Cyclometalated phenylquinoline rhodium complexes as protein kinase inhibitors

Article abstract of DOI:10.1016/j.ica.2012.04.035

A new metal-containing scaffold for the generation of rhodium(III)-based protein kinase inhibitors is introduced in which the pharmacophore ligand 4-phenylpyrrolo[3,4-c]quinoline-1,3(2H)-dione is designed to form two hydrogen bonds with the hinge region o

Full text of DOI:10.1016/j.ica.2012.04.035

Inorganica Chimica Acta 393 (2012) 261–268
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Inorganica Chimica Acta
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Cyclometalated phenylquinoline rhodium complexes as protein kinase inhibitors
⇑
Stefan Mollin, Sebastian Blanck, Klaus Harms, Eric Meggers
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße, 35043 Marburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 30 April 2012
A new metal-containing scaffold for the generation of rhodium(III)-based protein kinase inhibitors is
introduced in which the pharmacophore ligand 4-phenylpyrrolo[3,4-c]quinoline-1,3(2H)-dione is
designed to form two hydrogen bonds with the hinge region of the ATP-binding site. The phenylquinoline
ligand binds to rhodium(III) in a cyclometalated fashion by coordinating to the quinoline nitrogen and
forming a covalent bond to a carbon atom of the phenyl substituent. Additional acyclic tridentate ligands
were used to control the relative stereochemistry, whereas a chiral proline-derived tridentate ligand was
employed for the asymmetric synthesis of single enantiomers. Finally, protein kinase profiling and inhi-
bition data confirmed that the new rhodium(III)-phenylquinoline scaffold is suitable for the generation of
selective protein kinase inhibitors.
Metals in Medicine Special Issue
Dedicated to Prof. James Dabrowiak.
Keywords:
Rhodium
Cyclometalation
Kinase inhibitors
Chiral ligand
Ó 2012 Elsevier B.V. All rights reserved.
Asymmetric synthesis
1. Introduction
entate ligands are ideally suited to control the relative and even
absolute metal-centered configuration for the stereoselective syn-
Research from our group over the last several years has demon-
strated that substitutionally inert transition metal complexes are
sophisticated scaffolds for targeting protein pockets such as enzyme
active sites with very high affinities and exquisite selectivities [1,2].
The rich stereochemistry of octahedral metal coordination geome-
tries thereby provides a powerful tool for generating natural-
product-like rigid and globular molecular structures that can fill
protein pockets in unique fashions [3], as has been demonstrated
for the design of octahedral ruthenium [4], iridium [5], and rhodium
[6] complexes as highly potent and selective protein kinase inhibi-
tors. Our previously developed metallo-pyridocarbazole scaffold
was inspired by the natural product staurosporine and served for
the generation of ATP-competitive protein kinase inhibitors by
forming two key hydrogen bonds with the hinge region of the ATP
binding site (Fig. 1) [2]. Although this design strategy was highly
successful, we were seeking new scaffolds for metal-containing pro-
tein kinase inhibitors because of the somewhat cumbersome syn-
thesis of the pyridocarbazole heterocycle [7] combined with the
expectation that a positioning of the metal at a different position
within the ATP-binding site might allow us to discover metal-based
inhibitors with hitherto unobserved kinase inhibition properties
[8]. In this study, we now introduce such a simplified new design
in which cyclometalated rhodium(III) complexes with the pharma-
cophore ligand 4-phenylpyrrolo[3,4-c]quinoline-1,3(2H)-dione are
designed to interact with the hinge region of protein kinases
(Fig. 1). We furthermore demonstrate that carefully tailored multid-
thesis of substitutionally inert rhodium(III) complexes with biolog-
ical activities.
2. Results and discussion
2.1. Synthesis of 4-phenylpyrrolo[3,4-c]quinoline-1,3(2H)-dione
ligands
The ligand 4-phenyl-pyrrolo[3,4-c]quinoline-1,3(2H)-dione (1a)
and its benzylated derivative (1b) were synthesized according to
Scheme 1. The reaction of isatine (2) with ethyl benzoylacetate
(3) under basic conditions afforded through a Pfitzinger reaction
the dicarboxylic acid 4 (45%) according to a literature protocol
[9]. Next, reaction of 4 with acetic anhydride afforded the anhy-
dride 5, followed by a reaction with ammonium acetate or benzyl-
amine to obtain the desired ligands 1a and 1b in yields of 52% and
78% over two steps, respectively.
2.2. Synthesis of rhodium(III) complexes
Although we were not successful in synthesizing any stable
ruthenium complexes with ligands 1a or 1b, revealingly, the reac-
tion of 1b and 1a with RhCl3ꢀ3H2O in EtOH/H2O 1:1 at 90 °C for
3 h, followed by the addition of 2-[(pyridin-2-ylmethyl)thio]acetic
acid (6) and a continued heating for another 16 h afforded the com-
plexes 8 and 9, respectively, as single diastereomers albeit in some-
what low yields (Scheme 2, Table 1). Other diastereomers could not
be isolated although their formation in small amounts cannot be
entirely ruled out. In contrast, the reaction of 1a with RhCl3ꢀ3H2O
⇑
Corresponding author. Tel.: +49 6421 2821534; fax: +49 6421 2821535.
E-mail address: meggers@chemie.uni-marburg.de (E. Meggers).
0020-1693/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ica.2012.04.035

262
S. Mollin et al. / Inorganica Chimica Acta 393 (2012) 261–268
Table 1
Synthesis of rhodium complexes 8–11, 100, and 110.
Complex
R
X
Z
Yield (%)
8
9
Bn
H
H
Cl
Cl
Cl
Br
S
S
16
14
10/100
11/110
NCH3
NCH3
10/21a
12/19a
H
a
Diastereomers separated by silica gel chromatography.
Fig. 1. Previous and new design for metal complexes as protein kinase inhibitors.
Shown are the intended interactions of the so-called ‘‘pharmacophore chelate
ligand’’ with the hinge region of the ATP-binding site of protein kinases. Note that
the imide can hydrogen bond to the hinge region in two different orientations.
Fig. 2. Crystal structure of rhodium(III) quinoline complex 11. ORTEP drawing with
50% probability thermal ellipsoids. Selected bond distances (Å) and angles (°): Rh1–
C15 = 1.983(13), Rh1–O30 = 2.031(6), Rh1–N1 = 2.077(8), Rh1–N20 = 2.110(8),
Rh1–N23 = 2.222(11), Rh1–Br1 = 2.4343(15), C15–Rh1–O30 = 94.1(3), C15–Rh1–
N20 = 94.1(4), C15–Rh1–N23 = 173.7(3), C15–Rh1–Br1 = 91.0(3).
