plates were washed
mL TMB solution, quenched with
m
l
2.6. Blue native PAGE analysis of TNF-ae1c interaction
A solution of TNF-
a (20 mM) in presence or absence of 1c
(100 M) was analyzed using Blue-Native PAGE in 12% Poly-
m
acrylamide resolving gel following reported procedures [15].
3. Results and discussion
ties, despite giving neutral iridium(III) complexes. As
consequence, the three best complexes were 1c, 3c and 4a, with
IC50 values of 25 16 M, 34 M and 48 M, respectively.
a
Only one iridium cationic complex has been previously
m
3
m
7 m
described for TNF-
a
inhibition [10]. In this work, we prepared a
In a second series of experiments, a 1/1 mixture of two different
complexes 4a, 1c or 3c was used in the ELISA tests. Surprisingly, all
reactions demonstrated an increased inhibitory activity going from
9% to 19%, but yet unexplained (Fig. 2). The best synergic effect was
observed when the two complexes 3c and 4a where mixed. A 1/1/1
mixture of the three complexes proved also to be more efficient
that one complex alone, but to a lesser extent than the latter one.
Interestingly, this effect cannot simply be attributed to ligand ex-
change since none were observed as demonstrated by NMR cor-
relation studies of the different mixtures (see E.S.I.).
Finally, the influence of the nature of the light was evaluated in
ELISA tests with our three best complexes 1c, 3c and 4a (Fig. 3 up).
In the absence of light, the complexes were less potent. Interest-
ingly, the blue light induced an increase in the inhibitory activity
from 6% to 15%, and the white light was the most effective with an
increase up to 21%. In fact, all theses three complexes, including
either a ppy and/or bzq ligand, have previously demonstrated to
series of 51 racemic iridium(III) complexes, both neutral and
cationic, in order to give a good overview of the structure-function
relationships (Table 1).
Such complexes can be easily obtained with high isolated yields
ranging from 47 to 99%, via a two steps synthesis following known
procedures (see Scheme 1 and E.S.I) [13,16]. Their structures were
assessed by comparison with known X-ray structure of previously
published iridium complexes and by NMR (see E.S.I.). Amongst
them, 21 were never previously chemically synthesized and char-
acterized (in italics in the table). In our study, we thus decided to
select four cyclometalated C^N ligands 2-phenylpyridine (ppy) a, 1-
phenylpyrazole (ppz) b, 7,8-benzoquinoline (bzq)
c and 1-
phenylisoquinoline (piq) d and eleven ancillary N^N ligands 2,20-
bipyridine (bpy) 1 and its dimethyl analogue (4-Me-bpy) 2, 1,10-
phenanthroline (phen) 3, 2,9-dimethyl-1,10-phenanthroline (neo)
4, 3,4,7,8-tetramethyl-1,10-phenanthroline (tphen) 5, 2,20-dipyr-
idylmethane (dpm) 6, 2,20-dipyridylamine (dpa) 7 and its 3-, 4- and
5-dimethyl analogues, (3-Me-dpa) 8, (4-Me-dpa) 9 and (5-Me-dpa)
10 respectively, or N-methyl derivative (N-Me-dpa) 11. Combina-
tion of these C^N and N^N ligands led to a series of 42 cationic
complexes (C^N ¼ a-d, N^N ¼ 1e11, see Table 1). In addition, three
anionic ligands namely the anion of dpa (dpa-) 12, the anion of the
dibenzoylmethanate (dbm) 13 and the acetylacetonate (acac) 14
allowed us to obtain 9 neutral complexes (C^N ¼ a-d, N^N ¼ 12,
O^O ¼ 13e14, see Table 1).
present a maximum of absorption which can be ascribed to a
ligand-centred (LC) transition, in the UV region as well as a weak
and broad band of absorption at 425 nm, that corresponds to a d
* metal-to-ligand charge transfer ([1]MLCT) (Fig. 3 bottom) [13].
pep*
p
-
p
They also proved to own photoredox capacities that might be at the
origin of such increase activities. Such hypothesis was strengthened
by the observed lower inhibitory activities with ppz-complexes
(series b), which do not present any maximum of absorption in
the visible region. Therefore the iridium complex might interact
with the protein (and some amino acids) via a radical process and
then might be not the same at the end of the irradiation period.
However no change was observed using mass spectrometry of the
protein in the presence of such complex nor of the iridium complex
With these complexes in hands, we investigated their capacity
in inhibiting the TNF-a/TNF Receptor-1 interaction, using an ELISA
experiment to determine the half-maximal inhibitory concentra-
tion (IC50) values. Similar conditions than previously reported were

