Gold(I) N-heterocyclic carbene complexes with naphthalimide ligands as combined thioredoxin reductase inhibitors and DNA intercalators

Article abstract of DOI:10.1002/cmdc.201402049

Organometallic conjugates consisting of a gold(I) N-heterocyclic carbene (NHC) moiety and a naphthalimide were prepared and investigated as cytotoxic agents that interact with both DNA and the disulfide reductase enzyme thioredoxin reductase (TrxR). The c

Full text of DOI:10.1002/cmdc.201402049

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DOI: 10.1002/cmdc.201402049
Gold(I) N-Heterocyclic Carbene Complexes with
Naphthalimide Ligands as Combined Thioredoxin
Reductase Inhibitors and DNA Intercalators
Andreas Meyer,[a] Luciano Oehninger,[a] Yvonne Geldmacher,[b] Hamed Alborzinia,[c]
Stefan Wçlfl,[c] William S. Sheldrick,[b] and Ingo Ott*[a]
Organometallic conjugates consisting of a gold(I) N-heterocy-
clic carbene (NHC) moiety and a naphthalimide were prepared
and investigated as cytotoxic agents that interact with both
DNA and the disulfide reductase enzyme thioredoxin reductase
(TrxR). The complexes were potent DNA intercalators related to
their naphthalimide partial structure, inhibited TrxR as a conse-
quence of the incorporation of the gold(I) moiety, and trig-
gered efficient cytotoxic effects in MCF-7 breast and HT-29
colon adenocarcinoma cells. Strong effects on tumor cell me-
tabolism were noted for the most cytotoxic complex, chlori-
do[1-(3’-(4’’-ethylthio-1’’,8’’-naphthalimid-N’’-yl))-propyl-3-
methyl-imidazol-2-ylidene]gold(I) (4d). In conclusion, the con-
jugation of naphthalimides with gold(I) NHC moieties provided
a useful strategy for the design of bioorganometallic antican-
cer agents with multiple modes of action.
Introduction
1,8-Naphthalimides are a category of substances exhibiting
high antitumor activities based on an effective intercalation
into DNA and other effects such as apoptosis induction.[1]
Some of these compounds (e.g., amonafide, Figure 1) were
studied as anticancer agents in clinical trials but did not prog-
ress to extended therapeutic application. Optimization of
naphthalimide anticancer drugs is an ongoing process that has
led to a high number of very potent cytotoxic substances that
hold great promise for anticancer drug development.[2]
One promising strategy is the combination of the naphthali-
mide moiety with metal fragments aiming at the design of cy-
totoxic agents that act via multiple modes of action. To the
best of our knowledge, this concept was used for the first time
by Navarro-Ranninger and colleagues who reported in 1999 on
platinum(II)-naphthalimide conjugates, which combine the
concept of intercalation with that of DNA platination (see
Figure 1 for an example).[3] Interestingly, these complexes were
able to circumvent cisplatin resistance.
In 2009, we reported on naph-
thalimides containing gold(I)-
phosphane partial structures
that were attached via a thiolate
to the aromatic region of the
naphthalimide moiety.[4] The
complexes combined intercala-
tion with gold(I) based thiore-
doxin reductase (TrxR) inhibition
as a non-DNA-directed mecha-
Figure 1. Amonafide and examples of metal naphthalimide conjugates.
nism, and thus they opened op-
tions for the design of multitar-
get naphthalimides. Moreover,
[a] A. Meyer, Dr. L. Oehninger, Prof. Dr. I. Ott
Institute of Medicinal and Pharmaceutical Chemistry
Technische Universitꢀt Braunschweig
these conjugates induced apop-
tosis and inhibited angiogenesis, which was related to the
presence of the naphthalimide structure. The uptake of gold
into the nuclei of cancer cells could be confirmed by atomic
absorption spectroscopy and that of the naphthalimide struc-
ture by fluorescence microscopy. In recent reports, the cytotox-
icity and anticancer properties of naphthalimide metal conju-
gates with platinum,[5] ruthenium[6] and other metals[5a] have
been addressed. One interesting example is a fluorescent plati-
num(II) terpyridine complex, which was efficiently taken up
into tumor cells and induced apoptosis.[5b]
Beethovenstr. 55, 38106 Braunschweig (Germany)
[b] Dr. Y. Geldmacher, Prof. Dr. W. S. Sheldrick
Lehrstuhl fꢁr Analytische Chemie
Ruhr-Universitꢀt Bochum
44780 Bochum (Germany)
[c] Dr. H. Alborzinia, Prof. Dr. S. Wçlfl
Institute of Pharmacy and Molecular Biotechnology
Ruprecht-Karls-Universitꢀt Heidelberg
Im Neuenheimer Feld 364, 69120 Heidelberg (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201402049.
