To Transfer or Not to Transfer? Development of a Dinitrosyl Iron Complex as a Nitroxyl Donor for the Nitroxylation of an FeIII-Porphyrin Center

Article abstract of DOI:10.1002/chem.201503176

A positive myocardial inotropic effect achieved using HNO/NO^-, compared with NO· triggered attempts to explore novel nitroxyl donors for use in clinical applications in vascular and myocardial pharmacology. To develop M-NO complexes for nitroxy

Full text of DOI:10.1002/chem.201503176

DOI: 10.1002/chem.201503176
Communication
&
Bioinorganic Chemistry
To Transfer or Not to Transfer? Development of a Dinitrosyl Iron
III
Complex as a Nitroxyl Donor for the Nitroxylation of an Fe –
Porphyrin Center
[a]
[b]
[a]
[a]
[a]
Yu-Ting Tseng, Chien-Hong Chen, Jing-Yu Lin, Bing-Han Li, Yu-Huan Lu, Chia-
[a]
[a]
[c]
[c]
[d]
Her Lin, Hsin-Tsung Chen, Tsu-Chien Weng, Dimosthenes Sokaras, Huang-Yeh Chen,
[
d, e]
[a]
Yun-Liang Soo,
and Tsai-Te Lu*
opment of an exogenous nitroxyl donor as a novel approach
[
4–7]
for the acute treatment of heart failure.
Angeli’s salt
Abstract: A positive myocardial inotropic effect achieved
using HNO/NO , compared with NO·, triggered attempts
À
(Na N O ) and Piloty’s acid (PhSO NHOH) were predominantly
2
2
3
2
exploited as nitroxyl-releasing reagents at neutral and basic
pH, respectively, to explore the vascular and myocardial phar-
to explore novel nitroxyl donors for use in clinical applica-
tions in vascular and myocardial pharmacology. To devel-
op M-NO complexes for nitroxyl chemistry and biology,
modulation of direct nitroxyl-transfer reactivity of dinitro-
syl iron complexes (DNICs) is investigated in this study
À
macology of HNO/NO . Rapid decomposition of Angeli’s salt
À4 À1
À3 À1
(
k=6”10
s
at 258C and k=4–5”10
s
at 378C), rapid
6
À1 À1
dimerization of HNO to afford N O and H O (k=8”10 m s ),
2
2
III
and release of NO rather than nitroxyl from Piloty’s acid under
neutral aerobic conditions, however, limit the clinical potential
using a Fe -porphyrin complex and proteins as a specific
9
Me
probe. Stable dinuclear {Fe(NO) } DNIC [Fe(m- Pyr)(NO) ]
2
2 2
[
7]
of these compounds. As a consequence, a long-lasting HNO/
was discovered as a potent nitroxyl donor for nitroxylation
À
III
NO donor derived from steady nitroxyl-releasing compounds
of Fe -heme centers through an associative mechanism.
with an ON/OFF switch or from stable compounds with dedi-
Beyond the efficient nitroxyl transfer, transformation of
DNICs into a chemical biology probe for nitroxyl and for
pharmaceutical applications demands further efforts using
in vitro/in vivo studies.
III
cated nitroxyl-transfer reactivity toward the Fe center in heme
proteins is a much-needed target for pharmaceutical applica-
tions.
The intrinsic redox propensity of transition metals in metal–
nitrosyl complexes modulates the oxidation state of NO and
allows the potential use of MÀNO complexes in nitroxyl
n
À
[8–13]
HNO/NO (nitroxyl), compared to NO·, features a specific bio-
chemistry.
In particular, the electronic structure of {M(NO) }
x
III
logical reactivity in the nitroxylation of Fe -heme centers and
complexes (M=Fe or Co, x=1 or 2, n=7, 8, 9, or 10) regulates
III
modification of thiol residue in cysteine to sulfonamide/disul-
fide, in addition to the up-regulation of plasma levels of calci-
the redox switch for the reductive nitrosylation of the Fe -por-
phyrin complex/protein and controls the proton-induced ni-
[1–3]
[14–19]
9
10
tonin gene-related peptide (CGRP).