Scheme 1. Synthesis of 4-phenylpyrrolo[3,4-c]quinoline-1,3(2H)-diones 1a and b.
A crystal structure of complex 11 is shown in Fig. 2 and con-
firms the cyclometalation of the phenylquinoline ligand with one
formed Rh–C bond (Rh–C = 1.983(13) Å). The phenylquinoline li-
gand is twisted due to a steric interference between a carbonyl
group of the maleimide moiety and a closeby CH-group of the phe-
nyl ring. The tridentate ligand 7 coordinates in a facial fashion and
forms in the crystal an intermolecular hydrogen bond between the
in EtOH/H2O 1:1 at 90 °C for 2 h, followed by the addition of
2-[methyl(pyridin-2-ylmethyl)amino]acetic acid (7) and a contin-
ued heating for another 16 h provided the two diastereomers 10
(10%) and 100 (21%) which could be separated by silica gel chroma-
tography. The analogous bromide complexes 11 (12%) and 110 (19%)
were obtained when starting from in situ generated RhBr3 instead of
RhCl3.
Scheme 2. Synthesis of rhodium quinoline complexes 8–11, 100, and 110. X = Cl or Br. See Table 1 for more details.

S. Mollin et al. / Inorganica Chimica Acta 393 (2012) 261–268
263
coordinated carboxylate moiety and the imide NH, thus nicely
demonstrating the hydrogen donor ability of the maleimide
moiety.
2.3. Asymmetric synthesis with chiral ligands
In order to combine the control of relative and absolute metal-
centered configuration we employed the chiral proline-based li-
gands (S)-N-(pyridin-2-ylmethyl)proline {(S)-12} and its enantio-
mer (R)-N-(pyridin-2-ylmethyl)proline {(R)-12} [10]. Accordingly,
the reaction of 1a and 1b first with RhCl3ꢀ3H2O, followed by the
reaction with (S)-12 provided the complexes
K-(S)-13a and K-
(S)-13b in an asymmetric fashion as single enantiomers in yields
of 31% and 30%, respectively (Scheme 3). As to be expected, the
analogous reactions of 1a and 1b with RhCl3ꢀ3H2O and the mir-
ror-imaged ligand (R)-12 afforded the enantiomeric complexes
D
-(R)-13a (30%) and
D-(R)-13b (28%), respectively. The absolute
configuration of -(S)-13b was determined by X-ray crystallogra-
K
phy (Fig. 3, Table 2) and the remaining compounds were correlated
by CD-spectroscopy (Fig. 4). Interestingly, despite the formed Rh–C
bond due to cyclometalation of the phenylquinoline ligand, the ob-
tained complexes are surprisingly robust as can be seen in the
NMR-experiments shown in Fig. 5 in which no signs of decompo-
Fig. 3. Crystal structure of enantiomerically pure proline complex
K
-(S)-13b. Two
DMSO solvent molecules are omitted for clarity. ORTEP drawing with 50%
probability thermal ellipsoids. Selected bond distances (Å) and angles (°): Rh1–
C15 = 1.978(4), Rh1–N1 = 2.065(3), Rh1–N29 = 2.090(3), Rh1–N35 = 2.178(3), Rh1–
O28 = 2.029(2), Rh1–Cl1 = 2.3478(9), C15–Rh1–N29 = 97.51(14), O28–Rh1–
N29 = 84.10(11), N1–Rh1–N29 = 91.88(12), N29–Rh1–N35 = 78.41(12), N29–Rh1–
Cl1 = 171.20(9).
sition were detected for complex
D-(R)-13a after one week in the
presence of millimolar concentrations of the aliphatic thiol b-
mercaptoethanol.
2.4. Protein kinase inhibition
for individual PKC isoforms is therefore of high interest for the
development of drugs [15]. Whereas our initial protein kinase pro-
filing was performed with the racemic mixture of 13a, we deter-
mined IC50 values (concentration of inhibitor at which the
enzyme activity is reduced to 50%) for the individual enantiomers
To gain insight into the protein kinase inhibition properties of
phenylquinoline rhodium complexes [11], we tested the racemic
mixture
K-(S)-13a/D-(R)-13a for its protein kinase binding affinity
profile against the majority of the human protein kinases encoded
in the human genome (human kinome) [12]. This was accom-
plished by using an active-site-directed competition binding assay
with 451 different protein kinases (KINOMEscan, DiscoveRx) which
provides primary data (%ctrl = percent of control: 0% = highest
affinity, 100% = no affinity) that correlate with binding constants
K
-(S)-13a and
Fig. 7. As to be expected, the IC50 differ significantly with
13a (IC50 = 26 M) being by almost an order of magnitude more
potent than the mirror image -(R)-13a (IC50 = 229 42 M), indi-
cating specific molecular recognition between the chiral active site
of PKCd and -(S)-13a.
D
-(R)-13a against PKCd at 1
l
M ATP as shown in
K
-(S)-
5
l
D
l
(Kd) [13]. Interestingly, at a concentration of 10
lM rac-13a, only
K
a few protein kinases were identified as the main hits with %ctrl
values below 60%, namely YSK4 (44%), PKCd (47%), ZAP70 (50%),
MAP3K4 (51%), SRMS (53%), and NEK4 (58%). The human kinase
dendrogram shown in Fig. 6 demonstrates that these six kinases
are distributed among four protein kinase families.
We selected PKCd (d-isoform of protein kinase C) for further
investigations. PKCd belongs to the protein kinase C family of li-
pid-dependent serine/threonine kinases with a large number of
identified PKC isoforms, many of which are critical regulators of di-
verse cellular functions [14]. The development of specific inhibitors
3. Conclusion
We here introduced a new scaffold for rhodium(III) complexes
as protein kinase inhibitors which is based on the cyclometalation
of 4-phenylpyrrolo[3,4-c]quinoline-1,3(2H)-dione. Additionally
introduced acyclic tridentate ligands were used to control the rel-
ative metal-centered configuration, whereas the chiral proline-de-
rived ligands (S)- and (R)-N-(pyridin-2-ylmethyl)proline resulted
Scheme 3. Asymmetric synthesis of rhodium complexes
K-(S)-13a,b and D-(R)-13a and b.