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plexes 4a–d was achieved by reacting 3a–d with
Ag2O, which led to the formation of silver intermedi-
ates, and by a subsequent transmetallation reaction
using chlorido(dimethylsulfide)gold(I). Isolation and
purification of 4a–d was performed by filtration over
Celite, recrystallisation in diethylether and drying
over P2O5.
In the 1H NMR spectra of the gold(I) NHC com-
pounds 4a–d, the absence of the imidazole C2
proton signal at d=9.1–9.3 ppm is an example con-
firming the formation of the organometallic carbonÀ
gold bond. The high purity of 3a–d and 4a–d was
determined by elemental analyses, which differed
less than 0.5% from the theoretical values.
The interesting photophysical properties and often
intense fluorescence emissions of naphthalimides
and also of various transition metal complexes are
well known, and many examples have been reported
as efficient fluorescence sensors or imaging probes.[9]
Recently, we had reported on naphthalimides with
Scheme 1. Reagents and conditions: a) 1-(3’-aminopropyl)-imidazole, reflux in ethyl ace-
tate for 8 h; b) alkyl halide, reflux in toluene for 12 h; c) Ag2O in methanol/CH2Cl2, RT for
6 h, followed by addition of chlorido(dimethyl sulfide)gold(I) in CH2Cl2, RT for 4–24 h.
Here we report on a first series of novel gold(I) complexes
containing naphthalimide ligands (Scheme 1). The gold(I)
center was introduced in form of a gold(I) N-heterocyclic car-
bene (NHC) moiety, an organometallic functional group that
exhibits promising properties for anticancer drug design (e.g.,
TrxR inhibition, apoptosis induction) as reported by us and
others.[7] The gold(I) NHC center is incorporated into the side
chain of the naphthalimides at the position of an essential
amino nitrogen.[1a] Protonation of the side chain nitrogen
under physiological conditions leads to a positively charged
species that is thought to interact with the negatively charged
phosphate backbone of the DNA, and this interaction facili-
tates the intercalation of the flat aromatic ring system into the
DNA. Of note, effective interaction with the DNA can also be
achieved by incorporation of a quaternized cationic nitrogen
center in the respective position in the side chain.[8]
thioether or gold(I)-thiolate partial structures and the imaging
of their cellular uptake and intracellular localization by fluores-
cence microscopy.[4,9f] In this context, we measured UV/Vis and
fluorescence spectra exemplarily for the series 2a–4a with the
perspective of performing cellular localization studies by
means of fluorescence microscopy. However, the obtained re-
sults indicated that the fluorescence emission of 2a–4a was
too weak to perform this kind of experiments (for details, see
the Supporting Information).
Effects on tumor cell proliferation and inhibition of TrxR
The triggering of antiproliferative effects of the compounds
was investigated in two tumor cell lines, namely MCF-7 human
breast adenocarcinoma and HT-29 colon carcinoma cells
(Table 1). The gold-free imidazolium cations 3a–d caused mod-
erate cytotoxic potency against HT-29 cells with IC50 values in
the range of 27–57 mm, but afforded stronger activity in MCF-7
cells (IC50 =4–18 mm). Transformation into gold(I) NHC com-
plexes 4a–d led to a strong increase in cytotoxic activity in
both cell lines in the case of 4a, 4b and 4d, whereas with
This report provides a proof of concept that, upon introduc-
tion of imidazole-based gold(I) NHC fragments into the men-
tioned position of cytotoxic naphthalimides, active metallo-
drugs can be obtained. These carry essential properties of
both the naphthalimide and the gold(I) NHC partial structure.
The synthesis, characterization and biological evalua-
tion of the new complexes is described.
Table 1. Antiproliferative effects in HT-29 and MCF-7 cells and melting point shifts of
the respective compounds in 10 mm phosphate buffer (pH 7.2) at a [complex]/[DNA]
ratio of 0.1.
Results and Discussion
R1
R2
IC50 [mm][a]
IC50 [mm][a]
DTm [8C] IC50 [mm][a]
Chemistry
Compd
HT-29
MCF-7
TrxR
Naphthalimides with imidazole-containing side
chains, namely 2a and its thioether derivative 2b,
were prepared by heating the respective naphthalic
anhydrides 1a and 1b with 1-(3’-aminopropyl)-imida-
zole at reflux in ethyl acetate. The resulting naphtha-
limides were heated at reflux with an excess of an
akylhalide in toluene in order to obtain derivatives
containing imidazolium halides in the side chain (3a–
d). The formation of the target gold(I) NHC com-
3a
3b
3c
3d
4a
4b
4c
4d
H
H
H
CH3
56.8Æ0.7
31.3Æ8.9
43.1Æ10.2
27.5Æ16.2
4.0Æ0.7
9.2Æ0.2
17.1Æ1.7
5.2Æ0.6
4.6Æ3.6
4.6Æ1.5
6.3Æ0.6
5.8Æ2.9
2.1Æ0.5
3
4
10
n.d.