Moreover, a positive my-
troxyl-release reactivity.
{Fe(NO) } /{Fe(NO) } complexes
2 2
0
/1À
ocardial inotropic effect of nitroxyl, during a congestive heart
failure condition in particular, stimulated the study of a mecha-
nism for the endogenous generation of nitroxyl and the devel-
[Fe(NO) (Ar-nacnac)]
exhibit an electrochemically reversible
2
redox couple at À1.34 V, whereas the reduction potential for
III
+
[Fe (TPP)Cl] is À0.90 V versus Fc/Fc (Ar-nacnac = anion of
[
14,20]
[
(2,6-diisopropylphenyl)NC(Me)] CH).
In contrast to the in-
2
[
a] Y.-T. Tseng, J.-Y. Lin, B.-H. Li, Y.-H. Lu, Prof. C.-H. Lin, Prof. H.-T. Chen,
Prof. T.-T. Lu
Department of Chemistry, Chung Yuan Christian University No. 200
Chung Pei Rd. Taoyuan, 32023 (Taiwan)
E-mail: TTLu@cycu.edu.tw
9
ertness of the {Fe(NO) } complex [Fe(NO) (Ar-nacnac)] toward
2
2
III
III
[
Fe (TPP)Cl], reductive nitrosylation of [Fe (TPP)Cl] by
10
À
{Fe(NO)2} [Fe(NO) (Ar-nacnac)] to afford [Fe(TPP)(NO)] occurs
2
through a redox-coupled nitrosyl transfer pathway according
II
À
9
[
b] Prof. C.-H. Chen
to the formation of intermediates [Fe (TPP)Cl] and {Fe(NO)2}
Fe(NO) (Ar-nacnac)]. Harrop and co-workers reported a ther-
School of Medical Applied Chemistry, Chung Shan Medical University
No. 110, Section 1, Jianguo North Rd. Taichung, 40201 (Taiwan)
[
2
8
À
mally stable {Fe(NO)} complex [Fe(LN )(NO)] with a E1/2 of
4
[
c] Dr. T.-C. Weng, Dr. D. Sokaras
SLAC National Accelerator Laboratory 2575 Sand Hill Rd. Menlo Park
CA 94025 (USA)
7
8
[15]
À1.38 V for a {Fe(NO)} /{Fe(NO)} redox couple. A redox-cou-
pled nitrosyl-transfer mechanism was followed using this
8
À
[
d] H.-Y. Chen, Prof. Y.-L. Soo
{Fe(NO)} complex [Fe(LN )(NO)] to achieve the rapid conver-
4
National Synchrotron Radiation Research Center No. 101, Xin’an Rd.
Hsinchu, 30076 (Taiwan)
sion of metmyoglobin (metMb) to MbNO in aqueous buffer so-
lution at pH 7.2. Of interest, replacement of iron by cobalt to
[
e] Prof. Y.-L. Soo
Department of Physics, National Tsing Hua University No. 101
Section 2, Guangfu Rd., Hsinchu, 30013 (Taiwan)
8
afford the {Co(NO)} complex [Co(LN )(NO)] leads to an irrever-
4
sible Eox peak at 0.75 V and abolishes the reductive nitrosyla-
[
16]
tion reactivity. The release of HNO from this complex was
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503176.
[
16]
promoted after addition of 1 equiv of HBF4. This proton-in-
Chem. Eur. J. 2015, 21, 17570 – 17573
17570
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
[
25,8]
duced release of nitroxyl was also observed in the proposed
isopropylimidazole and benzimidazole) in a 1:1 molar ratio.
9
{
Fe(NO)2} intermediate [Fe(NO) P(C H -3-SiMe -2-S) (C H -3-
According to the single-crystal X-ray structure of DNIC 3
shown in Figure S1B, a butterfly geometry observed in DNIC 3
may explain the four IR nNO stretching peaks, as opposed to
2
6
3
3
2
6
3
À
SiMe -2-SH)] , which was derived from the reaction of
3
9
À
the {Fe(NO) } complex [Fe(NO) (Car) ] and P(C H -3-SiMe -2-
2
2
2
6
3
3
[
18]
À1
SH)3.
two strong IR nNO stretching peaks at 1774 and 1748 cm ob-
Regarding the pioneer studies on redox-coupled nitrosyl-
transfer and proton-induced nitroxyl-release reactivity of M-NO
complexes, we are prompted to elucidate the nature and
mechanism for the direct nitroxyl-transfer reactivity of dinitro-
served in DNIC [Fe(m-SEt)(NO) ] (2) containing an approximate
2
2
[
23]
center of inversion.