E. Sauvageot et al. / Journal of Organometallic Chemistry 808 (2016) 122e127
125
Table 1
Series of Iridium (III) complexes C^N ¼ aed.
C
Ir
C
Ir
C
Ir
N
N
N
O
O
N
N
N
N
[PF6]
C
C
C
N
N
N
O^O=13-14
N^N=12
N^N=1-11
C^N
a (ppy)
b (ppz)
c (bzq)
d (piq)
N^N
bpy 1
1a
2a
1b
1c
2c
1d
2d
4-Me-bpy 2
2b
phen 3
neo 4
3a
4a
3b
3c
4c
3d
4b
4d
tphen 5
5a
5b
5c
5d
dpm 6
dpa 7
6a
6b
6c
6d
7a
7b
7c
7d
3-Me-dpa 8
4-Me-dpa 9
8a
9a
8b
9b
8c
9c
8d
9d
5-Me-dpa 10
N-Me-dpa 11
10a
10b
10c
10d
11a
e
e
11d
dpa- 12
12a
12b
e
12d
O^O
dbm 13
13a
13b
14b
13c
e
e
acac 14
14a
14c

126
E. Sauvageot et al. / Journal of Organometallic Chemistry 808 (2016) 122e127
Scheme 1. Synthesis of the iridium complexes.
Table 2
Residual binding between TNF-a/TNF Receptor-1 when incubated with 50 mM of
racemic iridium(III) complexes (each value represents the average of three indi-
vidual measurements).
a (ppy)
b (ppz)
c (bzq)
d (piq)
bpy 1
4-Me-bpy 2
phen 3
neo 4
tphen 5
62
63
95
37
40
48
48
59
68
56
100
51
64
46
3
2
7
3
3
1
3
4
3
2
56
84
56
46
80
65
66
58
91
63
e
6
4
5
5
3
1
5
3
9
2
44
59
36
56
90
57
53
52
57
54
e
2
5
3
2
2
4
3
2
1
4
61
65
58
55
73
58
55
73
78
69
72
70
e
3
7
5
7
4
1
7
2
7
3
1
8
dpm 6
dpa 7
3-Me-dpa 8
4-Me-dpa 9
5-Me-dpa 10
N-Me-dpa 11
dpa- 12
2
7
3
78
55
45
1
2
2
e
dbm 13
acac 14
65
44
2
2
e
Fig. 3. (up) Increase of inhibitory activity when incubated with 50
mM of racemic
iridium(III) complexes with different lights. (bottom) Absorption spectra of 1c, 3c
and 4a.
Fig. 2. Increase of inhibitory activity when incubated with 50 mM of equimolar mixture
of multiple different racemic iridium(III) complexes.
itself (data not shown). Another hypothesis is that, under visible
light, the iridium is excited, and its geometry might be changed
allowing better interactions with the protein.
The biologically active form of TNF-a corresponds to the trimer.

E. Sauvageot et al. / Journal of Organometallic Chemistry 808 (2016) 122e127
127
bpy
2,20-bipyridine
bzq
7,8-benzoquinoline
dpa
dpm
LC
2,20-dipyridylamine
2,20-dipyridylmethane
Ligand-Centred
MLCT
neo
phen
piq
ppy
ppz
Metal-to-Ligand Charge Transfer
2,9-dimethyl-1,10-phenanthroline
1,10-phenanthroline
1-phenylisoquinoline
2-phenylpyridine
1-phenylpyrazole
tphen
TNF
3,4,7,8-tetramethyl-1,10-phenanthroline
Tumor Necrosis Factor
Fig. 4. Native Gel of TNF-a in the presence/absence of the racemic complex 1c.
Appendix A. Supplementary data
Indeed, previous works reported that small inhibitors like SPD304
were able to maintain the protein under its dimeric state, by pro-
moting subunit dissociation [4]. Leung et al. postulated a similar
biological mechanism when using the [Ir(ppy)2(biq)][PF6] complex
and used molecular modelling to assess their findings. However, in
this latter case, no direct evidence of such interaction has been
demonstrated so far. Through native gel analysis (Fig. 4), we were
able to show that in the absence of 1c, only one band corresponding
to the trimeric form is present. However, in the presence of 1c, this
band disappeared to the profit of a very faint smear band, at a size
corresponding to the dimeric form. This constitutes direct evidence
and strongly supports the previous observation of Leung et al. [10].
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.jorganchem.2016.02.001.
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demonstrated their capacity to inhibit the TNF-a/TNF Receptor-1
interaction at various degrees. Structure-activity relationship
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complexes on the dimeric form of TNF-a. All together, these results
pave the way for the development of efficient metal-based in-
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Acknowledgements
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This work was supported by the “Ministere de la Recherche et
des Nouvelles Technologies”, CNRS (Centre National de la Recher-
che Scientifique). The LABEX SynOrg (ANR-11-LABX-0029) is
acknowledged for a PhD grant (E.S.). The authors thank the “Agence
Nationale de la Recherche”, within the CSOSG program (ANR-12-
SECU-0002-02), and the “Region Basse-Normandie” for funding
(Post doc grant for R.M.).
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Table of abbreviation
acac
acetylacetonate
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