11
6
>1
n.d.
n.d.
>1
0.28Æ0.12
n.d.
n.d.
0.40Æ0.13
CH2CH3
CH2-Ph
CH3
SCH2CH3
H
H
H
CH3
CH2CH3
CH2-Ph
CH3
4.9Æ1.8
18.2Æ5.9
1.9Æ0.3
4
6
SCH2CH3
[a] Data represent the meanÆSEM of 2–3 experiments. n.d.=not determined.
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complex 4c this effect was only observed in HT-29 but not in
MCF-7 cells.
information on changes in the conformation of the nucleic
acid structure.
As mentioned above, TrxR is an important cancer target and
many gold(I) complexes are strong inhibitors of this enzyme
with IC50 values in the submicromolar range.[10] Comparing the
cytotoxicity values of the gold(I) species 4a–d indicates a pref-
erence for those complexes containing the sterically less de-
manding methyl group on one of the imidazole nitrogens
(R2 =CH3). Accordingly, 4a and 4d were selected as examples
to study the inhibition of TrxR. The gold-free analogues 3a
and 3d were selected as the corresponding negative referen-
ces. In fact, 4a and 4d effectively inhibited TrxR activity with
IC50 values of 0.28Æ0.12 and 0.40Æ0.13 mm, respectively, in an
assay that measures the activity of purified TrxR exposed to
the compounds. In contrast, 3a and 3d did not cause inhibi-
tion of TrxR up to the highest investigated concentration of
1.0 mm. The TrxR inhibition values of 4a and 4d are compara-
ble with those obtained with gold(I) complexes of the type
[AuICl(PR3)],[11] a benzimidazolylidene-containing NHC complex
[AuCl(NHC)][7d] or the recently reported gold(I) naphthalimide
derivative.[4b] This indicates that the gold(I) NHC fragment con-
tributes the expected TrxR inhibiting properties of the here re-
ported gold naphthalimide conjugates.
The CD spectra obtained with the imidazolium cations 3a–
c did not show strong changes in the intensity of the peak at
245 nm; however, the shape of this signal was deformed
(Figure 2). The positive signal at 275 nm was increased. Both
effects were most marked for 3c, and in general they indicate
that the imidazolium derivatives have a substantial influence
on the stacking of the bases with only minor modifications in
the helical conformation. Comparable effects had been ob-
Glutathione reductase was used as a reference enzyme that
is structurally and functionally related to TrxR and is commonly
inhibited less efficiently by gold species and also does not rep-
resent a preferred anticancer drug target. This enzyme was in-
hibited by 4a and 4d only at much higher concentrations
(IC50 =221.2Æ0.12 mm for 4a and IC50 =15.6Æ2.8 mm for 4d)
confirming an appropriate selectivity of the complexes for in-
hibiting the tumor-relevant enzyme TrxR.
Figure 2. CD spectra of CT-DNA and mixtures of the respective compounds
with CT-DNA {[compound]/[DNA]=0.2 for [DNA]=M(bp)} in 10 mm phos-
phate buffer (pH 7.2) after an incubation period of 1 h.
served previously using the same assay with different naphtha-
limides.[9f] While 4a induced similar changes compared to 3a–
c, derivatives 4b–d caused stronger modifications in the inten-
sity and shape of the band at 245 nm and strongly increased
the intensity of the positive signal at 275 nm. Complexes 4b
and 4d showed the strongest influence on the CD spectra.
In summary the observed changes indicate that the gold(I)
NHC derivatives were efficient intercalators that also distorted
the B conformation of DNA.
Interaction with DNA
The interaction with calf thymus CT-DNA was evaluated by
melting point and circular dichroism (CD) experiments.
By measuring the thermal denaturation temperature
changes (DTm) of DNA upon exposure to substances, their effi-
cacy of intercalation can be evaluated. For this purpose, DNA
was incubated with the compounds in a 1:10 ratio, and the
melting points were recorded. Values for 3a–c and 4a–d
ranged between 38C and 118C, which are in accordance with
differing intercalative potentials of the naphthalimides as well
as their gold(I) NHC complexes (Table 1). On the basis of their
DTm values, the most effective intercalators were 3c and 4a. In
the case of the imidazolium derivatives 3a–c, increasing the
size of the residues (R2) at the imidazole nitrogen was accom-
panied by an increase of DTm values, whereas this led to a de-
crease of the DTm values in the case of gold(I) NHC derivatives
4a–c.