DFT calculation of DNIC 3 rationalizes
and assigns these four IR nNO stretching peaks to the two
[Fe(NO) ] cores in DNIC 3 (Figure S1C in the Supporting Infor-
2
III
III
syl iron complexes (DNICs) using [Fe (TPP)Cl], Fe -myoglobin
mation).
III
9
9
…
(
metMb) from equine heart, and Fe -hemoglobin (metHb)
For dinuclear {Fe(NO) } -{Fe(NO) } DNICs, the Fe Fe distance
2 2
from swine as a specific probe under alternative conditions
regulates the antiferromagnetic coupling between the two
[
14–17,21,22]
1
9
(
Figure 1).
To gain the insight to the control of direct
S= = {Fe(NO) } cores and dictates the appearance of the dis-
2 2
9
[23,8,27]
tinctive EPR signal at g=2.03 for {Fe(NO)2} DNICs.
As
shown in Figure S2A in the Supporting Information, dinuclear
9
9
{
Fe(NO) } -{Fe(NO) } DNIC 3 displays an isotropic signal with
2 2
g=2.03 at 77 K. Compared to the EPR silent DNIC 2, replace-
Me
ment of the m-SEt ligands by m- Pyr ligands in DNIC 3 extends
…
the Fe Fe distance from 2.708(1) Š to 3.353(1) Š and weakens
9
[23]
the magnetic coupling between the two {Fe(NO) } centers.
2
Decrease of temperature-dependent effective magnetic
moment of DNIC 3 from 2.56 m at 300 K to 2.44 m at 100 K
B
B
9
9
supports the {Fe(NO) } -{Fe(NO) } electronic structure of DNIC
2
2
3
with weak magnetic coupling between the two
1
9
S= = {Fe(NO) } centers (Figure S2B in the Supporting Informa-
2
2
tion).
III
Reaction of complex [Fe (TPP)Cl] and DNICs 1, 2, and 3, re-
spectively, was investigated as the initial evaluation for the ni-
[
14,16]
troxyl-transfer reactivity of DNICs (Figure 1).
As shown in
Figure S3A and S3B in the Supporting Information, two strong
À1
IR nNO stretching peaks at 1773 and 1748 cm derived from
DNIC 2 and the UV/Vis absorption bands at 415, 505, and
III
5
69 nm derived from complex [Fe (TPP)Cl] remain unchanged
III
after the THF solution containing complexes [Fe (TPP)Cl] and 2
9
Figure 1. A) {Fe(NO)
[
2
III
} DNICs 1, 2, and 3 used in this study. B) Utilization of
III
was stirred for 8 h. In comparison, nitroxyl transfer from DNIC
Fe (TPP)Cl] and Fe -porphyrin center in metMb or metHb as a specific
probe to characterize the nitroxyl-transfer reactivity of {Fe(NO)
9
À
III
} DNICs 1, 2,
[Fe(SPh) (NO) ] (1) to complex [Fe (TPP)Cl] affording [Fe(TPP)-
2 2
2
and 3.
(
NO)] was completed in 8 h according to the shift of IR n
NO
À1
À1
stretching peaks from 1737 and 1693 cm to 1680 cm and
the shift of UV/Vis absorption bands from 415, 505, and
569 nm to 408, 534 and 601 nm (Figure 2A and Figure S4 in
nitroxyl-transfer reactivity, thermally stable mononuclear
9
À
{
{
Fe(NO)2} complex [Fe(SPh) (NO) ]
(1) and dinuclear
the Supporting Information). The reported E of À1.33 V for
2
2
1/2
9
9
9
10
Fe(NO) } -{Fe(NO) } complex [Fe(m-SEt)(NO) ] (2) were select-
{Fe(NO) } /{Fe(NO) } redox couple in DNIC 1 and the absence
2
2
2 2
2
2
ed to avoid the redox-coupled process as well as spontaneous
of Eox between À1.7 V and À0.7 V exclude the redox-coupled
[
23,24]
9
9
[24]
nitroxyl release.
In addition, dinuclear {Fe(NO) } -{Fe(NO) }
process between complexes [Fe(TPP)Cl] and 1.
2
2
Me
complex [Fe(m- Pyr)(NO) ] (3) embedded in a butterfly geom-
Upon addition of 0.25 equiv of DNIC 3 to complex
2
2
III
7
etry was synthesized in an attempt to probe the role of elec-
tronic structure in the modulation of nitroxyl-transfer reactivity.
Upon addition of one equiv of 3-methylpyrazole into the
CH Cl solution of freshly prepared Fe(CO) (NO) , a pronounced
[Fe (TPP)Cl], formation of {Fe(NO)} complex [Fe(TPP)(NO)] ac-
complished within 15 min demonstrates a rapid nitroxyl-trans-
fer reactivity featured by DNIC 3 (Figure 2B and Figure S5 in
the Supporting Information). Electrochemical interconversion
2
2
2
2
9
9
9
10
color change from red to brown occurs after this reaction solu-
tion was stirred overnight at ambient temperature. A shift of IR
among
{Fe(NO) } -{Fe(NO) } ,
{Fe(NO) } -{Fe(NO) } ,
and
2
2
2
2
10
10
{Fe(NO) } -{Fe(NO) } redox couples in DNIC 3 at E =À0.87 V
2
2
1/2
À1
+
nNO stretching frequencies from 1808 and 1760 cm to 1809,
and À1.18 V versus Fc/Fc , respectively, supports the direct
transfer of nitroxyl from {Fe(NO) } -{Fe(NO) } DNIC 3 to
À1
9
9
1
795, 1740, and 1726 cm indicated the formation of dinu-
2
2
Me
Me
III
clear DNIC [Fe(m- Pyr)(NO) ] (3, Pyr=3-methylpyrazolate)
[Fe (TPP)Cl] (Figure S6 in the Supporting Information). Forma-
2
2
À
(
yield 67%; see Figure S1A in the Supporting Information). This
tion of complexes [Fe(TPP)(NO)] and [FeCl (Ar-nacnac)] , de-
2
III
10
reaction is comparable to the formation of complex [Fe(m-
rived from the reaction of [Fe (TPP)Cl] and {Fe(NO)2}
R
À
Im)(NO) ] in the reaction of Fe(CO) (NO) and imidazole (or
[Fe(NO) (Ar-nacnac)] , suggests a net NO–Cl exchange mecha-
2
4
2
2
2
Chem. Eur. J. 2015, 21, 17570 – 17573
www.chemeurj.org
17571
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
associative mechanism for direct nitroxyl transfer from DNIC 3
to metMb. As shown in Figure 3D, reaction of 5 mm methemo-
globin (metHb) and 5 mm DNIC 3 affords HbNO and provides
an alternative support to the efficient nitroxyl-transfer reactivi-
III
ty of DNIC 3 toward the Fe -heme center in aqueous buffer so-
lution at pH 7.4. In contrast, DNIC 2 is unreactive toward the
III
Fe -porphyrin center in either metMb or metHb (Figure S7 in
the Supporting Information).
Efficient nitroxyl-transfer reactivity of DNIC 3 encouraged us
to conduct FeKb valence-to-core X-ray emission spectroscopy
(
V2C XES) and Fe K-edge X-ray absorption spectroscopy (XAS)
study (Table S1 and Figure S8 in the Supporting Informa-
[
27–31]
tion).