264
S. Mollin et al. / Inorganica Chimica Acta 393 (2012) 261–268
Table 2
Crystallographic data for rhodium complexes 11 and
K
-(S)-13b.a
11
K
-(S)-13bꢀ2DMSO
Chemical formula
Mr
C
26H20BrN4O4Rh
C35H28ClN4O4Rhꢀ2(C2H6SO)
635.28
863.23
Crystal system, space group
a, b, c (Å)
monoclinic, P21/c
10.559(3), 20.955(3), 11.697(2)
90, 103.165 (18), 90
2520.1 (9)
orthorhombic, P212121
10.1798(3), 11.6800(4), 31.2336(9)
90, 90, 90
3713.7 (2)
4
a
, b,
c
(°)
V (Å3)
Z
4
Radiation type
Mo K
2.30
a
Mo K
0.70
a
l
(mmꢁ1
)
Crystal size (mm)
Tmin, Tmax
Number of measured, independent and observed [I > 2
0.11 ꢂ 0.10 ꢂ 0.04
0.31 ꢂ 0.10 ꢂ 0.04
0.778, 1.100
25884, 7296, 6834
0.070
0.039, 0.094, 1.03
7296
483
0
0.61, ꢁ0.88
ꢁ0.02 (2)
852554
0.734, 0.974
r(I)] reflections
7730, 4029, 2116
0.091
0.063, 0.165, 0.94
4029
326
0
Rint
R[F2 > 2
r
(F2)], wR(F2), S
Number of reflections
Number of parameters
Number of restraints
D
qmax
,
D
qmin (e Åꢁ3
)
0.68, ꢁ1.18
Flack parameter (absolute structure)
–
CCDC No.b
852553
a
2
2
R1
=
R
||Fo| ꢁ |Fc||/
R
|Fo|; wR2 = [w(Fo ꢁ Fc2)2/
R
w(Fo2)2]1/2; S = {
R
[w(Fo ꢁ Fc2)2]/(n ꢁ p)}1/2
.
b
Crystallographic data (excluding structure factors) have been deposited in the Cambridge Crystallographic Data center. CIF files can be obtained from the CCDF free of
charge via http://www.ccdc.cam.ac.uk/data_request/cif.
in the asymmetric synthesis of single enantiomers. Protein kinase
profiling and inhibition experiments confirmed that this new rho-
dium(III)-phenylquinoline scaffold shows promise for the design of
inert rhodium(III)-based protein kinase inhibitors. Thus, this work
demonstrates that carefully tailored chiral multidentate ligands
are ideally suited to control relative and absolute stereochemistry
simultaneously for the asymmetric synthesis of substitutionally in-
ert metal complexes with biological activities.
20
15
10
5
Δ-(R)-13a
Λ-(S)-13a
0
4. Experimental
-5
-10
-15
-20
4.1. Materials and methods
Reactions were carried out using oven-dried glassware and con-
ducted under a positive pressure of nitrogen unless otherwise
specified. 2-Phenyl-3,4-dicarboxylic acid (4) was synthesized from
commercially available isatine (2) and ethyl benzoylacetate (3) as
described in the literature [9]. The ligands 2-[(pyridin-2-
ylmethyl)thio]acetic acid, 2-[methyl(pyridin-2-ylmethyl)amino]ace-
tic acid, and (R)- plus (S)-N-(pyridin-2-ylmethyl)proline were
synthesized as reported [16,17]. Rhodium(III) chloride trihydrate
300
350
400
450
500
550
600
Wavelength (nm)
Fig. 4. CD-spectra of the enantiomerically pure rhodium complexes
and
figure legend, the reader is referred to the web version of this article.)
K
-(S)-13a (red)
D
-(R)-13a (blue) in DMSO. (For interpretation of the references to color in this
12.0
11.0
10.0
9.0
8.0
ppm (t1)
Fig. 5. Stability evaluation of compound
NMR spectra right after the addition of b-mercaptoethanol (0 day) and after one week (7 days).
D H
-(R)-13a (8.3 mM) in DMSO-d6/D2O 5:1 in the presence of b-mercaptoethanol (4.2 mM). Shown are the aromatic regions of the 1

S. Mollin et al. / Inorganica Chimica Acta 393 (2012) 261–268
265
Fig. 6. Protein kinase selectivity of racemic complex 13a (10 lM) as determined by an active-site-directed affinity screening (KINOMEscan, DiscoveRx) against 451 human
protein kinases. Representation of the main hits (< 60% of control, large red circles) within the human kinase dendrogram which displays the protein kinase families and the
evolutionary relationships between the individual kinases. YSK4 = 44%, PKCd = 47%, ZAP70 = 50%, MAP3K4 = 51%, SRMS = 53%, and NEK4 = 58%.
spectrometer. Infrared spectra were recorded on a Bruker Alpha
FTIR. CD spectra were recorded on a JASCO J-810 CD spectropolar-
imeter with cuvettes of 1 mm pathlength. High resolution mass
spectra were obtained with a Finnigan LTQ-FT instrument using
either APCI or ESI.
100
80
60
40
20
0
4.2. Compound preparation
Λ-(S)-13a
Δ-(R)-13a
4.2.1. 4-Phenylpyrrolo[3,4-c]quinoline-1,3(2H)-dione (1a)
A solution of 2-phenyl-3,4-dicarboxylic acid (4) (5.87 g, 20.0
mmol) in acetic anhydride (120 mL) was heated to 130 °C for 3 h.
During this time the solution gradually changed from yellow to
black and the precipitation of a yellow solid was observed. The sol-
vent was removed in vacuo and anhydride 5 was obtained which
was used immediately for the next step. Anhydride 5 was dissolved
in glacial acetic acid (70 mL), ammonium acetate (2.31 g,
30.0 mmol) was added, and the solution was heated to reflux for
16 h. The solvent was removed in vacuo, the resulting brown/black
solid suspended in ethyl acetate (40 mL) and heated to reflux for
15 min leaving behind a yellow solid. The solid was filtered off,
washed with ethyl acetate, and dried in vacuo to provide 4-phenyl-
pyrrolo[3,4-c]quinoline-1,3(2H)-dione (1a) as yellow solid (2.85 g,
10.4 mmol, 52%). 1H NMR (300 MHz, DMSO-d6): d (ppm) 11.61 (s,
1H), 8.78 (dd, J = 8.3, 0.8 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 8.01–
7.92 (m, 3H), 7.86–7.81 (m, 1H), 7.56–7.51 (m, 3H). 13C NMR
10-6
10-5
10-4
Concentration (μM)
Fig. 7. IC50 curves of the two enantiomers
ATP concentrations of 1 M.
K-(S)-13a and
D
-(R)-13a against PKCd at
l
and other chemicals as well as all solvents were used as received
from standard suppliers. NMR spectra were recorded on an Avance
300 (300 MHz), DRX-400 (400 MHz), or Avance 500 (500 MHz)

266
S. Mollin et al. / Inorganica Chimica Acta 393 (2012) 261–268
(75 MHz, DMSO-d6): d (ppm) 169.1, 168.4, 154.4, 150.5, 138.0,
136.7, 132.8, 130.1, 129.52, 129.49, 127.7, 124.3, 122.4, 120.3. IR
(film, cmꢁ1): 3185, 3060, 1767, 1708, 1618, 1583, 1351, 1318,
1294, 1082, 1017, 772, 759, 724, 691, 649, 591, 488. HRMS: calcd.
for C17H11N2O2 (M+H)+ 275.0815, found 275.0812.
8.92 (dd, J = 8.2, 0.9 Hz, 1H), 8.19 (td, J = 7.7, 1.3 Hz, 1H), 8.00–7.94
(m, 1H), 7.91–7.85 (m, 1H), 7.81–7.77 (m, 2H), 7.23 (td, J = 7.6,
1.0 Hz, 1H), 7.14 (td, J = 7.7, 1.4 Hz, 1H), 6.61 (d, J = 7.4 Hz, 1H),
4.44 (d, J = 17.4 Hz, 1H), 4.40 (d, J = 17.0 Hz, 1H), 3.20 (d, J = 16.9
Hz, 1H), 3.17 (d, J = 16.3 Hz, 1H). 13C NMR (125 MHz, DMSO-d6): d
(ppm) 172.6, 168.2, 167.9, 163.3, 162.8 (d, J = 26.6 Hz), 161.1,
151.7, 151.1, 144.5, 139.8, 139.3, 133.4, 133.3, 131.9, 131.1, 129.6,
128.5, 124.8, 124.3, 123.4, 122.9, 122.8, 120.6, 54.9, 43.6. IR (film,
cmꢁ1) 3414, 3107, 3048, 2966, 2924, 1721, 1601, 1512, 1364,
1312, 1160, 1099, 1030, 769, 627. HRMS: calcd. for C25H18ClN3O4Rh
(M+H)+ 593.9756, found 593.9756.
4.2.2. 2-Benzyl-4-phenylpyrrolo[3,4-c]quinoline-1,3(2H)-dione (1b)
A
solution of 2-phenyl-3,4-dicarboxylic acid (4) (5.87 g,
20.0 mmol) in acetic anhydride (120 mL) was heated to 130 °C
for 3 h. During this time the solution gradually changed from yel-
low to black and the precipitation of a yellow solid was observed.
The solvent was removed in vacuo and anhydride 5 was obtained
which was used immediately for the next step. Anhydride 5 was
dissolved in glacial acetic acid (70 mL), benzyl amine (3.28 mL,
30.0 mmol) was added, and the solution was heated to 120 °C for
3 h. The solvent was removed in vacuo, the resulting brown/black
solid suspended in ethyl acetate (40 mL) and heated to reflux for
15 min leaving behind a yellow solid. The solid was filtered off,
washed with ethyl acetate, and dried in vacuo to provide 2-ben-
zyl-4-phenylpyrrolo[3,4-c]quinoline-1,3(2H)-dione (1b) as yellow
powder (5.68 g, 15.6 mmol, 78%). 1H NMR (300 MHz, DMSO-d6):
d (ppm) 9.81 (d, J = 7.6 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H), 8.05–7.99
(m, 1H), 7.97–7.93 (m, 2H), 7.90–7.85 (m, 1H), 7.56–7.53 (m,
3H), 7.41–7.27 (m, 5H), 4.82 (s, 2H). 13C NMR (75 MHz, DMSO-
d6): d (ppm) 167.6, 167.0, 154.2, 150.6, 137.2, 136.6, 136.4, 133.0,
130.1, 129.7, 129.62, 129.57, 128.5, 127.7, 127.5, 127.4, 124.3,
121.6, 120.1, 41.1. IR (film, cmꢁ1): 3056, 2940, 1705, 1619, 1683,
1553, 1491, 1429, 1390, 1347, 1109, 1069, 922, 775, 752, 696,
651, 626, 497. HRMS: calcd. for C24H17N2O2 (M+H)+ 365.1285,
found 365.1280.
4.2.5. Complexes 10/100
A
mixture of 4-phenylpyrrolo[3,4-c]quinoline-1,3(2H)-dione
(1a) (21.9 mg, 80.0 mol) in
l
mol) and RhCl3ꢀ3H2O (21.1 mg, 80.0
l
EtOH/H2O 1:1 (8.0 mL) was refluxed at 90 °C for 2 h. To the resulting
dark solution was added 2-[methyl(pyridin-2-ylmethyl)amino]ace-
tic acid (14.5 mg, 80.0 lmol) and the reaction mixture was refluxed
at 90 °C for further 16 h. Then, the solvent was removed and the
crude material was purified by silica gel chromatography with
CH2Cl2/MeOH (gradient 50:1 to 20:1). The combined product elu-
ents of each stereoisomer were dried in vacuo to provide complex
10 as orange solid (4.9 mg, 9.29
low solid (10.1 mg, 17.1 mol, 21%).
l
mol, 10%) and complex 100 as yel-
l
Complex 10: 1H NMR (300 MHz, DMSO-d6): d (ppm) 11.97 (bs,
1H), 9.55 (d, J = 5.2 Hz, 1H), 9.29 (dd, J = 7.9, 1.5 Hz, 1H), 8.92 (d,
J = 8.9 Hz, 1H), 8.86 (dd, J = 8.3, 1.1 Hz, 1H), 8.18 (td, J = 7.7,
1.6 Hz, 1H), 7.98–7.93 (m, 1H), 7.89 (dd, J = 7.6, 1.2 Hz, 1H), 7.73
(td, J = 7.6, 0.8 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.57 (td, J = 8.0,
1.5 Hz, 1H), 7.41 (td, J = 7.3, 1.5 Hz, 1H), 7.33 (td, J = 7.5, 1.4 Hz,
1H), 3.88 (d, J = 15.0 Hz, 1H), 3.57 (d, J = 14.9 Hz, 1H), 3.09 (d,
J = 17.0 Hz, 1H), 3.00 (d, J = 17.0 Hz, 1H), 1.60 (s, 3H). 13C NMR
(125 MHz, DMSO-d6): d (ppm) 178.2, 172.9 (d, J = 27.1 Hz) 168.3,
168.0, 165.2, 155.4, 151.1, 148.6, 144.8, 140.0, 139.3, 132.9,
132.8, 131.9, 130.2, 129.3, 126.6, 125.8, 125.1, 123.3, 123.2,
122.9, 120.2, 71.3, 66.0, 49.3. IR (film, cmꢁ1): 3413, 3052, 2925,
2855, 2734, 1723, 1643, 1449, 1363, 1311, 1097, 1024, 765, 630,
495. HRMS: calcd. for C26H20ClN4O4RhNa (M+Na)+ 613.0120, found
613.0126.
4.2.3. Complex 8
A mixture of 2-benzyl-4-phenylpyrrolo[3,4-c]quinoline-1,3(2H)-
dione (1b) (14.6 mg, 40.0
40.0 mol) in EtOH/H2O 1:1 (4.0 mL) was refluxed at 90 °C for 2 h.
To the resulting dark solution was added 2-[(pyridin-2-
ylmethyl)thio]acetic acid (7.3 mg, 40.0 mol) and the reaction mix-
lmol) and RhCl3ꢀ3H2O (10.5 mg,
l
l
ture was refluxed at 90 °C for further 16 h. Then, the solvent was re-
moved and the crude material was purified by silica gel
chromatography with CH2Cl2/MeOH (gradient 50:1 to 20:1). The
combined product eluents were dried in vacuo to provide complex
Complex 100: 1H NMR (300 MHz, DMSO-d6): d (ppm) 12.01 (bs,
1H), 9.89 (d, J = 8.8 Hz, 1H), 9.40 (d, J = 5.7 Hz, 1H), 9.29 (dd,
J = 8.0, 1.3 Hz, 1H), 8.96 (dd, J = 8.3, 1.2 Hz, 1H), 8.20 (td, J = 7.7,
1.4 Hz, 1H), 8.02–7.96 (m, 1H), 7.93–7.87 (m, 1H), 7.83–7.78 (m,
1H), 7.71 (d, J = 7.7 Hz, 1H), 7.24 (td, J = 7.7, 1.2, 1H), 7.13 (d,
J = 7.6 Hz, 1.4 Hz, 1H), 6.72 (dd, J = 7.7, 0.8 Hz, 1H), 4.04 (d,
J = 16.2 Hz, 1H), 3.91 (d, J = 16.2 Hz, 1H), 3.05 (s, 2H), 1.66 (s, 3H).
8 as yellow solid (4.4 mg, 6.40 l
mol, 16%). 1H NMR (300 MHz,
DMSO-d6): d (ppm) 9.74 (d, J = 5.7 Hz, 1H), 9.59 (d, J = 8.8 Hz, 1H),
9.14 (dd, J = 8.0, 1.4 Hz, 1H), 8.92 (dd, J = 8.3, 1.2 Hz, 1H), 8.19 (td,
J = 7.7, 1.4 Hz, 1H), 8.02–7.96 (m, 1H), 7.93–7.87 (m, 1H), 7.81–
7.76 (m, 2H), 7.49–7.46 (m, 2H), 7.40–7.30 (m, 3H) 7.23 (td,
J = 7.6, 1.2 Hz, 1H), 7.15 (td, J = 7.4, 1.5 Hz, 1H), 6.62 (dd, J = 7.7,
0.9 Hz, 1H), 4.94 (s, 2H), 4.43 (d, J = 17.3 Hz, 1H), 4.40 (d,
J = 17.4 Hz, 1H), 3.20 (d, J = 3.4 Hz, 2H). IR (film, cmꢁ1): 3454,
3108, 3050, 2956, 2141, 1772, 1713, 1622, 1437, 1395, 1348,
1276, 1225, 1169, 1124, 765, 700, 636. HRMS: calcd. for
13C NMR (125 MHz, DMSO-d6):
d (ppm) 173.5, 169.9 (d,
J = 28.1 Hz) 168.2, 168.0, 163.5, 159.4, 151.2, 149.8, 144.4, 140.0,
139.3, 133.4, 132.0, 130.5, 129.5, 128.0, 125.0, 124.4, 123.0,
122.5, 120.4, 70.7, 69.6, 49.4. IR (film, cmꢁ1): 3409, 3047, 2748,
1721, 1596, 1506, 1449, 1370, 1327, 1099, 1028, 884, 772, 631,
539, 500. HRMS: calcd. for C26H20ClN4O4RhNa (M+Na)+ 613.0120,
found 613.0125.
C
C
32H24ClN3O4Rh (M+H)+ 684.0226, found 684.0225; calcd. for
32H23ClN3O4RhNa (M+Na)+ 706.0045, found 706.0047.
4.2.4. Complex 9
4.2.6. Complexes 11/110
A mixture of 4-phenylpyrrolo[3,4-c]quinoline-1,3(2H)-dione (1a)
A mixture of RhCl3ꢀ3H2O (21.1 mg, 80.0
720 mol) in H2O (4.0 mL) was heated to 90 °C for 1 h. Then, 4-phe-
nylpyrrolo[3,4-c]quinoline-1,3(2H)-dione (1a, 21.9 mg, 80.0 mol)
lmol) and KBr (86.0 mg,
(11.0 mg, 40.0
lmol) and RhCl3ꢀ3H2O (10.5 mg, 40.0
lmol) in EtOH/
l
H2O 1:1 (4.0 mL) was refluxed at 90 °C for 2 h. To the resulting dark
l
solution was added 2-[(pyridin-2-ylmethyl)thio]acetic acid (7.3 mg,
40.0 lmol) and the reaction mixture was refluxed at 90 °C for fur-
ther 16 h. Then, the solvent was removed and the crude material
was purified by silica gel chromatography with CH2Cl2/MeOH (gra-
dient 50:1 to 30:1). The combined product eluents were dried in va-
and EtOH (8.0 mL) were added to the dark red solution and the mix-
ture was heated to 90 °C for 2 h. To the further darkened solution
was added 2-[methyl(pyridin-2-ylmethyl)amino]acetic acid
(14.5 mg, 80.0 lmol) and the reaction mixture was refluxed at
90 °C for 16 h. The solvent was removed and the crude material
was purified by silica gel chromatography with CH2Cl2/MeOH (gra-
dient 50:1 to 20:1). The combined product eluents of each stereoiso-
mer were dried in vacuo to provide complex 11 as orange solid
cuo to provide complex 9 as yellow solid (3.4 mg, 5.73 lmol, 14%).
1H NMR (300 MHz, DMSO-d6): d (ppm) 12.04 (bs, 1H), 9.74 (d,
J = 5.7 Hz, 1H), 9.59 (d, J = 8.9 Hz, 1H), 9.16 (dd, J = 7.9, 1.2 Hz, 1H),

S. Mollin et al. / Inorganica Chimica Acta 393 (2012) 261–268
267
(6.0 mg, 9.44
l
mol, 12%) and complex 110 as yellow solid (9.8 mg,
90 °C for further 16 h. Then, the solvent was removed and the
crude material was purified by silica gel chromatography with
CH2Cl2/MeOH (gradient 50:1 to 20:1). The combined product elu-
15.0 mol, 19%).
l
Complex 11: 1H NMR (300 MHz, DMSO-d6): d (ppm) 11.98 (bs,
1H), 9.69 (d, J = 4.6 Hz, 1H), 9.32 (dd, J = 7.9, 1.4 Hz, 1H), 8.92 (d,
J = 8.9 Hz, 1H), 8.86 (dd, J = 8.3, 1.1 Hz, 1H), 8.18 (td, J = 7.7,
1.6 Hz, 1H), 7.97–7.93 (m, 1H), 7.88 (dd, J = 7.7, 1.1 Hz, 1H), 7.73
(td, J = 7.6, 0.9 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.56 (td, J = 8.0,
1.5 Hz, 1H), 7.40 (td, J = 7.2, 1.5 Hz, 1H), 7.31 (td, J = 7.5, 1.3 Hz,
1H), 3.91 (d, J = 15.0 Hz, 1H), 3.56 (d, J = 14.9 Hz, 1H), 3.09 (d,
J = 17.0 Hz, 1H), 2.97 (d, J = 17.0 Hz, 1H), 1.58 (s, 3H). 13C NMR
(125 MHz, DMSO-d6): d (ppm) 178.6, 172.3 (d, J = 26.1 Hz), 168.3,
168.0, 165.1, 155.5, 151.1, 149.2, 144.7, 140.0, 139.3, 133.2,
132.7, 131.9, 130.2, 129.3, 127.0, 126.0, 125.0, 123.3, 123.1,
120.2, 71.2, 65.6, 49.0. IR (film, cmꢁ1): 3411, 2919, 2852, 2718,
1721, 1605, 1511, 1448, 1370, 1307, 1096, 1023, 890, 761, 629,
495. HRMS: calcd. for C26H20BrN4O4RhNa (M+Na)+ 656.9615, found
656.9621.
ents were dried in vacuo to provide complex
ange solid (15.8 mg, 22.4 mol, 28%).
D-(R)-13a as red or-
l
1H NMR (300 MHz, DMSO-d6): d (ppm) 11.98 (bs, 1H), 9.57 (d,
J = 4.6 Hz, 1H), 9.18 (dd, J = 7.8, 1.6 Hz, 1H), 8.80 (dd, J = 8.3,
1.1 Hz, 1H), 8.49 (d, J = 9.0 Hz, 1H), 8.19 (td, J = 7.7, 1.6 Hz, 1H),
8.00–7.93 (m, 2H), 7.68 (td, J = 7.7, 0.8 Hz, 1H), 7.57 (d, J = 7.7 Hz,
1H), 7.44–7.27 (m, 3H), 3.89 (d, J = 15.1 Hz, 1H), 3.30 (d,
J = 15.1 Hz, 1H), 3.07 (dd, J = 9.3, 6.9 Hz, 1H), 2.40–2.32 (m, 1H),
2.21–2.13 (m, 1H), 2.01–1.89 (m, 1H), 1.46–1.30 (m, 2H), 0.82–
0.73 (m, 1H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 181.7,
174.5 (d, J = 26.8 Hz), 168.4, 168.0, 165.3, 156.3, 150.8, 148.5,
144.3, 139.9, 139.4, 133.9, 132.2, 132.1, 129.3, 129.2, 126.2,
125.8, 125.0, 123.1, 122.7, 120.2, 72.6, 69.4, 58.7, 30.7, 22.9. IR
(film, cmꢁ1): 3426, 3140, 3048, 2923, 2854, 2738, 1770, 1723,
1617, 1507, 1447, 1366, 1306, 1096, 1053, 1025, 766, 494.
Complex 110: 1H NMR (300 MHz, DMSO-d6): d (ppm) 12.00 (bs,
1H), 9.87 (d, J = 8.6 Hz, 1H), 9.41 (d, J = 5.9 Hz, 1H), 9.29 (dd,
J = 7.9, 1.1 Hz, 1H), 8.96 (dd, J = 8.4, 1.2 Hz, 1H), 8.22 (td, J = 7.6,
1.5 Hz, 1H), 8.01–7.96 (m, 1H), 7.92–7.88 (m, 1H), 7.82–7.79 (m,
1H), 7.71 (d, J = 7.6 Hz, 1H), 7.24 (td, J = 7.7, 1.1 Hz, 1H), 7.14 (d,
J = 7.7, 1.2 Hz, 1H), 6.72 (dd, J = 7.7, 0.9 Hz, 1H), 4.03 (d,
J = 16.5 Hz, 1H), 3.92 (d, J = 16.4 Hz, 1H), 3.05 (s, 2H), 1.65 (s, 3H).
639.0271. CD (DMSO): k, nm (De
, Mꢁ1 cmꢁ1): 402 nm (+11.5),
353 nm (ꢁ14.7). HRMS: calcd. for
C
28H23ClN4O4Rh (M+H)+
617.0457, found 617.0454.
4.2.9. Complex
A mixture of 2-benzyl-4-phenylpyrrolo[3,4-c]quinoline-1,3(2H)-
dione (1b; 29.2 mg, 80.0 mol)
K-(S)-13b
13C NMR (100 MHz, DMSO-d6):
d
(ppm) 174.2, 169.8 (d,
l
mol) and RhCl3ꢀ3H2O (10.5 mg, 80.0
l
J = 27.2 Hz), 168.3, 168.1, 163.7, 159.4, 151.5, 151.4, 144.4, 140.1,
139.4, 133.9, 133.4, 132.1, 130.6, 129.6, 128.4, 125.5, 124.5,
123.2, 123.0, 122.7, 120.5, 70.8, 69.2, 49.1. IR (film, cmꢁ1): 3383,
3051, 2925, 2737, 1769, 1723, 1618, 1509, 1449, 1367, 1310,
1098, 1026, 887, 768, 628, 495. HRMS: calcd. for C26H20BrN4O4Rh-
Na (M+Na)+ 656.9615, found 656.9619.
in EtOH/H2O 1:1 (8.0 mL) was refluxed at 90 °C for 2 h. To the result-
ing dark solution was added (S)-N-(pyridin-2-ylmethyl)proline
(18.3 mg, 80.0 lmol) and the reaction mixture was refluxed at 90 °C
for further 16 h. The solvent was removed and the crude material
was purified by silica gel chromatography with CH2Cl2/MeOH (gradi-
ent 50:1 to 20:1). The combined product eluents were dried in vacuo
to provide rhodium complex
K-(S)-13b as orange solid (17.0 mg,
4.2.7. Complex
mixture of 4-phenylpyrrolo[3,4-c]quinoline-1,3(2H)-dione
(1a; 21.9 mg, 80.0 mol) in
EtOH/H2O 1:1 (8.0 mL) was refluxed at 90 °C for 2 h. To the result-
ing dark solution was added (S)-N-(pyridin-2-ylmethyl)proline
K
-(S)-13a
24.0
l
mol, 30%). 1H NMR (300 MHz, DMSO-d6): d (ppm) 9.57 (d,
A
J = 4.8 Hz, 1H), 9.22 (dd, J = 7.8, 1.5 Hz, 1H), 8.83 (dd, J = 8.4, 1.0 Hz,
1H), 8.52 (d, J = 9.0 Hz, 1H), 8.20 (td, J = 7.7, 1.6 Hz, 1H), 8.01–7.94
(m, 2H), 7.70 (td, J = 7.6, 0.9 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.50–
7.28 (m, 8H), 4.93 (s, 2H), 3.90 (d, J = 15.2 Hz, 1H), 3.33 (d,
J = 15.2 Hz, 1H), 3.08 (d, J = 16.2 Hz, 1H), 2.40–2.32 (m, 1H), 2.21–
2.13 (m, 1H), 1.99–1.91 (m, 1H), 1.44–1.30 (m, 2H), 0.80–0.71 (m,
1H). IR (film, cmꢁ1): 3458, 3056, 2927, 1773, 1712, 1641, 1583,
1508, 1445, 1396, 1359, 1054, 1027, 764, 636, 502. CD (DMSO): k,
l
mol) and RhCl3ꢀ3H2O (10.5 mg, 80.0
l
(18.3 mg, 80.0 lmol) and the reaction mixture was refluxed at
90 °C for further 16 h. Then, the solvent was removed and the
crude material was purified by silica gel chromatography with
CH2Cl2/MeOH (gradient 50:1 to 20:1). The combined product
eluents were dried in vacuo to provide complex
K
-(S)-13a as red
nm (De
, Mꢁ1 cmꢁ1) 267 (+8.9), 357 (+10.0), 400 (ꢁ3.8). HRMS: calcd.
orange solid (15.3 mg, 24.8
l
mol, 31%). 1H NMR (300 MHz,
for C35H29ClN4O4Rh (M+H)+ 707.0927, found 707.0920.
DMSO-d6): d (ppm) 11.98 (bs, 1H), 9.57 (d, J = 4.6 Hz, 1H), 9.18
(dd, J = 7.8, 1.5 Hz, 1H), 8.80 (dd, J = 8.4, 1.0 Hz, 1H), 8.49 (d,
J = 9.0 Hz, 1H), 8.19 (td, J = 7.7, 1.6 Hz, 1H), 8.00–7.93 (m, 2H),
7.67 (td, J = 7.6, 0.9 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.44–7.27 (m,
3H), 3.90 (d, J = 15.2 Hz, 1H), 3.29 (d, J = 15.1 Hz, 1H), 3.07 (dd,
J = 9.3, 6.9 Hz, 1H), 2.40–2.32 (m, 1H), 2.21–2.13 (m, 1H), 1.99–
1.92 (m, 1H), 1.46–1.30 (m, 2H), 0.85–0.71 (m, 1H). 13C NMR
(100 MHz, DMSO-d6): d (ppm) 181.7, 174.5 (d, J = 26.4 Hz), 168.4,
168.0, 165.3, 156.3, 150.8, 148.5, 144.3, 139.9, 139.4, 133.9,
132.2, 132.1, 129.3, 129.2, 126.2, 125.8, 125.0, 123.1, 122.7,
120.2, 72.6, 69.4, 58.7, 30.7, 22.9. IR (film, cmꢁ1): 3429, 2051,
2738, 1769, 1722, 1620, 1507, 1447, 1367, 1308, 1272, 1095,
4.2.10. Complex
A mixture of 2-benzyl-4-phenylpyrrolo[3,4-c]quinoline-1,3(2H)-
dione (1b; 29.2 mg, 80.0
mol) and RhCl3ꢀ3H2O (10.5 mg, 80.0
mol) in EtOH/H2O 1:1 (8.0 mL) was refluxed at 90 °C for 2 h. To
the resulting dark solution was added (R)-N-(pyridin-2-
ylmethyl)proline (18.3 mg, 80.0 mol) and the reaction mixture
was refluxed at 90 °C for further 16 h. The solvent was removed
and the crude material was purified by silica gel chromatography
with CH2Cl2/MeOH (gradient 50:1 to 20:1). The combined product
D-(R)-13b
l
l
l
eluents were dried in vacuo to provide complex
D-(R)-13b as orange
solid (15.8 mg, 22.4
l
mol, 28%). 1H NMR (300 MHz, DMSO-d6): d
1025, 764, 626, 494. CD (DMSO):
K
, nm (
D
e
, Mꢁ1 cmꢁ1) 353
(ppm) 9.57 (d, J = 5.2 Hz, 1H), 9.21 (dd, J = 7.8, 1.5 Hz, 1H), 8.83
(dd, J = 8.4, 1.1 Hz, 1H), 8.52 (d, J = 9.0 Hz, 1H), 8.20 (td, J = 7.7,
1.6 Hz, 1H), 8.01–7.94 (m, 2H), 7.73–7.67 (m, 1H), 7.58 (d,
J = 7.7 Hz, 1H), 7.50–7.28 (m, 8H), 4.93 (s, 2H), 3.89 (d, J = 15.2 Hz,
1H), 3.34–3.32 (m, 1H), 3.10–3.04 (m, 1H), 2.40–2.32 (m, 1H),
2.21–2.12 (m, 1H), 1.99–1.92 (m, 1H), 1.46–1.30 (m, 2H), 0.79–
0.71 (m, 1H). 13C NMR (125 MHz, DMSO-d6): d (ppm) 181.8, 174.6
(d, J = 26.4 Hz), 167.0, 166.6, 164.9, 156.3, 151.1, 148.6, 144.3,
139.5, 139.3, 136.2, 134.0, 132.5, 132.0, 129.5, 129.4, 128.6, 127.9,
127.6, 126.3, 125.9, 125.1, 123.2, 123.1, 121.7, 120.1, 72.7, 69.4,
58.8, 41.6, 30.7, 22.9. IR (film, cmꢁ1): 3410, 3054, 2928, 1709,
(+15.4), 401 (ꢁ11.9), 472 (+2.3). HRMS: calcd. for C28H23ClN4O4Rh
(M+H)+ 617.0457, found 617.0452; calcd. for C28H22ClN4O4RhNa
(M+Na)+ 639.0277, found 639.0270.
4.2.8. Complex
mixture of 4-phenylpyrrolo[3,4-c]quinoline-1,3(2H)-dione
(1a; 21.9 mg, 80.0 mol) in
D-(R)-13a
A
l
mol) and RhCl3ꢀ3H2O (10.5 mg, 80.0
l
EtOH/H2O 1:1 (8.0 mL) was refluxed at 90 °C for 2 h. To the result-
ing dark solution was added (R)-N-(pyridin-2-ylmethyl)proline
(18.3 mg, 80.0 lmol) and the reaction mixture was refluxed at

268
S. Mollin et al. / Inorganica Chimica Acta 393 (2012) 261–268
(d) T.W. Hambley, Science 318 (2007) 1392;
(e) A. Mukherjee, P.J. Sadler, Wiley Encycl. Chem. Biol. (2009) 1;
(f) K.L. Haas, K.J. Franz, Chem. Rev. 109 (2009) 4921;
1635, 1407, 1437, 1394, 1357, 1314, 1052, 1026, 1002, 762, 732,
699, 635, 500. CD (DMSO): k, nm (
De
, Mꢁ1 cmꢁ1) 267 (ꢁ9.3), 357
(ꢁ10.4), 400 (+3.9). HRMS: calcd. for C35H29ClN4O4Rh (M+H)+
(g) A. Levina, A. Mitra, P.A. Lay, Metallomics 1 (2009) 458;
(h) E.A. Hillard, G. Jaouen, Organometallics 30 (2011) 20;
(i) G. Gasser, I. Ott, N. Metzler-Nolte, J. Med. Chem. 54 (2011) 3.
[2] E. Meggers, G.E. Atilla-Gokcumen, H. Bregman, J. Maksimoska, S.P. Mulcahy, N.
Pagano, D.S. Williams, Synlett 8 (2007) 1177.
707.0927, found 707.0918.
4.3. Assays with protein kinases
[3] (a) E. Meggers, Curr. Opin. Chem. Biol. 11 (2007) 287;
(b) E. Meggers, Chem. Commun. (2009) 1001;
(c) C.L. Davies, E.L. Dux, A.-K. Duhme-Klair, Dalton Trans. (2009) 10141.
[4] (a) J. Maksimoska, L. Feng, K. Harms, C. Yi, J. Kissil, R. Marmorstein, E. Meggers,
J. Am. Chem. Soc. 130 (2008) 15764;
The protein kinase selectivity profile of the racemic mixture of
13a at an assay concentration of 10 lM was derived from an ac-
tive-site-directed affinity screening against 451 human protein ki-
(b) L. Feng, Y. Geisselbrecht, S. Blanck, A. Wilbuer, G.E. Atilla-Gokcumen, P.
Filippakopoulos, K. Kräling, M.A. Celik, K. Harms, J. Maksimoska, R.
Marmorstein, G. Frenking, S. Knapp, L.-O. Essen, E. Meggers, J. Am. Chem.
Soc. 133 (2011) 5976.
nases (KINOMEscan, DiscoveRx) [13]. Determination of IC50-values
with PKCd: Various concentrations of the ruthenium complexes
(S)-13a and -(R)-13a were incubated at room temperature in
20 mM MOPS, 30 mM Mg(OAc)2, 0.8 g/ L BSA, 10% DMSO (result-
ing from the inhibitor stock solution), pH 7.0, in the presence of
substrate PKCtide (50 M), PKC Lipid Activator (purchased from
K-
D
[5] A. Wilbuer, D.H. Vlecken, D.J. Schmitz, K. Kräling, K. Harms, C.P. Bagowski, E.
Meggers, Angew. Chem., Int. Ed. 49 (2010) 3839.
[6] S. Dieckmann, R. Riedel, K. Harms, E. Meggers, Eur. J. Inorg. Chem. (2012) 813.
[7] (a) H. Bregman, D.S. Williams, E. Meggers, Synthesis (2005) 1521;
(b) N. Pagano, J. Maksimoska, H. Bregman, D.S. Williams, R.D. Webster, F. Xue,
E. Meggers, Org. Biomol. Chem. 5 (2007) 1218.
[8] For different designs of metal-containing protein kinase inhibitors, see: (a) J.
Spencer, A.P. Mendham, A.K. Kotha, S.C.W. Richardson, E.A. Hillard, G. Jaouen,
L. Male, M.B. Hursthouse, Dalton Trans. (2009) 918;
l
l
l
Millipore Scientific), and human PKCd (2.0 nM) (purchased from
Mo Bi Tec). After 30 min, the reaction was initiated by adding
ATP to a final concentration of 1
l
M and approximately 0.1
-33P]ATP. Reactions were performed in a total volume of
L. After 45 min, the reaction was terminated by spotting
L on a circular P81 phosphocellulose paper (2.1 cm diameter,
lCi/
[
c
lL
(b) B. Biersack, M. Zoldakova, K. Effenberger, R. Schobert, Eur. J. Med. Chem. 45
(2010) 1972;
(c) S. Blanck, T Cruchter, A. Vultur, R. Riedel, K. Harms, M. Herlyn, E. Meggers,
Organometallics 30 (2011) 4598.
25
15
l
l
Whatman), followed by washing three times with 0.75% phospho-
ric acid and once with acetone. The dried P81 papers were trans-
ferred to a scintillation vial, 5 mL of scintillation cocktail was
added, the counts per minute (CPM) were measured with a Beck-
mann Coulter™ LS6500 Multi-Purpose Scintillation Counter, and
corrected by the background CPM. The IC50 values were deter-
mined in triplicate from sigmoidal curve fits.
[9] R.F.C. Brown, K.J. Coulston, F.W. Eastwood, M.R. Moffat, Tetrahedron 48 (1992)
7763.
[10] For asymmetric coordination chemistry, see: (a) J.-L. Pierre, Coord. Chem. Rev.
178–180 (1998) 1183;
(b) U. Knof, A. von Zelewsky, Angew. Chem., Int. Ed. 38 (1999) 302;
(c) H. Brunner, Angew. Chem., Int. Ed. 38 (1999) 1194;
(d) P.D. Knight, P. Scott, Coord. Chem. Rev. 242 (2003) 125;
(e) C. Ganter, Chem. Soc. Rev. 32 (2003) 130;
(f) J. Lacour, V. Hebbe-Viton, Chem. Soc. Rev. 32 (2003) 373;
(g) H. Amouri, M. Gruselle, Chirality in Transition Metal Chemistry: Molecules,
Supramolecular Assemblies and Materials, Wiley, 2008;
(h) E. Meggers, Chem. Eur. J. 16 (2010) 752;
4.4. Single crystal X-ray diffraction studies
(i) E. Meggers, Eur. J. Inorg. Chem. (2011) 2911.
Single crystals of complex 11 were obtained upon standing in a
[11] For rhodium complexes with biological activities, see: (a) B. Weber, A. Serafin,
J. Michie, C. van Rensburg, J.C. Swarts, L. Böhm, Anticancer Res. 24 (2004) 763;
(b) A. Dorcier, W.H. Ang, S. Bolano, L. Gonsalvi, L. Juillerat-Jeannerat, G.
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K
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Acknowledgements
We thank the German Research Foundation (DFG Grant No. ME
1805/2-1) and the National Institutes of Health USA(CA114046) for
support of this research. S.B. acknowledges a stipend from the
Fonds der Chemischen Industrie.
Appendix A. Supplementary material
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