Effects on cellular metabolism
The influence of 5 and 10 mm of selected compounds 3a, 4a
and 4d on the cellular metabolism of MCF-7 cells was moni-
tored online by using a metabolic sensor chip analysis system
(BIONAS), which allows to monitor the cellular oxygen con-
sumption (respiration rate, Figure 3a), changes on the cellular
morphology (impedance, Figure 3b), as well as cell stress (ex-
tracellular acidification rate, Figure 3c).[12]
With the gold-free 3a and complex 4a a slight decrease of
the cellular respiration was noted but no relevant changes of
cell impedance or extracellular acidification. Complex 4d in-
duced a stronger and dose-dependent decrease of the respira-
tion rate. At the higher exposure concentration of 4d (10 mm)
this was accompanied by immediate effects on the extracellu-
lar acidification and delayed (after 8 h of exposure) effects on
the cell impedance. All effects of 4d were irreversible (no re-
covery of the metabolic parameters after washing the cells
with drug-free medium, see the final RM phase in Figure 3)
Characteristic changes can be induced in the CD spectra of
DNA in the presence of small molecules. The CD spectrum of
DNA exhibits a negative peak at approximately 245 nm, which
is caused by the helical B conformation, and a positive peak at
approximately 275 nm that is caused by base stacking.
Changes in the range of 220–350 nm thus provide important
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Figure 3. Real-time response of MCF-7 cell metabolism in response to 3a, 4a and 4d. Treatment (exposure) started after 5 h of equilibration and was contin-
ued for 24 h. a) Standard respiration rate, b) standard cell impedance, and c) acidification rate; RM=running medium (without compound).
and are in good agreement with the high cytotoxicity of this
compound as well as the strong effects on DNA observed in
the CD studies.
esting, but rare, where this strategy has been applied very suc-
cessfully.
Together with these works, our results may suggest that the
metal NHC moiety could be used as an organometallic func-
tional group or as a pharmacophore in medicinal chemistry
and drug design. Further application and evaluation of this
general strategy appears promising and is the subject of ongo-
ing research.
Conclusions
Naphthalimide conjugates with a gold(I) NHC partial structure
in the side chain were prepared and studied biologically in
comparison to the respective imidazolium precursors. Com-
pounds 2a–4a exhibited only low fluorescence emission in so-
lution, and hence fluorescence microscopy studies in cells
were not performed. However, it could be speculated that
compounds 3d or 4d might show stronger emissive proper-
ties based on their thioether substituents on the naphthali-
mide, which might open options for cellular bioimaging in
future studies.[4,9f]
Experimental Section
General
All reagents and solvents were used as received from Sigma Al-
drich or Fluka. Rat liver thioredoxin reductase (TrxR), baker’s yeast
glutathione reductase (GR) and trypsin from bovine pancreas were
obtained from Sigma Aldrich. 1H NMR spectra were recorded on
a Bruker DRX-400 AS NMR System, 13C NMR spectra on a Bruker AV
II-600 AS NMR System, and MS spectra on a FinniganMAT4515. The
purity of the target compounds (>95%) was confirmed by ele-
mental analysis (Flash EA112, Thermo Quest Italia). For all com-
pounds undergoing biological evaluation, the experimental values
differed less than 0.5% from the calculated ones. The synthesis of
1b[9f,15] and 2a[6] is described elsewhere.
The introduction of the gold(I) NHC fragment into the side
chain led to higher cytotoxic activity, with 4c in MCF-7 cells as
the only exception. Strong effects on cell metabolism (respira-
tion, cell impedance, extracellular acidification) were noted for
4d, which was the most cytotoxic complex. Effective inhibition
of the enzyme TrxR was confirmed for selected examples as
a likely contributing factor. Moreover, the gold(I) NHC partial
structure led to an enhanced interaction with DNA. Hence, it
can be concluded that the conjugation of naphthalimides with
gold(I) NHC moieties provides an useful strategy for the design
of bioorganometallic anticancer agents with multiple (nonrelat-
ed) modes of action. In this context, the combination of TrxR
inhibition with DNA intercalation appears particularly interest-
ing because these are mechanisms that are both relevant in
anticancer research but not directly linked with each other
(redox- and DNA-metabolism, respectively).
Synthesis
3’-(4’’-Ethylthio-1’’,8’’-naphthalimid-N’’-yl)-1-propyl-imidazol
(2b): Compound 1b (258.2 mg, 1 equiv) and 1-(3-aminopropyl)-
imidazole (1.5 equiv) were held at reflux in EtOAc (40 mL) for 6 h.
The solution was cooled to RT, and the product was isolated by
precipitation. The obtained white solid was filtered off and dried
over P2O5 to give 2b as a white powder (yield not determined):
3
1H NMR ([D6]DMSO): d=8.53–8.46 (m, 2H, ArH), 8.34 (d, J=7.9 Hz,
3
3
1H, ArH), 7.85 (dd, J=8.4, 7.4 Hz, 1H, ArH), 7.72 (d, J=8.0 Hz, 1H,
From a broader viewpoint, the here reported gold com-
pounds represent conjugates between an active drug (naph-
thalimide) and a metal–NHC fragment. The chemical biology
and medicinal chemistry of this type of organometallic moiety
has been intensively studied over the last years but so far it
has not been used frequently for modifying the properties of
existing bioactive agents or in the context of drug targeting.
Metal–NHC conjugates with peptides[13] or caffeine[14] are inter-
4
4
ArH), 7.66 (dd, J=1.1 Hz, 1H, NCHN), 7.22 (dd, J=1.1 Hz, 1H, CH
imidazole), 6.88 (dd, 4J=1.1 Hz, 1H, CH imidazole), 4.05 (dt, 2J=
12.0 Hz, 3J=7.2 Hz, 4H, NCH2-), 3.28 (q, 3J=7.3 Hz, 2H, SCH2CH3),
2.09 (p, 3J=7.1 Hz, 2H), 1.39 ppm (t, 3J=7.3 Hz, 3H, SCH2CH3);
13C NMR ([D6]DMSO): d=163.30 (CO), 163.25 (CO), 144.43 (ArC),
137.20 (NCHN), 130.94 (ArC), 130.40 (ArC), 129.46 (ArC), 128.53
(ArC), 128.29 (ArC), 127.59 (ArC), 127.07 (ArC), 122.75 (CH imida-
zole), 122.66 (CH imidazole), 119.19 (ArC), 118.37 (ArC), 44.06
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(NCH2-), 37.25 (NCH2-), 29.32 (SCH2-), 25.17 (NCH2CH2CH2N), 13.37
(SCH2CH3); Anal. calcd for C20H19N3O2S: C 65.73, H 5.24, N 11.50,
found: C 65.51, H 5.11, N 11.46.
122.22 (CH imidazole), 118.30 (ArC), 46.91 (NCH2CH2-), 36.63
(NCH2CH2-), 35.74 (NCH3), 28.39 (SCH2CH3), 25.19 (NCH2CH2CH2N),
13.37 ppm (SCH2CH3); Anal. calcd for C21H22IN3O2S: C 49.71, H 4.37,
N 8.28, found: C 49.95, H 4.40, N 8.15.
General procedure for the synthesis of 3a–d: Compound 2a or
2b (0.5 mmol, 1 equiv) and an excess of the respective alkyl halide
(3 equiv) were heated to reflux in toluene (30 mL) for 24 h. After
cooling to RT, the solvent was removed in vacuo, and the remain-
ing solid was resuspended in tetrahydrofurane (THF). The precipi-
tate was filtered off and dried in vacuo and over P2O5, resulting in
a white solid, which corresponded to the desired pure product.
General procedure for synthesis of the gold NHC complexes 4a–
d: The respective imidazolium halide 3a–d (0.25 mmol, 1 equiv)
and Ag2O (1 equiv) were added to a dried Schlenk tube. The mix-
ture was back flashed with N2 (3ꢁ), and then dry CH2Cl2 (10 mL)
was added. The flask was closed, and the mixture was stirred for
4–24 h at RT in the dark. A solution of chlorido(dimethyl sulfide)-
gold(I) in CH2Cl2 (73.6 mg, 0.25 mmol, in 10 mL) was added, and
the reaction mixture was stirred for another 4–24 h at RT in the
dark. The obtained suspension was filtered over Celite (281 nm),
and the solvent was removed at 900 mbar and 358C to prevent
decomposition. The obtained solid was recrystallized from Et2O
and dried over P2O5.
1-(3’-(1’’,8’’-Naphthalimid-N’’-yl))-propyl-3-methylimidazolium
iodide (3a): White powder (201.3 mg, 90%): 1H NMR ([D6]DMSO):
d=9.12 (dd, 4J=1.8 Hz, 1H, NCHN), 8.56–8.44 (m, 4H, ArH), 7.90
(dd, 3J=8.3, 7.3 Hz, 2H, ArH), 7.81 (dd, 4J=1.8 Hz, 1H, imidazole
4
3
CH), 7.71 (dd, J=1.8 Hz, 1H, imidazole CH), 4.29 (t, J=6.6 Hz, 2H,
NCH2CH2-), 4.12 (t, 3J=6.5 Hz, 2H, NCH2CH2-), 3.86 (s, 3H),
2
3
2.24 ppm (dt, J=13.6 Hz, J=6.6 Hz, 1H, NCH2CH2CH2N); 13C NMR
([D6]DMSO): d=163.66 (CO), 136.65 (NCHN), 134.35 (ArC), 131.26
(ArC), 130.69 (ArC), 127.42 (ArC), 127.20 (ArC), 123.50 (ArC), 122.22
(CH imidazole), 122.08 (CH imidazole), 46.91 (NCH2-), 36.68 (NCH2-),
35.74 (NCH3), 28.40 ppm (NCH2CH2CH2N); Anal. calcd for
C19H18IN3O2: C 51.02, H 4.06, N 9.39, found: C 50.63, H 4.02, N 9.17.
Chlorido[1-(3’-(1’’,8’’-naphthalimid-N’’-yl))-propyl-3-methyl-imida-
1
zol-2-ylidene]gold(I) (4a): White powder (45.5 mg, 33%): H NMR
3
4
3
(CDCl3) d=8.61 (dd, J=7.3 Hz, J=1.1 Hz, 2H, ArH), 8.24 (dd, J=
8.4 Hz, 4J=1.1 Hz, 2H, ArH), 7.78 (dd, 3J=8.2 Hz, 3J=7.3 Hz, 2H,
ArH), 7.24 (d, 4J=1.9 Hz, 1H, CH imidazolylidene), 6.96 (d, 4J=
3
1.9 Hz, 1H, CH imidazolylidene), 4.32 (t, J=6.8 Hz, 2H, NCH2CH2-),
3
4.24 (t, J=7.0 Hz, 2H, NCH2CH2-), 3.84 (s, 3H, NCH3), 2.34 ppm (p,
1-(3’-(1’’,8’’-Naphthalimid-N’’-yl))-propyl-3-ethylimidazolium
iodide (3b): White powder (126.9 mg, 55%): 1H NMR ([D6]DMSO):
d=9.20 (dd, 4J=1.8 Hz, 1H, NCHN), 8.53–8.45 (m, 4H, ArH), 7.89
3J=6.9 Hz, 2H, NCH2CH2CH2N). 13C NMR (CDCl3) d=171.53 (NHC),
164.26 (CO), 134.28 (ArC), 131.64 (ArC), 131.50 (ArC), 128.20 (ArC),
127.03 (ArC), 122.37 (ArC), 121.70 (CH imidazolylidene), 120.73 (CH
imidazolylidene), 49.20 (NCH2-), 38.34 (NCH3), 37.39 (NCH2-),
29.47 ppm (NCH2CH2CH2N). Anal. calcd for C19H17N3ClO2Au: C 41.36,
H 3.11, N 7.62, found: C 40.99, H 2.91, N 7.19.
4
(dd, 3J=8.2, 7.3 Hz, 2H, ArH), 7.84 (dd, J=1.8 Hz, 1H, CH imida-
zole), 7.82 (dd, 4J=1.8 Hz, 1H, CH imidazole), 4.29 (t, 3J=6.6 Hz,
2H, NCH2-), 4.20 (q, 3J=7.3 Hz, 2H, NCH2CH3), 4.12 (t, 3J=6.5 Hz,
2H, NCH2-), 2.34–2.20 (m, 2H, NCH2CH2CH2N), 1.41 ppm (d, 3J=
7.3 Hz, 2H, NCH2CH3); 13C NMR ([D6]DMSO): d=163.63 (CO), 135.81
(NCHN), 134.34 (ArC), 131.24 (ArC), 130.68 (ArC), 127.39 (ArC),
127.18 (ArC), 122.32 (CH imidazole), 122.02 (CH imidazole), 46.95
(NCH2CH3), 44.18 (NCH2-), 36.65 (NCH2-), 28.26 (NCH2CH2CH2N),
14.95 (NCH2CH3); Anal. calcd for C20H20IN3O2: C 52.07, H 4.37, N
9.11, found: C 52.06, H 4.21, N 8.79.
Chlorido[1-(3’-(1’’,8’’-naphthalimid-N’’-yl))-propyl-3-ethyl-imida-
1
zol-2-ylidene]gold(I) (4b): White powder (14.2 mg, 10%): H NMR
3
3
(CDCl3) d=8.61 (dd, J=7.1, 1.1 Hz, 2H, ArH), 8.24 (dd, J=8.3 Hz,
4J=1.1 Hz, 2H, ArH), 7.78 (dd, J=8.2 Hz, J=7.3 Hz, 2H, ArH), 7.24
(d, J=2.0 Hz, 1H, CH imidazolylidene), 6.99 (d, J=1.9 Hz, 1H, CH
imidazolylidene), 4.32 (t, 3J=6.8 Hz, 2H, NCH2CH2-), 4.25 (t, 3J=
3
3
3
3
3
7.0 Hz, 2H, NCH2CH2-), 4.23 (q, J=7.3 Hz, 2H, NCH2CH3), 2.35 (dt,
1-(3’-(1’’,8’’-Naphthalimid-N’’-yl))-propyl-3-benzylimidazolium
3J=6.9 Hz, 2H, NCH2CH2CH2N), 1.47 ppm (t, 3J=7.3 Hz, 3H,
NCH2CH3); 13C NMR (CDCl3): d=170.52 (NHC), 164.27 (CO), 134.27
(ArC), 131.65 (ArC), 131.50 (ArC), 128.21 (ArC), 127.03 (ArC), 122.38
(ArC), 120.74 (CH imidazolylidene), 119.82 (CH imidazolylidene),
49.29 (NCH2-), 46.60 (NCH2-), 37.41 (NCH2-), 29.44 (NCH2CH2CH2N),
16.46 ppm (NCH2CH3). Anal. calcd for C20H19N3ClO2Au: C 42.46, H
3.38, N 7.43, found: C 42.51, H 2.93, N 7.07.
1
bromide (3c): White powder (188.2 mg, 79%): H NMR ([D6]DMSO):
d=9.33 (dd, 4J=1.8 Hz, 1H, NCHN), 8.52–8.47 (m, 4H, ArH), 7.90
4
(dd, 3J=8.2, 7.3 Hz, 2H, ArH), 7.87 (dd, J=1.8 Hz, 1H, CH imida-
zole), 7.83 (dd, 4J=1.8 Hz, 1H, CH imidazole), 7.47–7.36 (m, 5H,
NCH2(C6H5)), 5.45 (s, 2H, NCH2Ph), 4.37–4.25 (m, 2H, NCH2-), 4.11 (t,
3J=6.5 Hz, 2H, NCH2-), 2.31–2.17 ppm (m, 2H, NCH2CH2CH2N);
13C NMR ([D6]DMSO): d=163.67 (CO), 136.34 (NCHN), 134.75 (ArC),
134.37 (ArC), 131.29 (ArC), 130.70 (ArC), 128.95 (ArC), 128.67 (ArC),
128.21 (ArC), 127.45 (ArC), 127.21 (ArC), 122.79 (CH imidazole),
122.47 (CH imidazole), 122.11 (ArC), 51.90 (NCH2Ph), 47.06 (NCH2-),
36.62 (NHCH2-), 28.28 ppm (NCH2CH2CH2N); Anal. calcd for
C25H22BrN3O2: C 63.03, H 4.65, N 8.82, found: C 62.88, H 4.56, N
8.66.
Chlorido[1-(3’-(1’’,8’’-naphthalimid-N’’-yl))-propyl-3-benzyl-imida-
zol-2-ylidene]gold(I) (4c): White powder (17.3 mg, 11%): 1H NMR
3
4
3
(CDCl3): d=8.61 (dd, J=7.3 Hz, J=1.2 Hz, 2H, ArH), 8.25 (dd, J=
8.3 Hz, 4J=1.1 Hz, 2H, ArH), 7.78 (dd, 3J=8.2, 7.3 Hz, 2H, ArH),
4
7.47–7.29 (m, 5H, NCH2(C6H5)), 7.23 (d, J=2.0 Hz, 2H, CH imidazo-
lylidene), 6.89 (d, J=2.0 Hz, 1H, CH imidazolylidene), 5.39 (s, 2H,
4
3
3
NCH2Ar,), 4.35 (t, J=6.8 Hz, 2H, NCH2CH2CH2N), 4.27 (t, J=7.0 Hz,
2H, NCH2CH2CH2N), 2.37 ppm (dt, 3J=7.0 Hz, 2H, NCH2CH2CH2N);
Anal. calcd for C25H21N3ClO2Au (% calcd/found): C 47.82, H 3.37, N
6.69, found: C 47.93, H 3.41, N 6.41.
1-(3’-(4’’-Ethylthio-1’’,8’’-naphthalimid-N’’-yl))-propyl-3-methyli-
midazolium iodide (3d): White powder (yield not determined):
4
1H NMR ([D6]DMSO): d=9.12 (dd, J=1.8 Hz, 1H, NCHN), 8.56–8.49
3
3
(m, 2H, ArH), 8.37 (d, J=8.0 Hz, 1H, ArH), 7.89 (dd, J=8.5, 7.4 Hz,
1H, Ar H), 7.80 (dd, 4J=1.8 Hz, 1H, CH imidazole), 7.76 (d, 3J=
Chlorido[1-(3’-(4’’-ethylthio-1’’,8’’-naphthalimid-N’’-yl))-propyl-3-
methyl-imidazol-2-ylidene]gold(I) (4d): White powder (yield not
determined): 1H NMR (CDCl3): d=8.62 (dd, 3J=7.3 Hz, 4J=1.1 Hz,
1H ArH), 8.59 (dd, 3J=8.4 Hz, 4J=1.2 Hz, 1H, ArH), 8.48 (d, 3J=
7.9 Hz, 1H, ArH), 7.76 (dd, 3J=8.5, 7.3 Hz, 1H, ArH), 7.56 (d, 3J=
4
8.0 Hz, 1H, ArH), 7.71 (dd, J=1.8 Hz, 1H, CH imidazole), 4.28 (dd,
3
3J=6.5 Hz, 2H, NCH2-), 4.09 (t, J=6.5 Hz, 2H, NCH2-), 3.85 (s, 3H,
NCH3), 3.30 (q, 3J=7.3 Hz, 2H, SCH2CH3), 2.28–2.16 (m, 2H,
NCH2CH2CH2N), 1.40 ppm (t, 3J=7.3 Hz, 3H, SCH2CH3); 13C NMR
([D6]DMSO): d=163.43 (CO), 163.39 (CO), 144.62 (ArC), 136.65
(NCHN), 131.00 (ArC), 130.46 (ArC), 129.60 (ArC), 128.56 (ArC),
127.62 (ArC), 127.15 (ArC), 123.50 (ArC), 122.71 (CH imidazole),
4
7.9 Hz, 1H, ArH), 7.24 (d, J=1.9 Hz, 1H, CH imidazolylidene), 6.95
(d, 4J=1.9 Hz, 1H, CH imidazolylidene), 4.31 (t, 3J=6.8 Hz, 2H,
NCH2CH2-), 4.22 (t, 3J=7.0 Hz, 2H, NCH2CH2-), 3.84 (s, 3H, NCH3),
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3.21 (q, 3J=7.4 Hz, 2H, SCH2CH3), 2.33 (p, 3J=6.9 Hz, 2H,
NCH2CH2CH2N), 1.49 ppm (t, 3J=7.4 Hz, 3H, SCH2CH3); 13C NMR
(CDCl3): d=171.51 (NHC), 164.15 (CO), 164.12 (CO), 145.93 (ArC),
131.78 (ArC), 131.08 (ArC), 130.46 (ArC), 129.60 (ArC), 128.41 (ArC),
126.64 (ArC), 122.80 (ArC), 122.64 (ArC), 121.67 (CH imidazolyli-
dene), 120.76 (CH imidazolylidene), 118.66 (ArC), 49.20 (NCH2CH2-),
38.35 (NCH2CH2-), 37.35 (NCH3), 29.48 (SCH2CH3), 26.38
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft
(DFG) is thankfully acknowledged.
Keywords: DNA · gold · naphthalimides · N-heterocyclic
carbenes · thioredoxin reductase
(NCH2CH2CH2N),
13.52 ppm
(SCH2CH3);
Anal.
calcd
for
C21H21N3ClSO2Au: C 41.22, H 3.46, N 6.87, found: C 41.05, H 3.34, N
6.47.
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Received: February 27, 2014
Published online on && &&, 0000
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A. Meyer, L. Oehninger, Y. Geldmacher,
H. Alborzinia, S. Wçlfl, W. S. Sheldrick,
I. Ott*
Multiple modes of action: The conju-
gation of naphthalimides with gold(I)
NHC moieties led to higher cytotoxic ac-
tivity, strong effects on cell metabolism,
and effective inhibition of TrxR for se-
lected compounds. Moreover, the
&& – &&
Gold(I) N-Heterocyclic Carbene
Complexes with Naphthalimide
Ligands as Combined Thioredoxin
Reductase Inhibitors and DNA
Intercalators
gold(I) NHC partial structure led to an
enhanced interaction with DNA.
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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