V2C XES was used to probe DE
of NO and pro-
s2s*Às2p
vide a quantitative measurement of the NO oxidation state in
Fe-NO complexes, based on the linear relationship between
[
28]
DE
of NO and its oxidation state. For dinuclear DNICs
s2s*Às2p
2
and 3, replacement of the bridging thiolate ligands in
DNIC 2 with bridging pyrazolate ligands in DNIC 3 elongates
the FeÀNO bond and enhances the nitroxyl character in
DNIC 3 (Table S1 in the Supporting Information). Fe K-edge
pre-edge energy of 7114.0 eV observed in DNIC 3, compared
to 7113.5 eV exhibited by DNIC 1 and 7113.8 eV exhibited by
III
DNIC 2, demonstrates the buildup of an electron-deficient Fe
À
center containing two NO ligands polarized by the pyrazolate
bridging ligands. Presumably, decreased FeÀNO bonding inter-
III
action between the electron-deficient Fe center in DNIC 3 and
À
its NO ligands, as evidenced by the elongated FeÀNO bond
distance (Table S1 in the Supporting Information), boosts the
III
nitroxyl transfer to the Fe -porphyrin complex and proteins.
With the use of V2C XES in spectroscopic measurements for
quantitative determination of NO oxidation state, continuing
efforts on the study of DNICs, however, are required to unravel
the correlation among its electronic structure, dominant Fe-to-
NO bonding interaction versus dominant NO-to-Fe bonding in-
teraction, FeÀNO and NÀO bond lengths, and dedicated con-
trol of nitroxyl-transfer reactivity.
III
Figure 2. A) Reaction of complex [Fe (TPP)Cl] and DNIC 1 in a 2:1 molar
ratio traced by IR. The spectra are measured after the reaction solution was
stirred for 0 (black), 60, 90, 120, 180, 240, 300, 360 (dotted lines), and
80 min (dashed line). B) IR spectra of DNIC 3 (black) and after its reaction
4
III
with 4 equiv of complex [Fe (TPP)Cl] for 15 min (dashed line).
III
nism for the reductive nitrosylation of [Fe (TPP)Cl] by
10
À [14]
9
{
Fe(NO)2} [Fe(NO) (Ar-nacnac)] . Presumably, direct nitroxyl
In summary, we explored a stable dinuclear {Fe(NO)2}
2
III
transfer from DNIC 3 to [Fe (TPP)Cl] affords [Fe(TPP)(NO)] with
the proposed formation of [Fe(m- Pyr)Cl ] (see the Supporting
DNIC 3 as a potent nitroxyl donor for direct nitroxyl transfer
Me
III
toward the Fe -porphyrin complex and proteins through an as-
2
2
Information for details).
sociative mechanism. Beyond the efficient nitroxyl-transfer re-
III
To apply DNIC 3 as a novel nitroxyl donor in aqueous condi-
tions, assessment of the nitroxyl-transfer reactivity of DNIC 3
activity toward Fe -heme centers, discovery of DNIC 3 as
a lead compound will trigger the development of DNICs as
a chemical biology probe for nitroxyl and for clinical transla-
tion in vascular and myocardial pharmacology.
III
III
using Fe -myoglobin (metMb) and Fe -hemoglobin (metHb) as
a specific probe is a critical intermediate step for prospective
[
15,22]
applications in nitroxyl chemistry and biology (Figure 1).
UV/Vis absorption bands at 348, 623, and 780 nm exhibited by
Acknowledgements
DNIC 3 remain unchanged for 24 h in 25 mm phosphate buffer
(
pH 7.4) at 258C. This demonstrates the null nitroxyl-release re-
We gratefully acknowledge the financial support from grant
MOST 102-2113M-033-009-MY2 and MOST 103-2632M033-001-
MY3 from the Ministry of Science and Technology (Taiwan). T.-
T.L. also thanks Prof. Jhy-Der Chen for the support with electro-
chemical studies, Mr. Ling-Yun Jang and Dr. Feng-Chun Lo for
the help on the S/Cl K-edge XAS, and Prof. Wen-Feng Liaw for
valuable discussions.
activity of DNIC 3. In the reaction of 10 mm metMb and 10 mm
DNIC 3, shift of the UV/Vis absorption bands from 407, 503
and 629 nm to 419, 543, and 577 nm indicates the rapid forma-
7
tion of {Fe(NO)} species in myoglobin (MbNO) and demon-
strates the efficient nitroxyl-transfer reactivity of DNIC 3 toward
the Fe -porphyrin center (Figure 3A). From the linear depend-
III
ence of the rate of formation of MbNO on the concentration
of DNIC 3 and metMb, a second-order rate constant of 438Æ
À1 À1
1
5m
s
is derived (Figure 3B and 3C). This also supports the
Chem. Eur. J. 2015, 21, 17570 – 17573
www.chemeurj.org
17572
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
[9] S. Ye, F. Neese, J. Am. Chem. Soc.
2010, 132, 3646–3647.
[
[
[
[
[
[
10] L. E. Goodrich, F. Paulat, V. K. Pra-
neeth, N. Lehnert, Inorg. Chem.
2010, 49, 6293–6316.
11] J. Fitzpatrick, H. Kalyvas, J. Shearer,
E. Kim, Chem. Commun. 2013, 49,
5550–5552.
12] R. Pulukkody, M. Y. Darensbourg,
Acc. Chem. Res. 2015, 48, 2049–
2058.
13] M.-L. Tsai, C.-C. Tsou, W.-F. Liaw,
Acc. Chem. Res. 2015, 48, 1184–
1193.
14] Z. J. Tonzetich, F. Heroguel, L. H.
Do, S. J. Lippard, Inorg. Chem.
2011, 50, 1570–1579.
15] A. K. Patra, K. S. Dube, B. C. Sand-
ers, G. C. Papaefthymiou, J. Conra-
die, A. Ghosh, T. C. Harrop, Chem.
Sci. 2012, 3, 364–369.
[
16] M. A. Rhine, A. V. Rodrigues, R. J.
Bieber Urbauer, J. L. Urbauer, T. L.
Stemmler, T. C. Harrop, J. Am.
Chem. Soc. 2014, 136, 12560–
12563.
[17] C.-Y. Chiang, M. Y. Darensbourg, J.
Biol. Inorg. Chem. 2006, 11, 359–
370.
Figure 3. A) Reaction of 10 mm DNIC 3 with 10 mm metmyoglobin (metMb) in 25 mm phosphate buffer at pH 7.4
black line) results in the formation of MbNO (red line). The UV/vis spectra are measured every 50 s, whereas the
arrows indicate the change of the UV/vis spectra. B) Dependence of the rate for the conversion of metMb into
[
[
[
[
18] T.-T. Lu, C.-H. Chen, W.-F. Liaw,
Chem. Eur. J. 2010, 16, 8088–8095.
19] J. H. Enemark, R. D. Feltham, Coord.
Chem. Rev. 1974, 13, 339–406.
20] L. A. Bottomley, K. M. Kadish, Inorg.
Chem. 1981, 20, 1348–1357.
21] L. E. Goodrich, S. Roy, E. E. Alp, J.
Zhao, M. Y. Hu, N. Lehnert, Inorg.
Chem. 2013, 52, 7766–7780.
22] D. Andrei, D. J. Salmon, S. Donzelli,
A. Wahab, J. R. Klose, M. L. Citro,
J. E. Saavedra, D. A. Wink, K. M. Mir-
anda, L. K. Keefer, J. Am. Chem. Soc.
(
MbNO on the concentration of [metMb]. 10, 7.5, 5, and 2.5 mm of metMb and 10 (black), 20 (red), 30 (blue), 40
(
magenta), and 50 mm (green) of DNIC 3 were used. Considering the rate law: rate=kobs[metMb], five kobs were de-
rived from the linear regression fit to the rate versus [metMb]. C) Dependence of kobs on the concentration of
À1 À1
[
DNIC 3]. The slope of the linear regression fit indicates a second-order rate constant k of 438Æ15m
s
consid-
ering the rate law: rate=k[DNIC 3][metMb]. D) Reaction of 5 mm DNIC 3 with 5 mm methemoglobin (metHb) in
5 mm phosphate buffer at pH 7.4 (black line) results in the formation of HbNO (red line). The UV/Vis spectra are
measured every 100 s, whereas the arrows indicate the change of the UV/Vis spectra.
2
[
2010, 132, 16526–16532.
Keywords: bioinorganic chemistry
nitroxyl · X-ray emission spectroscopy
·
nitrosyl complexes
·
[23] T.-T. Lu, C.-C. Tsou, H.-W. Huang, I.-J. Hsu, J.-M. Chen, T.-S. Kuo, Y. Wang,
W.-F. Liaw, Inorg. Chem. 2008, 47, 6040–6050.
[
[
24] F.-T. Tsai, S.-J. Chiou, M.-C. Tsai, M.-L. Tsai, H.-W. Huang, M.-H. Chiang, W.-
F. Liaw, Inorg. Chem. 2005, 44, 5872–5881.
25] X. Wang, E. B. Sundberg, L. Li, K. A. Kantardjieff, S. R. Herron, M. Lim,
P. C. Ford, Chem. Commun. 2005, 477–479.
[
[
1] J. C. Irvine, R. H. Ritchie, J. L. Favaloro, K. L. Andrews, R. E. Widdop, B. K.
Kemp-Harper, Trends in pharmacol. Sci. 2008, 29, 601–608.
2] C. G. Tocchetti, B. A. Stanley, C. I. Murray, V. Sivakumaran, S. Donzelli, D.
Mancardi, P. Pagliaro, W. D. Gao, J. van Eyk, D. A. Kass, D. A. Wink, N.
Paolocci, Antioxid. Redox Signaling 2011, 14, 1687–1698.
[
[
26] M.-L. Tsai, C.-H. Hsieh, W.-F. Liaw, Inorg. Chem. 2007, 46, 5110–5117.
27] M.-C. Tsai, F.-T. Tsai, T.-T. Lu, M.-L. Tsai, Y.-C. Wei, I.-J. Hsu, J.-F. Lee, W.-F.
Liaw, Inorg. Chem. 2009, 48, 9579–9591.
[
[
3] K. Matsuo, H. Nakagawa, Y. Adachi, E. Kameda, K. Aizawa, H. Tsumoto, T.
Suzuki, N. Miyata, Chem. Pharm. Bull. 2012, 60, 1055–1062.
4] N. Paolocci, T. Katori, H. C. Champion, M. E. St John, K. M. Miranda, J. M.
Fukuto, D. A. Wink, D. A. Kass, Proc. Natl. Acad. Sci. USA 2003, 100,
[
[
28] T.-T. Lu, T.-C. Weng, W.-F. Liaw, Angew. Chem. Int. Ed. 2014, 53, 11562–
11566; Angew. Chem. 2014, 126, 11746–11750.
29] J. E. M. N. Klein, B. Miehlich, M. S. Holzwarth, M. Bauer, M. Milek, M. M.
Khusniyarov, G. Knizia, H. J. Werner, B. Plietker, Angew. Chem. Int. Ed.
5
537–5542.
5] A. Arcaro, G. Lembo, C. G. Tocchetti, Curr. Heart Fail. Rep. 2014, 11, 227–
35.
6] H. N. Sabbah, C. G. Tocchetti, M. Wang, S. Daya, R. C. Gupta, R. S. Tunin,
R. Mazhari, E. Takimoto, N. Paolocci, D. Cowart, W. S. Colucci, D. A. Kass,
Circ. Heart Fail. 2013, 6, 1250–1258.
2014, 53, 1790–1794; Angew. Chem. 2014, 126, 1820–1824.
[
[
[
[
30] C. J. Pollock, S. DeBeer, J. Am. Chem. Soc. 2011, 133, 5594–5601.
31] T.-T. Lu, S.-H. Lai, Y.-W. Li, I.-J. Hsu, L.-Y. Jang, J.-F. Lee, I.-C. Chen, W.-F.
Liaw, Inorg. Chem. 2011, 50, 5396–5406.
2
[
[
7] J. F. DuMond, S. B. King, Antioxid. Redox Signaling 2011, 14, 1637–1648.
8] J. L. Hess, C. H. Hsieh, S. M. Brothers, M. B. Hall, M. Y. Darensbourg, J.
Am. Chem. Soc. 2011, 133, 20426–20434.
Received: August 11, 2015
Published online on October 22, 2015
Chem. Eur. J. 2015, 21, 17570 – 17573
www.chemeurj.org
17573
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim