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Synthesis, characterization, and biological properties of rhenium(I) tricarbonyl complexes bearing nitrogen-donor ligands
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Synthesis, characterization, and biological properties of rhenium(I) tricarbonyl
complexes bearing nitrogen-donor ligands
Brendan L. Murphy, Sierra C. Marker, Valencia J. Lambert, Joshua J. Woods,
Samantha N. MacMillan, Justin J. Wilson
PII: S0022-328X(19)30507-8
DOI: https://doi.org/10.1016/j.jorganchem.2019.121064
Reference: JOM 121064
To appear in: Journal of Organometallic Chemistry
Received Date: 14 November 2019
Revised Date: 2 December 2019
Accepted Date: 3 December 2019
Please cite this article as: B.L. Murphy, S.C. Marker, V.J. Lambert, J.J. Woods, S.N. MacMillan, J.J.
Wilson, Synthesis, characterization, and biological properties of rhenium(I) tricarbonyl complexes
bearing nitrogen-donor ligands, Journal of Organometallic Chemistry (2020), doi: https://doi.org/10.1016/
j.jorganchem.2019.121064.
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© 2019 Published by Elsevier B.V.
Synthesis, characterization, and biological properties of rhenium(I)
tricarbonyl complexes bearing nitrogen-donor ligands
Brendan L. Murphy‡, Sierra C. Marker†, Valencia J. Lambert§, Joshua J. Woods†+,
Samantha N. MacMillan†, and Justin J. Wilson*†
‡
Department of Radiology, Weill Cornell Medicine, New York, New York 10065,
United States.
†
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New
York 14853, United States.
§
College of Human Ecology, Cornell University, Ithaca, New York 14853, United
States.
+
Robert F. Smith School for Chemistry and Biomolecular Engineering, Cornell
University, Ithaca, New York 14853, United States.
Keywords: rhenium, photophysical properties, anticancer agents, metal-based
drugs
Abstract
Rhenium(I) tricarbonyl complexes have properties that make them valuable for
various biomedical applications, such as imaging, cancer treatment, and bactericidal
uses. The ability to modify the ligand coordination sphere of these complexes
enables researchers to fine-tune and optimize their properties for biological use. In
this study, we explored the role of axial nitrogen-donor ligands. Specifically, the
compounds fac-[Re(CO) (phen)(L)]+, where phen = 1,10-phenanthroline, and L =
3
pyridine (Re-py), piperidine (Re-pip), morpholine (Re-morph), and
thiomorpholine (Re-thio), were synthesized and characterized. X-ray crystal
structures of these complexes show that they obtain an expected pseudo-octahedral
geometry with the three CO ligands arranged in a facial manner. Additionally, the
X-ray crystal structure of a byproduct from these reactions, the hydroxo-bridged
dinuclear Re compound [(CO) (phen)Re(µ-OH)Re(phen)(CO) ]+, is described.
3 3
The photophysical properties of these complexes were investigated in detail,
revealing that they are photoluminescent in air-equilibrated pH 7.4 phosphate-
buffered saline with quantum yields ranging from 1.7 to 3.1%. Both the quantum
yields and emission energies were found to correlate with the basicity of the axial
nitrogen donor, whereby more basic ligands give rise to smaller quantum yields and
lower-energy emissions. These four compounds were further evaluated for their
potential as fluorescence microscopy imaging agents. Of the four compounds, only
Re-py showed detectable intracellular luminescence in HeLa cells. Lastly, the
cytotoxicity of these compounds in HeLa cells were determined. None of the four
compounds is significantly cytotoxic as reflected by their 50% growth inhibitory
concentrations that exceed 30 µM.
1
1. Introduction
The highly stable rhenium(I) tricarbonyl, Re(CO) , structural motif has been
3
explored for decades for its novel photophysical and catalytic properties [1,2]. It has
been realized in recent years that these properties make such complexes appealing
for biological applications as well. Most notably, these Re(CO) complexes have
3
found use as imaging agents and have shown promise for antibacterial and
anticancer applications [3–9]. The synthetic ease by which these complexes can be
modified via straightforward ligand substitution reactions has enabled researchers to
access a diverse range of complexes with spectroscopic and biological properties
tuned for different uses in biology.
Re(CO) complexes bearing diimine ligands of the type
3
[Re(CO) (NN)(X/L)]0/1+, where NN is a diimine ligand and X and L are anionic or
3
neutral axial ligands, typically possess the most favorable photophysical properties
for biological imaging, by virtue of their luminescent metal-to-ligand charge
transfer (MLCT) excited state [7,10–13]. Modifications to the diimine ligand can
have a profound effect on both the photophysical and biological properties of the
Re(CO) complex by altering the energy of the accepting ligand-based π-orbitals,
3
the rates of axial ligand substitution [14], and the overall complex lipophilicity. The
nature of the axial ligand plays a subtler, albeit important, role in modulating these
properties. The use of an appropriate axial ligand, for example, can give rise to
complexes with enhanced photoluminescent quantum yields [1,2]. Additionally,
certain ligands, such as phosphines, give rise to CO photosubstitution processes by
exerting a strong trans influence in the excited state [15,16].
The types of axial nitrogen-donor ligands that have been employed on
Re(CO) complexes have been predominately limited to analogues of pyridine [17–
3
30]. Thus, there remains a need to gain a more comprehensive understanding of the
importance of this class of ligands for tuning the properties of these complexes. In
this study, we aimed to explore the use of alternative nitrogen-donors to investigate
the role of these ligands on the photophysical and biological properties of the
resulting Re(CO) complexes. We chose the nitrogen donors piperidine (pip),
3
morpholine (morph), and thiomorpholine (thio) based on their differential donor
strengths, which are reflected by their pK values that range from 5 to 11. To aid in
a
comparative purposes, we used the simple diimine ligand 1,10-phenanthroline
(phen) throughout. The photophysical and biological properties of these newly
prepared compounds were then evaluated. This study adds to the growing interest in
Re(CO) complexes for use in biology and further elucidates how the properties of
3
these compounds can be rationally modified by the appropriate ligand choice.
2. Results and Discussion
2.1. Synthesis and Characterization
The three Re(CO) complexes fac-[Re(CO) (phen)(pip)]OTf (Re-pip), fac-
3 3
[Re(CO) (phen)(morph)]OTf (Re-morph), and fac-[Re(CO) (phen)(thio)]OTf
3 3
(Re-thio), where OTf = trifluoromethanesulfonate, were synthesized by treating
2
fac-[Re(CO) (phen)Cl] with AgOTf in refluxing tetrahydrofuran (THF) to remove
3
the axial chloride ligand as insoluble AgCl, followed by the addition of an excess of
either pip, morph, or thio (Scheme 1). Although analytically pure Re-morph was
obtained as a precipitate directly from the reaction mixture, Re-pip and Re-thio
required additional purification via crystallization from THF. Re-pip has been
previously reported, but its synthesis and characterization have not been described
in detail [31]. For comparative purposes, the previously reported complex fac-
[Re(CO) (phen)(py)]OTf (Re-py), where py = pyridine, was also prepared in a
3
similar manner, and its characterization data are consistent with those in the
literature [17,31]. Re-pip, Re-morph, and Re-thio were characterized by 1H
(Figures S1–S3) and 19F (Figures S4–S6) NMR spectroscopy, IR spectroscopy
(Figures S7–S10), electrospray ionization mass spectrometry (ESI-MS, Figures
S11–S13), and single-crystal X-ray diffraction, and their purities were verified by
elemental analysis and high-performance liquid chromatography (HPLC, Figures
S14–S16). Their 1H NMR spectra show all of the expected resonances for these
compounds. Notably, the axial and equatorial hydrogen nuclei of the pip, morph,
and thio ligands are inequivalent, indicating that chair-chair interconversion of these
six-membered cyclic donor ligands is slow on the NMR timescale at room
temperature [32–34]. The 19F NMR spectra of these complexes reveal a single
resonance at –77 ppm, corresponding to the OTf – counterion. IR spectroscopic
analysis of these complexes reveals the presence of intense CO stretching modes in
the range of 1890–1930 cm–1. For Re-pip, Re-thio, and Re-py three distinct peaks
corresponding to CO stretching modes are apparent. This result is consistent with
their C symmetry, which will give rise to 3 IR-allowed transitions [35]. By
s
contrast, the IR spectrum of Re-morph displayed an additional set of 3 CO
stretching modes. Notably, all other characterization data of this complex support
the conclusion that this complex is a single, pure species. Therefore, we hypothesize
that the presence of additional CO stretching modes reflects the existence of two
isomeric forms of this complex. Because the IR timescale is substantially faster than
that of NMR spectroscopy, the fact that these putative isomers are observed by the
former technique but not the latter suggests that they are interconverting rapidly (>
1012 s–1) [36]. Such timescales may be afforded by isomers that would exist upon
rotation of the morph ligand about the Re–N vector. For example, dynamic IR
spectroscopy has been used to probe the fast isomeric interconversion of
tricarbonyl(η4-1,5-cyclooctadiene)iron(0) [36–38], in which the carbonyl ligands
move between apical and basal sites on this complex via a turnstile-like mechanism.
3
Scheme 1. Synthetic scheme for the preparation of fac-[Re(CO) (phen)(L)]+
3
complexes.
