N, O -Chelating quinoline-based half-sandwich organorhodium and -iridium complexes: Synthesis, antiplasmodial activity and preliminary evaluation as transfer hydrogenation catalysts for the reduction of NAD+

Article abstract of DOI:10.1039/c9dt02030f

Two Rh(iii) and Ir(iii) half-sandwich quinoline-based complexes were synthesised and evaluated for their in vitro antiplasmodial activity against the chloroquine-sensitive NF54 and multi-drug resistant K1 strains of the human malaria parasite, Plasmodium falciparum. These half-sandwich organometallic complexes can also facilitate transfer hydrogenation, by converting β-nicotinamide adenine dinucleotide (NAD⁺) to its reduced form (NADH) in the presence of sodium formate. Co-administration of the iridium(iii) complex with sodium formate enhances the antiplasmodial activity in the chloroquine-resistant (K1) strain of Plasmodium falciparum, intimating that metal-mediated transfer hydrogenations can be achieved in malarial parasitic cells.

Full text of DOI:10.1039/c9dt02030f

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N,O-chelating quinoline-based half-sandwich
View Article Online
DOI: 10.1039/C9DT02030F
organorhodium and -iridium complexes: synthesis,
antiplasmodial activity and preliminary evaluation as
transfer hydrogenation catalysts for the reduction of NAD+
Tameryn Stringer, Diana R. Melis and Gregory S. Smith*
Department of Chemistry, University of Cape Town, Rondebosch, Cape Town, South Africa.
*Corresponding author. E-mail: Gregory.Smith@uct.ac.za
Abstract
Two Rh(III) and Ir(III) half-sandwich quinoline-based complexes were synthesised and evaluated
for their in vitro antiplasmodial activity against the chloroquine-sensitive NF54 and multi-drug
resistant K1 strains of the human malaria parasite, Plasmodium falciparum. These half-
sandwich organometallic complexes can also facilitate transfer hydrogenation, by converting β-
nicotinamide adenine dinucleotide (NAD+) to its reduced form (NADH) in the presence of sodium
formate. Co-administration of the iridium(III) complex with sodium formate enhances the
antiplasmodial activity in the chloroquine-resistant (K1) strain of Plasmodium falciparum,
intimating that metal-mediated transfer hydrogenations can be achieved in malarial parasitic
cells.
Introduction
Malaria is an infectious parasitic disease that affects the lives of many people, specifically
in tropical and sub-tropical regions around the world. In 2016, there were a reported 216 million
cases of malaria, an increase in about 5 million since the previous year.1 The most commonly
used antimalarials are routinely under threat, due to the prevalence of drug-resistant parasites.
Alternative therapies capable of overcoming these resistance mechanisms are required to
combat new malaria infections. Chloroquine (CQ) has been used extensively, but its efficacy
has declined due to rising resistance. Artemisinin-based combination therapy (ACT) is
currently used to delay the onset of drug-resistant parasites, however, there have been recent
reports of resistance occurring, mainly in Asia.2 Metal-based compounds are becoming
promising antimicrobial drug leads3-4, largely due to the success of ferroquine (FQ), a
ferrocene-containing analogue of CQ. Metal complexes are biologically diverse and can give
rise to mechanisms not accessible by their organic counterparts, hence paving the way for
metal-based drug development.5-8
1

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Rising resistance caused by the continuous mutation of the Plasmodium parasite requires
novel strategies to combat this challenge. Exploiting the catalytic properties of metal-
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DOI: 10.1039/C9DT02030F
containing complexes may lead to novel ways to evade resistance mechanisms and lower the
concentration of administration, reducing undesirable side-effects. Intracellular catalytic
reactions mediated by metal complexes have attracted considerable attention in recent
years.9-10 These complexes can potentially be administered in lower dosages, leading to lower
toxicity.9-10 Metallodrugs have been reported to reduce molecules inside cells, specifically by
means of transfer hydrogenation reactions.9-10 Transition metal complexes containing Ru, Os,
Rh or Ir are effective as transfer hydrogenation catalysts, with several complexes showing
good conversions and turnover frequencies.11-12 The stability of the complexes in air and water
make them attractive in the design of biofriendly catalysts. Several complexes are capable of
catalyzing hydride transfer reactions under biological conditions.13-17 For example, iridium(III)-
pyridine complexes have been shown to utilize NADH as a hydrogen source to target cancer
cells, leading to the formation of a metal-hydride complex which transfers a hydride to
molecular oxygen.18 This results in an increase in cellular hydrogen peroxide as well as
reactive oxygen species (ROS).18 Ruthenium(II) complexes reduce nicotinamide adenine
dinucleotide (NADH) for hydride transfer to reduce biomolecules.16-17 In the reverse reaction,
hydride transfer to nicotinamide adenine dinucleotide (NAD+) has also been demonstrated
using formate as a source of hydrogen.15-16 Ruthenium(II) complexes containing a toluene
sulfonamide moiety decrease the amount of NAD+ in cancer cells (A2780) when co-
administered with sodium formate.19
Transfer hydrogenation reactions in biological applications have been extensively studied in
terms of anticancer applications, but to the best of our knowledge has not been applied to
infectious diseases, specifically malaria. The use of catalytically active complexes14,20 may
lead to lower toxicity upon administration, and in addition to this, the complexes may be able
to overcome resistance mechanisms, particularly in CQ-resistant strains of Plasmodium
falciparum, the deadliest strain of the disease. In this study, we report the synthesis of model,
biofriendly half-sandwich rhodium and iridium complexes and evaluate their ability to catalyse
the transfer hydrogenation of NAD+ to NADH in a cell-free environment. In addition, the effect
of co-administration of the organometallic quinoline complexes (1 and 2, Fig. 1) and sodium
formate on parasite viability is also investigated.
2

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Cl
Cl
HN
N
N
HN
N
N
Ir
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DOI: 10.1039/C9DT02030F
Cl
Cl
Rh
O
O
Cl
Cl
2
1
Fig. 1 Quinoline-based half-sandwich organoiridium (1) and organorhodium (2) complexes
investigated in this study
Results and discussion
Following a systematic approach to develop catalysts to study transfer hydrogenation
reactions in parasites, two model complexes (1 and 2) were synthesized by combining the
biofriendly Rh(III) and Ir(III) complexes with a quinoline scaffold, a known, biologically
significant antimalarial pharmacophore. The half-sandwich complexes were prepared by
reacting the known ligand precursor21 with either [IrCp*Cl2]2 or [RhCp*Cl2]2 in the presence of
triethylamine to yield complexes 1 and 2 respectively (Scheme S1). Both complexes were
1
13
†
characterized by H NMR, C NMR, IR spectroscopy and HR-mass spectrometry (see ESI ).
To the best of our knowledge, no examples of cyclopentadienyl iridium(III) and rhodium(III)
complexes ligated by N,O-chelating salicylaldimine ligands have been reported for transfer
hydrogenation reactions. The quinoline complexes 1 and 2 were initially studied qualitatively
as catalysts for the reduction of β-nicotinamide adenine dinucleotide (NAD+) to form β-
nicotinamide adenine dinucleotide reduced (NADH) in the presence of sodium formate by
1
means of H NMR spectroscopy over 1 hour at 310 K, pH 7.4 (Fig. 2). To demonstrate the
ability of the complexes to effect these transformations, the spectrum of complex 2 was
recorded 5 minutes after sample preparation and again at 1 hour. Differences in the NMR
spectra confirm the regioselective reduction of NAD+ to 1,4-NADH. The signal designated as
* is attributed to NAD+ at t = 0 hour. New signals attributed to 1,4-NADH (*), are observed at t
= 1 hour, confirming regioselective conversion of NAD+ by complex 2. Similarly, complex 1
+
†
also converts NAD to 1,4-NADH under these conditions (Fig. S1, ESI ).
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DOI: 10.1039/C9DT02030F
Fig. 2 1H NMR spectra of a mixture of rhodium quinoline complex 2, NAD+ and sodium formate
in MeOD/D2O at 310K. * = signal for NAD+ and * = signals for 1,4-NADH
Catalytic conversion of NAD+ to NADH using complexes 1 and 2 with sodium formate as a
hydrogen source was then followed by an experiment modified from the pLDH assay.22
Plasmodium lactate dehydrogenase (pLDH) is an enzyme responsible for converting pyruvate
to lactate using co-factor NADH.22-23 The pLDH assay utilizes this property to specifically
detect the pLDH enzyme. The MalStat™ method to detect parasite viability was reported by
Makler et al (Fig. 3).23-24 In this assay, pLDH in infected lysed blood cells oxidizes lactate to
pyruvate and at the same time reduces the co-factor APAD+ to APADH. Addition of a
tetrazolium dye (yellow in colour) allows monitoring of the conversion of lactate to pyruvate, in
turn allowing the pLDH enzyme to be monitored, because pLDH activity has been shown to
follow closely with parasitemia.22-23 The APADH that forms is able to reduce the tetrazolium
dye, (usually nitroblue tetrazolium (NBT)), to a blue formazan in the presence of phenazine
ethosulfate.
4

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DOI: 10.1039/C9DT02030F
Fig. 3 Principle of the pLDH assay used in drug screening assays to monitor parasite viability.
Using a modified experimental design, the principle of the pLDH assay was utilized to
monitor the activity of the synthesized complexes as transfer hydrogenation agents in a cell-
free environment (Scheme 1). Here, different concentrations of the complex (1 or 2) were
incubated with sodium formate and NAD+ at pH 7.4 for 6 hours. In the presence of formate,
the complexes facilitate the conversion of NAD+ to NADH. The NADH reduces the nitroblue
tetrazolium to formazan, in a manner analogous to that performed by APADH in the MalStat™
assay (Fig. 3). The activity of the complexes can therefore be monitored as the yellow
tetrazolium salt is converted to the blue formazan compound. The absorbance (collected at
600 nm) is proportional to the amount of formazan present, which correlates with the transfer
hydrogenation activity of the complexes.
Cl
O
H
H
HN
N
N
O
NH2
NH2
*Cp
Cl
M
NH2
O
N
N
NH2
N
N
N
O
P
O-
O
P
O-
N
O
P
O-
O
P
O-
Cl
N
N+
O
O
O
N
O
O
O
O
O
N
O
O
HCOONa
OH
OH
OH
OH
OH
OH
OH
OH
NAD+
NADH
O
H
H
NH2
N
NH2
NO2
NO2
N
N
O
P
O-
O
P
O-
N
O
O
O
N
O
O
NH
N
N
N
N
N
OH
OH
OH
OH
N+
NADH
N
MeO
MeO
2
2
Formazan
(Blue)
Tetrazolium
(Yellow)
Scheme 1. Principle used to monitor transfer hydrogenation activity of complexes 1 and 2.
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The experiments were conducted in a 96-well plate using ten concentrations of each complex
(serially diluted) with the highest concentration being 2250 µM, along with two negative
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DOI: 10.1039/C9DT02030F
controls (DMSO only and NAD only – no complex added). Complexes 1 and 2 were incubated
in quadruplicate at 37°C at pH 7.4, in the presence of sodium formate and NAD+, prior to
addition of the nitroblue tetrazolium solution. After addition of the nitroblue reagent, the wells
containing the complexes change to blue, suggesting the conversion of NAD+ to NADH due
to the formation of the formazan. This confirms that both complexes can facilitate transfer
hydrogenation of NAD+ to NADH in the presence of sodium formate due to the increase in
absorbance as the concentration of the complex is increased. Overall, an increase in formazan
indirectly intimates an increase in transfer hydrogenation activity for the complexes as the
concentration increases. The iridium complex (1) shows slightly better activity (Fig. 4)
compared to the rhodium derivative (2), but in both cases, there is a correlation between the
amount of complex present and the amount of formazan formed. This confirms that the
complexes can facilitate transfer hydrogenation in a cell-free environment at 37°C and pH 7.4.
1.5
Complex 1
Complex 2
1.0
0.5
0.0
4
9
8
5
0
1
1
2
5
0
1
3
7
4
8
6
2
5
1
2
5
1
2
1
2
Complex concentration (uM)
Fig. 4 Absorbance measurements obtained from transfer hydrogenation experiments for
complexes 1 and 2.
The proposed mechanism for transfer hydrogenation (Scheme 2) is based on mechanisms
elucidated in similar studies.25 The catalytic cycle is believed to involve a cationic solvated
metal complex (A), with sodium formate as the hydride source. Complex A reacts with sodium
formate to produce complex B. Complex B is converted into the metal-hydride species (C) via
a β-hydrogen elimination reaction, liberating CO2. The oxygen group of the amide moiety of
NAD+ coordinates to the metal center, at the same time hydride transfer occurs, forming
transition state (D). This transition state allows for the regioselective hydride transfer at C4
forming the 1,4-dihydro product (NADH) and the solvated catalyst precursor (A).
6

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O
CO2
NH2
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NAD+
N+
R
Ir
N
H
O
C
Ir
O
N
NH2
I
O
H
Ir
N+
R
N
OOCH
O
B
+
HCOO-
D
Ir
O
N
NH2
R
+
H
II
O
H
N
Ir
N
solv
O
A
O
III
Ir
H
H
O
N
NH2
solv
O
NH2
H
N
R
N+
R
NADH
Scheme 2. Proposed catalytic cycle for the conversion of NAD+ to NADH by the iridium
complex (1)
The antiplasmodial activity of complexes 1 and 2 was assessed (in the absence of sodium
formate) in the NF54 CQ-sensitive and K1 CQ-resistant strains of P. falciparum (Table 1). The
complexes are active (low nanomolar) in the NF54 strain of P. falciparum but reveal cross-
resistance in the K1 strain as seen by the loss in antiplasmodial activity at the tested
concentrations. Both complexes were not active up to 1000 ng/ml in the K1 strain of P.
falciparum.
Table 1. Antiplasmodial activities of 1, 2 and CQ against the NF54 and K1 strains of P.
falciparum
Compound
IC50 NF54 ± SE (nM) IC50 K1 ± SE (nM)
1
192 ± 23
182 ± 31
17 ± 2
> 1000
> 1000
247 ± 15
2
CQ
The antiplasmodial activity of both complexes 1 and 2 was then assessed in the presence of
sodium formate (0, 5, 10 and 20 mM concentrations) in the K1 (CQ-resistant) strain to
†
delineate any changes in the biological activity (Fig. S3-S4, ESI ). At a complex concentration
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of 1000 ng/ml, the iridium complex (1) in combination with sodium formate had a significant
effect on parasite viability when assessed in vitro (Fig. 5) in comparison with the rhodium
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DOI: 10.1039/C9DT02030F
analogue (2). A decrease in parasite viability of about 50% (0 vs 20 mM formate) was observed
for complex 1, whereas only an 8% difference was observed for the rhodium complex at the
same formate concentrations. The latter was found to be statistically insignificant based on a
two-tailed t-test at the 95% confidence level. This demonstrates that sodium formate has very
little influence on parasite viability. The enhanced activity of complex 1 in combination with
sodium formate suggests that co-administration gives rise to transfer hydrogenation in the
parasite. This, in combination with the cell-free data shows that the iridium complex (1) may
affect the regulation of NAD+ in the parasite. Studies in various species of Plasmodium have
shown that NAD+ levels are elevated during the asexual blood stage of the parasite’s
development, with infected erythrocytes showing more than 5-fold higher concentrations
compared to uninfected red blood cells.26-30 NAD+ is an important co-factor in the glycolytic
pathway, which is an essential energy producing pathway needed for the growth and
development of the parasite. More recently, NAD+ was shown to play a role as an enzyme
substrate in various cellular processes including calcium signaling, and DNA repair.31-32
Fig. 5 Parasite viability observed in the K1 strain when 1000 ng/ml concentrations of 1 and 2
were incubated with sodium formate (0, 5, 10 and 20 mM). Statistical significance was
calculated using a two-tailed t-test (error bars showing 95 % CI) and is expressed relative to
the control using asterisks.
An NMR study ((Fig. S5-S7, ESI†) mimicking the biological conditions was conducted to
investigate the disparity in parasite viability and transfer hydrogenation for the two complexes.
However, this preliminary study does not point to any correlation between stability in the
growth medium and the disparity in transfer hydrogenation activity between complexes 1 and
2. The general sentiment relates more to concentration effects, suggesting that complex 2
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may indeed kill the parasite, but not at the same mass concentration as reported. More
extensive studies are required to address this differentiation.
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DOI: 10.1039/C9DT02030F
Conclusions
In summary, two model quinoline-containing complexes containing either a Rh(III) or Ir(III) ion
were synthesized and evaluated for their transfer hydrogenation ability to convert β-
nicotinamide adenine dinucleotide (NAD+) to its reduced form (NADH) in the presence of
sodium formate. This was monitored by 1H Nuclear Magnetic Resonance (NMR) Spectroscopy
and substantiated using the nitroblue tetrazolium assay under cell-free conditions. Both the
NMR spectroscopic studies and the nitro blue tetrazolium assessment confirm the catalytic
properties of the complexes. As the complexes facilitate the formation of NADH from NAD+ in
the presence of formate, the presence of NADH facilitates the conversion of nitro blue
tetrazolium to formazan giving rise to a deep blue colour, indicating transfer hydrogenation.
Consequently, the complexes were screened for their antiplasmodial activities in the
chloroquine-sensitive NF54 and chloroquine-resistant K1 strains of Plasmodium falciparum.
The complexes displayed good activity in the sensitive strain (IC50 < 1000 nM), however, in
the resistant strain, the complexes lose their activity. The K1 strain of P. falciparum was then
treated with various concentrations of sodium formate (0, 5, 10 and 20 mM) with the
complexes. It was found that the iridium complex (1) at 1000 ng/ml concentration, showed a
formate-concentration dependence as a stepwise increase in antiplasmodial activity was
observed in the resistant strain, as the concentration of the sodium formate increased. This
preliminary study has demonstrated that co-administration of organometallic complexes with
a hydride source may be used to overcome resistance mechanisms and target cellular co-
factors like NAD+ and in so doing possibly affecting the glycolytic pathway. As encouraging as
these results may seem in view of bioorganometallic antiplasmodial studies, we will further
investigate this intracellular transfer hydrogenation chemistry within malarial parasites, with a
view to quantifying the amount of NAD+/NADH, studying possible cellular localisation, catalytic
efficiency and ways to improve catalytic performance. We envision this to lead to the
development of novel biotechnologies.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Financial support from the University of Cape Town and the National Research Foundation
(NRF; UID: 111707) of South Africa is gratefully acknowledged.
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Electronic Supporting Information (ESI) available: NMR spectra of complexes, deDtaOiI:ls10o.10f…39/.C.9,DT02030F
NMR spectra related to reactivity studies,…... For ESI, see…..
Notes and references
1 World Health Organization malaria report 2017, Geneva, Switzerland.
2
World health Organization status report 2017, Artemisinin and artemisinin-based
combination therapy resistance, April 2017.
3
4
5
6
7
8
9
Y.C. Ong, S. Roy, P.C. Andrews, G. Gasser, Chem. Rev., 2019, 119, 730-796.
D. Gambino, L. Otero, Inorg. Chim. Acta, 2018, 472, 58-75.
K.D. Mjos, C. Orvig, Chem. Rev., 2014, 114, 4540-4563.
P.F. Salas, C. Herrman, C. Orvig, Chem. Rev., 2013, 113, 3450-3492.
M. Navarro, W. Castro, C. Biot, Organometallics, 2012, 31, 5715-5727.
G. Gasser, N.Metzler-Nolte, Curr. Opin. Chem. Biol.,2012, 16, 84-91.
J.J. Soldevila-Barreda, N. Metzler-Nolte, Chem. Rev., 2019, 110, 829-869 and
references cited therein.
10 (a) J.J. Soldevila-Barreda, P.J. Sadler, Curr. Opin. Chem. Biol. 2015, 25, 172-183;
(b) A.L. Noffke, A. Habtemariam, A.M. Pizarro, P.J. Sadler, Chem. Commun.
2012, 48, 5219-5246.
11 G. Chelucci, S. Baldino, W. Baratta, Acc. Chem. Res., 2015, 48, 363-379.
12
X. F. Wu, C. Wang, J. L. Xiao, Plat. Met. Rev., 2010, 54, 3-19.
13 J. P. C. Coverdale, I. Romero-Canelon, C. Sanchez-Cano, G. J. Clarkson, A.
Habtemariam, M. Wills, P. J. Sadler, Nat. Chem., 2018, 10, 347-354.
14 J. Furrer, G.S. Smith, B. Therrien, Metal Complexes as Enzyme Inhibitors and
Catalysts in Living Cells (Ch.11), In Inorganic Chemical Biology: Principles,
Techniques and Applications (Ed.: G. Gasser), John Wiley & Sons, UK, 2014, 341-
371.
10

Page 11 of 13
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15 R. Ruppert, S. Herrman, E. Steckhan, J. Chem. Soc., Chem. Commun., 1988,
1150 - 1151.
View Article Online
DOI: 10.1039/C9DT02030F
16 J. J. Soldevila-Barreda, P. C. A. Bruijnincx, A. Habtemariam, G. J. Clarkson, R. J.
Deeth, P. J. Sadler, Organometallics, 2012, 31, 5958-5967.
17 S. Betanzos-Lara, Z. Liu, A. Habtemariam, A. M. Pizarro, B. Qamar, P. J. Sadler,
Angew. Chem. Int. Ed., 2012, 51, 3897-3900.
18 Z. Liu, I. Romero-Canelon, B. Qamar, J. M. Hearn, A. Habtemariam, N. P. E. Barry,
A. M. Pizarro, G. J. Clarkson, P. J. Sadler, Angew. Chem. Int. Ed., 2014, 53, 3941-
3946.
19 J. J. Soldevila-Barreda, I. Romero-Canelon, A. Habtemariam, P. J. Sadler, Nat.
Commun., 2015, 6.
20 T. Gianferrara, I. Bratsos, E. Alessio, Dalton Trans., 2009, 7588-7599.
21 T. Stringer, D. Taylor, H. Guzgay, A. Shokar, A. Au, P.J. Smith, D.T.Hendricks,
K.M. Land, T.J. Egan, G.S. Smith, Dalton Trans., 2015, 44, 14906-14917.
22 M. T. Makler, J. M. Ries, J. A. Williams, J. E. Bancroft, R. C. Piper, B. L. Gibbins,
D. J. Hinrichs, Am. J. Trop. Med. Hyg., 1993, 48, 739-741.
23 M. T. Makler, D. J. Hinrichs, Am. J. Trop. Med. Hyg., 1993, 48, 205-210.
24 R. Piper, J. Lebras, L. Wentworth, A. Hunt-Cooke, S. Houze, P. Chiodini, M.
Makler, Am. J. Trop. Med. Hyg., 1999, 60, 109-118.
25 H. C. Lo, C. Leiva, O. Buriez, J. B. Kerr, M. M. Olmstead, R. H. Fish, Inorg. Chem.,
2001, 40, 6705-6716.
26 J. K. O'Hara, L. J. Kerwin, S. A. Cobbold, J. Tai, T. A. Bedell, P. J. Reider, M.
Llinas, Plos. One, 2014, 9.
27
K. Nagarajan, Biochim. Biophys. Acta, 1964, 93, 176-&.
28 K. L. Olszewski, J. M. Morrisey, D. Wilinski, J. M. Burns, A. B. Vaidya, J. D.
Rabinowitz, M. Linas, Cell Host. Microbe., 2009, 5, 191-199.
29 I. W. Sherman, Am. J. Trop. Med. Hyg., 1966, 15, 814-&.
30 C. R. Zerez, E. F. Roth, S. Schulman, K. R. Tanaka, Blood, 1990, 75, 1705-1710.
11

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Page 12 of 13
31 R. A. Billington, S. Bruzzone, A. De Flora, A. A. Genazzani, F. Koch-Nolte, M.
Ziegler, E. Zocchi, Mol. Med., 2006, 12, 324-327.
View Article Online
DOI: 10.1039/C9DT02030F
32 M. Nakamura, A. Bhatnagar, J. Sadoshima, Circ. Res., 2012, 111, 604-610.
12

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338x190mm (96 x 96 DPI)