2.2. X-Ray Crystallography
Single crystals were obtained for all four complexes, and their crystal structures
were determined by X-ray crystallography. The structures are shown in Figure 1,
and selected interatomic distances and angles are collected in Table 1 and Table
S2. All complexes attain the expected octahedral geometry for a low-spin d6 metal
center. Notably, the structures of both Re-morph and Re-thio show that the morph
and thio ligands coordinate to the Re center through the nitrogen atoms rather than
the oxygen or sulfur donors, respectively. The six-membered pip, morph, and thio
ligands all attain a stable chair conformation, with the Re center occupying an
equatorial site on the bound nitrogen. Despite the different pK values and donor
a
strengths of the axial ligands, the Re–N interatomic distances are invariant
axial
across the three complexes with distances between 2.246(3)–2.257(2) Å. For Re-
py, however, this Re–N interatomic distance is 2.216(2) Å, somewhat shorter
axial
than those for Re-pip, Re-morph, and Re-thio. This slightly shorter distance may
be a consequence of the weak π-acceptor capabilities of py in contrast to the pure σ
donors pip, morph, and thio. The lack of variance in the axial ligand bond distances
of Re-pip, Re-morph, and Re-thio suggests that the Re–N interatomic
axial
separation is a poor metric for the donor strength of these axial ligands, which
should be related to their pK values. The Re–N distances are similar among
a equatorial
the four complexes with values ranging from 2.170(2)–2.182(2) Å. In comparison,
the four complexes also exhibit similar Re–CO and Re–CO interatomic
axial equatorial
distances of 1.908(3)–1.923(2) Å and 1.913(3)–1.927(2) Å, respectively. Lastly, all
interatomic angles are relatively invariant between the four complexes.
Table 1. Selected Interatomic Distances (Å).a
Selected Interatomic Re-pip Re-morph Re-thio Re-py
Distances (Å)
Re-N 2.182(2) 2.181(2) 2.181(2) 2.178(2)
1
Re-N 2.179(2) 2.175(2) 2.178(2) 2.170(2)
2
4
Re-N 2.246(3) 2.249(2) 2.257(2) 2.216(2)
3
Re-C 1.908(3) 1.922(3) 1.923(2) 1.918(3)
1
Re-C 1.915(3) 1.913(3) 1.927(2) 1.924(3)
2
Re-C 1.924(3) 1.923(3) 1.921(2) 1.919(3)
3
aAtoms are labeled as shown in Figure 1. Numbers in parentheses are the estimated
standard deviations for the last significant figure.
Figure 1. X-ray crystal structures of Re-pip, Re-morph, Re-thio, Re-py, and
[(CO) (phen)Re(µ-OH)Re(phen)(CO) ]+. Ellipsoids are drawn at 50% probability.
3 3
Non-acidic hydrogen atoms and the counterions are omitted for clarity.
While attempting to crystallize Re-pip, we serendipitously obtained and
analyzed a crystal of the dirhenium µ-hydroxo species, [(CO) (phen)Re(µ-
3
OH)Re(phen)(CO) ]+ (Figure 1, Table S3). This complex cation and related
3
analogues with 2,2ʹ-bipyridine and 4,4ʹ-dimethyl-2,2ʹ-bipyridine ligands have
previously been reported [39–43]. Although these complexes can be obtained in
moderate yield from the reaction of [Re(CO) (NN)(OTf)] with KOH under
3
5
anhydrous conditions, they have more often been isolated in low yields as reaction
byproducts that arise from the presence of adventitious hydroxide [39]. The
discovery of [(CO) (phen)Re(µ-OH)Re(phen)(CO) ]+ as an unintended byproduct
3 3
in our synthesis of Re-pip is most likely a consequence of small amounts of water
present in the THF solution that are deprotonated by the pip ligand. Our observation
that this byproduct only arises from the reaction with pip is consistent with the fact
that this ligand is the most basic of the axial nitrogen donors explored in this study.
The structure of [(CO) (phen)Re(µ-OH)Re(phen)(CO) ]+ reveals that the
3 3
Re–(OH)–Re vector is bent with an angle of 133.18(13)°. For the related complexes
[(CO) (NN)Re(µ-OH)Re(NN)(CO) ]+, where NN = 2,2ʹ-bipyridine and 4,4ʹ-
3 3
dimethyl-2,2ʹ-bipyridine, the Re–(OH)–Re angles range from 132.8(6)–140.50(7)°
[39–42], and different polymorphs of the Br– salt of [(CO) (phen)Re(µ-
3
OH)Re(phen)(CO) ]+ have Re–(OH)–Re angles that range from 130.90(7)–
3
140.70(19)° [43]. These data indicate that this angle is highly dependent on the
solid-state packing of this compound. Additionally, the bridging OH ligand within
this compound class is known to form hydrogen bonds with acceptors in the crystal
lattice [43]. In the structure reported here, a hydrogen bond between this bridging
ligand and an acetonitrile solvent molecule is present, as characterized by a O–N
distance of 3.043(5) Å (Figure S17). The distance between the Re centers and the
bridging hydroxide ligand in this crystal structure are 2.144(3) (Re –OH) and
1
2.134(2) (Re –OH) Å, indicating that this interaction is relatively symmetric. The
2
Re–C distances of the carbonyl ligands that are trans to the bridging hydroxide are
1.902(4) and 1.918(4) Å. Notably, these distances are not significantly different
from other Re–C distances in the mononuclear structures, indicating that the
bridging hydroxide does not give rise to a significant trans influence. Generally,
these bond metrics are consistent with the previously reported bridging hydroxide
complexes discussed above [39–43].
2.3. Photophysical Properties
Modifications of the axial ligands of the diimine Re(CO) complexes can
3
substantially alter their photophysical properties, giving rise to photoreactive and
highly luminescent compounds [1,2]. The appropriate tuning of these properties can
render these complexes useful for biological applications, such as imaging [10–13].
The photophysical properties of Re-pip, Re-morph, Re-thio, and Re-py in
physiologically relevant air-equilibrated pH 7.4 phosphate-buffered saline (PBS)
with less than 1% acetonitrile are reported in Table 2. All complexes exhibit similar
absorbance profiles (Figure 2) with peaks at 223 nm, 255 nm, 278 nm, 325 nm, and
367 nm. The higher energy bands (< 325 nm) can reasonably be assigned to π–π*
intraligand (IL) transitions, and the lower energy absorbance maximum at 367 nm
arises from the excitation to the MLCT state [44–49]. Notably, the electronic
absorbance spectra of these four compounds are effectively identical. This result
indicates that the axial nitrogen donor ligands have a small effect on the IL and
MLCT transitions. Because the MLCT arises from a transition of an electron in a
metal d orbital with π symmetry (t set) to the diimine π* ligand, the absence of a
2g
6
significant effect is consistent with the predominately σ-donor nature of these axial
ligands.
Table 2. Photophysical properties of rhenium complexes.
Compound λ , nm (ε, M–1cm–1) Φ , % (λ , nm)a τ (µs)a τ(nitrogen, µs)a,b
max lum max
Re-pip 225 (31300 ± 1300), 1.66 ± 0.06 (565) 0.31 0.49
257 (18200 ± 800),
278 (22100 ± 900),
326 (5100 ± 200),
368 (3500 ± 100)
Re-morph 224 (30700 ± 1900), 2.14 ± 0.16 (560) 0.52 0.70
256 (17700 ± 1300),
278 (22400 ± 1600),
325 (5300 ± 400),
368 (3400 ± 200)
Re-thio 222 (32300 ± 1000), 2.38 ± 0.31 (560) 0.47 0.97
257 (18400 ± 600),
278 (23300 ± 800),
325 (5600 ± 200),
367 (3700 ± 30)
Re-py 223 (35300 ± 600), 3.09 ± 0.30 (545) 0.62 1.00
254 (22800 ± 400),
277 (28300 ± 600),
325 (6400 ± 100),
367 (3900 ± 100)
aλ = 350 nm bLuminescence lifetime measured in nitrogen-saturated pH 7.4 PBS.
ex
Evaluation of the photoluminescence properties of these complexes reveals
them to have modest emission quantum yields ranging from 1.66–3.09% (Table 2)
under air-equilibrated aqueous conditions. Within this series, Re-pip has the lowest
quantum yield, and Re-py has the highest. The energies of these emissions, which
arise from relaxation of the 3MLCT state, vary slightly among these complexes. Re-
py has the highest energy 3MLCT emission at 18,350 cm–1, whereas Re-pip has the
lowest energy 3MLCT emission at 17,700 cm–1. For Re-morph and Re-thio, these
energies are effectively the same at 17,860 cm–1. These results can be somewhat
correlated to the basicity of the axial donor ligands. For example, py is the least
basic (conjugate acid pK = 5.0) and gives rise to the Re complex with the highest
a
quantum yield and emission energy, whereas pip is the most basic (conjugate acid
pK = 11.2) and gives rise to the lowest quantum yield and emission energy. Morph
a
and thio, which have similar basicities (conjugate acid pK = 8.4 and 9.0,
a
respectively), also confer their Re(CO) complexes with nearly identical emission
3
properties that fall between those of Re-py and Re-pip. This trend relating basicity
of axial donor ligands with 3MLCT emission energy has previously been reported
[31]. The greater effect of the axial ligand on the 3MLCT excited state and not on
the 1MLCT ground state would indicate that the axial nitrogen-donor ligand is
contributing more to the triplet excited state.
7
Figure 2. UV-vis (left) and emission (right) spectra of Re-pip (blue), Re-morph
(red), Re-thio (green), and Re-py (purple) in PBS with <1% acetonitrile at 25 °C
(10 µM).
The excited state lifetimes were also determined for these complexes in air-
equilibrated and deoxygenated PBS (Table 2). Lifetimes for all complexes range
from 0.3 to 0.6 µs, under ambient conditions (Figure S18–S21). In the absence of
oxygen, these lifetimes are approximately twice as long (Figure S18–S21). This
result is consistent with the known sensitivity of the 3MLCT state of Re(CO)
3
complexes to quenching by oxygen [50].
2.4. Biological Properties
To assess the suitability of these complexes for biological applications, we carried
out confocal fluorescence microscopy studies using HeLa cervical cancer cells. The
HeLa cells were treated with 100 µM of the compounds for 2 h prior to imaging. Of
these four compounds, only Re-py gave rise to an emission intensity that was
distinguishable from the background autofluorescence in the cells. Based on
colocalization studies using LysoTracker Red and MitoTracker Red, Re-py appears
to not significantly accumulate in either the lysosomes or the mitochondria (Figure
3 and S22). Its localization is mostly in the cytosol. Fluorescence microscopy
imaging studies of A549 lung cancer cells treated with 200 µM of Re-py for 2 h
were previously investigated [17]. In this prior study, however, no significant
intracellular luminescence from this compound was detected. This discrepancy with
the present work most likely arises from the use of different cell lines. Thus, the
cellular uptake and intracellular luminescence of these Re(CO) complexes may be
3
highly dependent on the type of cells investigated. It is noteworthy that, despite the
similar emission quantum yields of the four complexes measured in a cuvette, only
Re-py could effectively be imaged in cells. The failure of Re-pip, Re-morph, and
Re-thio for use in this application could arise in part due to poorer accumulation of
these compounds in cells. Additionally, it has been noted that the
photoluminescence properties of Re(CO) complexes are sensitive to their local
3
environments [51–54]. As such, the uptake and intracellular localization of these
compounds may not be accurately reflected by fluorescence microscopy
8
measurements. Non-environment sensitive methods like inductively-coupled
plasma mass spectrometry or optical emission spectroscopy can provide a more
accurate assessment of the complex uptake.
Figure 3. Confocal fluorescence microscopy images of HeLa cells untreated or
treated with Re-py (100 µM) and LysoTracker Red for 2 h (scale bar = 10 microns).
Given the reported anticancer activity of related Re(CO) complexes [3–7],
3
we evaluated the in vitro cytotoxicity of Re-pip, Re-morph, Re-thio, and Re-py in
HeLa cells by the 3-(4,5-dimethylthiazol-2-yl)-2,5-tetrazolium bromide (MTT)
assay. The resulting dose-response curves are shown in Figure 4 and the 50%
growth inhibitory concentration (IC ) values are collected in Table 3. Among these
50
four complexes, Re-pip and Re-morph are not active at concentrations below 100
µM. Re-py and Re-thio exhibit modest activity as characterized by IC values of
50
51 and 36 µM, respectively. Thus, these complexes are significantly less active than
the clinically approved metal-based drug cisplatin, which exhibits an IC value of
50
6.6 µM in HeLa cells, and other Re(CO) complexes explored in our lab with IC
3 50
values of less than 10 µM [55–58]. The low activity of these complexes may be
related to their low intracellular luminescence, which may suggest that they are
poorly taken up by cells.
Table 3. IC values of rhenium complexes and cisplatin in HeLa cells.
50
Compound IC (µM)
50
Re-pip > 164
Re-morph > 185
Re-thio 36 ± 3
Re-py 51 ± 5
cisplatin 6.6 ± 0.7
9
Figure 4. Dose-response curves of Re-pip (blue circles), Re-morph (red
diamonds), Re-thio (green crosses), and Re-py (purple stars) in HeLa cells.
3. Conclusions
In this study, we have prepared a small set of Re(CO) diimine complexes with
3
axial nitrogen-donor ligands of differing basicity and evaluated their biological
properties. For this class of compounds, the axial ligand appears to have only a
minor influence on the photophysical properties of these complexes. This minimal
effect may be a consequence of the σ-donor properties of the ligands evaluated,
which interact poorly with the π symmetry metal d orbitals that modulate the
photophysical properties of these complexes. Furthermore, the imaging properties
and cytotoxic activities of these complexes are poor in comparison to other
Re(CO) complexes that have been evaluated for similar applications [3–9]. These
3
results suggest that alterations to the axial ligand, involving the use of different
donor atoms or ligand types, would be a more promising avenue for achieving
complexes with greater biological relevance. Alternatively, a number of Re(CO)
3
complexes bearing py-based axial ligands have found use as imaging and cytotoxic
agents [18–30]. In these cases, more dramatic alterations of the py ligand, with
targeting groups for example, were able to achieve these successful results. The
combination of the subtle changes of axial ligand donor strength, as evaluated in
this study, with ligands that are tuned specifically for targeting or enhanced
biological activity may yield new interesting Re(CO) complexes for probing
3
cellular systems. Although increasing the donor strength of the axial ligand
decreases the emissive properties of the complex, this characteristic appears not to
directly correlate with the cytotoxicity of the complexes. This result indicates that
donor strength of the ligands surrounding the metal center may not be the key driver
for the anticancer activity of this class of compounds and that other factors, such as
ligand lipophilicity, may have more profound influences on their biological
activities.
10
4. Experimental
4.1. Methods and Materials
Rhenium carbonyl was purchased from Pressure Chemicals (Pittsburgh,
Pennsylvania, USA). The ligand 1,10-phenanthroline (phen) was purchased from
Sigma Aldrich (St. Louis, Missouri, USA) and was used as received. Re(CO) Cl
5
[58] and fac-[Re(CO) (phen)Cl] [59,60] were synthesized as previously described.
3
All solvents were ACS grade or higher. All reactions were carried out under
ambient atmospheric conditions without any effort to exclude water or oxygen.
4.2. Physical Measurements
NMR samples were prepared as solutions using MeOH-d or DMSO-d as a
4 6
solvent. NMR spectra were acquired on a Varian Inova 400 MHz spectrometer. 1H
NMR chemical shifts were referenced to residual solvent peaks versus
tetramethylsilane (TMS) at 0 ppm. 19F NMR spectra were referenced using an
external standard of KPF in D O (19F δ = –72 ppm vs CFCl at 0 ppm). Samples
6 2 3
for IR spectroscopy were prepared as KBr pellets and were analyzed on a Nicolet
Avatar 370 DTGS (ThermoFisher Scientific, Waltham, MA). Analytical HPLC was
carried out on a LC-20AT pump with a SPD-20AV UV-vis detector monitored at
270 and 220 nm (Shimadzu, Japan) using an Ultra Aqueous C18 column (100 Å, 5
µm, 250 mm × 4.6 mm, Restek, Bellefonte, PA) at a flow rate of 1 ml/min with a
mobile phase containing 0.1% trifluoroacetic acid (TFA) in H O or MeOH. The
2
method consisted of 5 min at 10% MeOH, followed by a linear gradient to 100%
MeOH over 20 min. High-resolution mass spectra (HRMS) were recorded on an
Exactive Orbitrap mass spectrometer in positive ESI mode (ThermoFisher
Scientific, Waltham, MA) with samples injected as acetonitrile/water solutions with
1% formic acid. Elemental analyses (C, H, N) were performed by Atlantic Microlab
Inc. (Norcross, Georgia, USA). UV-visible spectra were recorded on a Cary 8454
UV-vis (Agilent Technologies, Santa Clara, CA) or a Beckman Coulter DU800
UV-vis using 1-cm quartz cuvettes. Lifetime measurements were collected as
described below. Luminescence quantum yield measurements were carried out on a
Beckman Coulter DU800 UV-vis and Varian Eclipse Fluorometer.
4.3. X-Ray Crystallography
X-ray quality crystals of the complexes were grown by vapor diffusion of diethyl
ether into acetonitrile or THF solutions of the complex. Low temperature X-ray
diffraction (100 K) data was collected on a Rigaku XtaLAB Synergy diffractometer
equipped with a 4-circle Kappa goniometer and HyPix 6000HE Hybrid Photon
Counting (HPC) detector with monochromated Mo Ka radiation (l = 0.7107 Å).
Diffraction images were processed using the CrysAlisPro [61] software. The
structure was solved through intrinsic phasing using SHELXT [62] and refined
against F2 on all data by full-matrix least-squares with SHELXL [63,64] following
established strategies [65]. All non-hydrogen atoms were refined anisotropically.
11
Hydrogen atoms bound to heteroatoms were located in the Fourier difference map
and subsequently refined semifreely with the help of distance restraints. The
isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times
(1.5 times for methyl groups) the Ueq value of the atoms that they are linked to.
Crystallographic data collection and refinement parameters are given in Table S1.
4.4. Emission Quantum Yield
The luminescence quantum yields were measured relative to the standard quinine
sulfate (Φ = 0.52, 0.05 M H SO ), which was cross-referenced in our lab to
2 4
harmaline (Φ = 0.32, 0.05 M H SO ) [66]. An excitation wavelength of 350 nm was
2 4
used for the samples and standards. The compounds were measured as solutions in
pH 7.4 PBS with <1% acetonitrile with the absorbance maintained below 0.1 to
prevent inner filter effects [66]. At least five different concentrations of the samples
and standards were measured by UV-vis and fluorescence spectroscopy, and the
absorbance at 350 nm was plotted versus the integrated emission intensity. The
slopes of the resulting lines were used in the equation:
(1)
where Φ is the quantum yield of the reference, quinine sulfate, and S is the slope
ref
of either the sample or the reference, and η is the refractive index of the solvent.
4.5. Lifetime Measurements
Laser excitation for the phosphorescence lifetime measurements was provided by
pulsing the 405 nm laser line from a four-line iChrome MLE laser (Toptica
Photonics AG, Munich, Germany). The diode laser in the iChrome was triggered by
a DG535 Digital Delay/Pulse Generator (Stanford Research, Sunnyvale, CA) at 100
KHz and delivered 100 ns FWHM 405 nm excitation pulses. The 405 nm pulses
were fiber-delivered to a sample-filled cuvette and phosphorescence was collected
at 90 degrees to a Bialkali photomultiplier tube (HC125, Hamamatsu, Bridgewater,
NJ) through a 470 nm long pass filter (HQ470lp, Chroma Technology, Bellows
Falls, VT). The time-resolved photon counts were collected in 40 ns time bins using
a SR430 Multi-channel scaler (Stanford Research, Sunnyvale, CA). Data was
transferred to a PC via the SR430 GPIB bus and fit to the standard exponential
decay model using MagicPlot Pro software. Measurements were collected in PBS
solutions at 30–50 nM. For deoxygenated measurements, nitrogen gas was bubbled
into the PBS solutions for 30 min and then the lifetime was determined.
4.6. Synthetic Procedures
4.6.1. Synthesis of fac-[Re(CO) (phen)(piperidine)]OTf (Re-pip)
3
A mixture of [Re(CO) (phen)Cl] (0.200 g, 0.42 mmol) and AgOTf (0.106 g, 0.42
3
mmol) in THF (48 ml) was heated to reflux for 3 h in the dark. The white solid
12
AgCl was removed via vacuum filtration. To the remaining yellow filtrate,
piperidine (0.183 g, 2.1 mmol) was added, and the resulting solution was heated to
reflux for an additional 24 h. The reaction mixture was allowed to cool to room
temperature, concentrated to about 5–10 ml, and then placed in a –20 °C freezer
overnight. The yellow crystals that formed were then filtered and washed with THF.
The crude product was purified by recrystallizing twice by allowing a concentrated
solution of the compound in THF (2–4 ml) to slowly evaporate at room
temperature. Yield: 0.050 g (17%). 1H NMR (400 MHz, MeOH-d ): δ 9.51 (d, 2H),
4
9.09 (d, 2H), 8.41 (s, 2H), 8.20 (dd, 2H), 4.25 (t, 1H), 2.89 (d, 2H), 2.69 (m, 2H),
1.50 (m, 1H), 1.36 (m, 3H), 1.15 (m, 2H). 19F NMR (376 MHz, MeOH-d , external
4
stnd: KPF ): –77.08. IR (KBr, cm–1): 2025 s, 1932 s, 1893 s. ESI-MS (pos. ion
6
mode, CH CN:H O 70:30 and 1% formic acid): 536.0945 m/z ([M]+, calcd.
3 2
536.0984). Anal. Calcd. for C H F N O ReS: C, 36.84; H, 2.80; N, 6.14. Found:
21 19 3 3 6
C, 36.66; H, 2.80; N, 6.12.
4.6.2. Synthesis of fac-[Re(CO) (phen)(morpholine)]OTf (Re-morph)
3
A mixture of fac-[Re(CO) (phen)Cl] (0.200 g, 0.42 mmol) and AgOTf (0.106 g,
3
0.42 mmol) in THF (48 ml) was heated to reflux for 3 h in the dark. The white solid
AgCl was removed via vacuum filtration. To the remaining yellow filtrate,
morpholine (0.183 g, 2.1 mmol) was added, and the resulting solution was heated to
reflux for an additional 24 h. The reaction mixture was allowed to cool to room
temperature, and yellow precipitate formed, which was filtered and washed with
cold THF (~20 ml). Yield: 0.134 g (47%). 1H NMR (400 MHz, MeOH-d ): δ 9.52
4
(d, 2H), 9.10 (d, 2H), 8.41 (s, 2H), 8.21 (dd, 2H), 4.83 (t, 1H), 3.46 (d, 2H), 3.19 (t,
2H), 2.81 (m, 2H), 2.64 (d, 2H). 19F NMR (376 MHz, MeOH-d , external stnd:
4
KPF ): –77.08. IR (KBr, cm–1): 2033 s, 1940 s, 1919 s, 1903 s. ESI-MS (pos. ion
6
mode, CH CN:H O 70:30 and 1% formic acid): 538.0739 m/z ([M]+, calcd.
3 2
538.0777). Anal. Calcd. for C H F N O ReS: C, 34.99; H, 2.50; N, 6.12. Found:
20 17 3 3 7
C, 35.07; H, 2.46; N, 6.05.
4.6.3. Synthesis of fac-[Re(CO) (phen)(thiomorpholine)]OTf (Re-thio)
3
A mixture of fac-[Re(CO) (phen)Cl] (0.241 g, 0.50 mmol) and AgOTf (0.127 g,
3
0.50 mmol) in THF (52 ml) was heated to reflux for 3 h in the dark. The white solid
AgCl was removed via vacuum filtration. To the remaining yellow filtrate,
thiomorpholine (0.258 g, 2.5 mmol) was added, and the resulting solution was
heated to reflux for an additional 24 h. The reaction mixture was allowed to cool to
room temperature and THF was removed by rotary evaporation. The dark yellow
solid was then taken up in 65 °C THF (3–5 ml). The hot solution was stored at –20
°C, inducing the precipitation of a yellow solid. The yellow precipitate was filtered
and washed with cold THF. Yield: 0.067 g (19%). 1H NMR (400 MHz, MeOH-d ):
4
δ 9.52 (d, 2H), 9.11 (d, 2H), 8.43 (d, 2H), 8.31 (dd, 2H), 4.58 (t, 1H), 3.20 (d, 2H),
2.90 (m, 2H), 2.45 (m, 2H), 2.26 (d, 2H). 19F NMR (376 MHz, MeOH-d , external
4
stnd: KPF ): –77.08. IR (KBr, cm–1): 2027 s, 1930 s, 1896 s. ESI-MS (pos. ion
6
mode, CH CN:H O 70:30 and 1% formic acid): 554.0513 m/z ([M]+, calcd.
3 2
554.0548). Anal. Calcd. for C H F N O ReS : C, 34.19; H, 2.44; N, 5.98. Found:
20 17 3 3 6 2
C, 34.40; H, 2.34; N, 6.15.
13
4.6.4. Synthesis of fac-[Re(CO) (phen)(pyridine)]OTf (Re-py)
3
fac-[Re(CO) (phen)(pyridine)]+ was synthesized as previously described [17,31].
3
1H NMR (400 MHz, DMSO-d ): δ 9.77 (d, 2H), 9.04 (d, 2H), 8.46 (d, 2H), 8.31 (s,
6
2H), 8.26 (dd, 2H), 7.86 (t, 1H), 7.32 (t, 2H). 19F NMR (376 MHz, DMSO-d ,
6
external stnd: KPF ): –77.04. IR (KBr, cm–1): 2027 s, 1928 sh, 1911 s.
6
4.7. Cell Culture and Cytotoxicity
HeLa (cervical cancer) cell line was obtained from American Type Culture
Collection (ATCC) and cultured using Dulbecco’s Modified Eagle’s Medium
(DMEM) supplemented with 10% fetal bovine serum (FBS). The cell line was
grown in a humidified incubator at 37 °C with an atmosphere of 5% CO . Cells
2
were passed at 80–90% confluence using trypsin/EDTA. Cells were tested monthly
for mycoplasma contamination with the PlasmoTest™ mycoplasma detection kit
from InvivoGen.
All compounds were dissolved in DMSO to prepare a 10–20 mM stock
solution, which was diluted in growth media to contain <1% DMSO. Cells were
grown to 80–90% confluence, detached with trypsin/EDTA, seeded in 96-well
plates at 4000 cells/well in 100 µL of growth media, and incubated for 24 h. The
medium was removed and replaced with fresh medium (200 µL) containing varying
concentrations of the desired compound or media. The cells were then incubated for
an additional 48 h. The medium was removed from the wells, and MTT in DMEM
(200 µL, 1 mg/mL) was added. The additional 48 h incubation was performed to
ensure that the cells were in the logarithmic growth phase and that the cells had
adequate time to regrow after exposure to the complexes. After 4 h, the
MTT/DMEM solution was removed, and the formazan crystals were dissolved in
200 µL of an 8:1 mixture of DMSO and pH 10 glycine buffer. The absorbance at
570 nm in each well was measured using a BioTek Synergy HT plate reader. Cell
viability was determined by normalizing the absorbance of the treated wells to
untreated wells. The concentrations of the compounds versus % viability were
plotted to produce the dose-response curves, which were analyzed using a logistic
sigmoid function fit with MagicPlot Pro software. The reported IC values are the
50
average of at least three independent experiments with six replicates per
concentration level.
4.8. Colocalization using Confocal Fluorescence Microscopy
A total of 1 × 105 HeLa cells were seeded onto 35 mm glass bottom dishes. After 24
h, the cells were treated with the rhenium compounds (100 µM) for 2 h or the
specific dye for 30 min in DMEM media. After the indicated time, the media was
removed and the cells were washed with PBS and fresh media was added. Right
before imaging, the media was removed and imaging buffer was added (20 mM
HEPES pH 7.4, 135 mM NaCl, 5 mM KCl, 1.8 mM CaCl , 1 mM MgCl , 1 mg/mL
2 2
glucose, and 1 mg/mL bovine serum albumin). The cells were imaged with a Zeiss
LSM 800 or Zeiss LSM 880 confocal laser-scanning microscope. The rhenium
complex was imaged using a 405 nm laser excitation with a 410–550 nm emission
14
filter and images were processed using ImageJ software. For MitoTracker Red and
LysoTracker Red DND-99 treatment, 1 µL of 100 µM dye was added to 3 mL of
medium 30 min prior to imaging and the dyes were excited with a 561 nm laser
with an emission filter from 630–700 nm.
Appendix A. Supporting data.
Complex characterization data, crystal data tables, transient emission decay
profiles, and confocal fluorescence microscopy images can be found in the
Supplementary data online at DOI:
Accession Codes.
CCDC 1965772–1965776 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Author Information
Corresponding Author
*E-mail: jjw275@cornell.edu
ORCID
Justin J. Wilson: 0000-0002-4086-7982
Notes
The authors declare no competing financial interests.
Acknowledgements.
This research was supported by Cornell University and by the Office of the
Assistant Secretary of Defense for Health Affairs through the Ovarian Cancer
Research Program under award no. W81XWH-17-1-0097. This work made use of
the NMR facility at Cornell University, which is supported, in part, by the NSF
under award number CHE-1531632. We thank Prof. Jeremy Baskin and Prof.
Warren Zipfel for allowing us to use their confocal fluorescence microscope and
assistance with fluorescence decay lifetime measurements, respectively.
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19
Highlights
• Rhenium tricarbonyl complexes with four different axial N-donor ligands were
synthesized
• These complexes were characterized by X-ray crystallography
• These complexes exhibit moderate photoluminescent quantum yields
• These compounds are not significantly cytotoxic in HeLa cells
• Confocal fluorescence microscopy was used to study their use as cellular imaging
agents
Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: