Luminescent rhenium(I) polypyridine complexes appended with an α- D -glucose moiety as novel biomolecular and cellular probes

Article abstract of DOI:10.1002/chem.201101399

Glowing sweets! Three luminescent rhenium(I) polypyridine complexes have been modified with an α-D-glucose moiety. Their biomolecular binding, bacterial staining, and cellular-uptake properties have been examined (see figure). Various experimental results

Full text of DOI:10.1002/chem.201101399

DOI: 10.1002/chem.201101399
Luminescent Rhenium(I) Polypyridine Complexes Appended with
an a-d-Glucose Moiety as Novel Biomolecular and Cellular Probes
Man-Wai Louie, Hua-Wei Liu, Marco Ho-Chuen Lam, Yun-Wah Lam, and
Kenneth Kam-Wing Lo*[a]
Glucose is the most impor-
tant carbohydrate in cellular
metabolism and an energy
source for the growth of cells.[1]
One of the most characteristic
phenotypes of rapidly growing
cancer cells is their propensity
to catabolize glucose at high
rates, possibly due to the over-
expression of glucose transport-
ers (GLUTs).[2] Thus, the in
vitro and in vivo monitoring of
glucose utilization in cancer
cells has attracted much atten-
tion. Different reporting and
therapeutic units such as radio-
active
labels,[3a]
IRDye
800CW,[3b] organic fluorophor-
es,[3c,d] and two-photon dyes[3e]
have been conjugated to glu-
cose or 2-deoxyglucose for the
diagnosis and treatment of vari-
ous tumors or cancers. Despite
Scheme 1. Structures of the rhenium(I) polypyridine complexes.
the development of these reagents, the possibility of using
luminescent transition-metal glucose conjugates as glucose-
uptake tracers and cancer cell imaging reagents has not
been explored.[4] With our ongoing interest in luminescent
rhenium(I) polypyridine complexes as biological probes,[5]
we envisage that modification of these complexes with an a-
d-glucose pendant will generate useful luminescent probes
for biomolecules and cancer cells.
4,7-diphenyl-1,10-phenanthroline (Ph2-phen) (3)) and their
glucose-free counterparts [Re(N^N)(CO)3A(py-3-Et)]-
(CF3SO3) (py-3-Et=3-(ethylthioureidyl)pyridine, N^N=
phen (1a), Me4-phen (2a), Ph2-phen (3a)) (Scheme 1). The
glucose complexes were synthesized from the addition reac-
G
CHTUNGTRENNUNG
AHCTUNGTRENNUNG
tion of the isothiocyanate complexes [Re
ACHUTGTNRENU(NG N^N)(CO)3ACHTUNGTRENNUNG(py-3-
NCS)]
AHCTUNGTRENNUNG
deacetylation (see the Supporting Information, Schemes S1
1
Herein we report three rhenium(I) polypyridine glucose
and S2). All the complexes were characterized by H NMR
complexes [Re
(N^N)(CO)
N
U
spectroscopy, positive-ion ESI-MS, and IR spectroscopy and
gave satisfactory elemental analyses (see the Supporting In-
formation). Upon irradiation, the complexes exhibited in-
tense and long-lived green-to-yellow triplet metal-to-ligand
(N-(6-(N’-(4-(a-d-glucopyranosyl)phenyl)thioureidyl)hex-
yl)thioureidyl)pyridine, N^N=1,10-phenanthroline (phen)
(1), 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4-phen) (2),
charge-transfer (MLCT; dp(Re)!p*
ACHTUNGTREN(NUNG N^N)) emission (see
the Supporting Information, Table S1).[6] The structured
[a] M.-W. Louie, Dr. H.-W. Liu, M. H.-C. Lam, Dr. Y.-W. Lam,
Dr. K. K.-W. Lo
emission band and very long lifetime of complex 2 in alco-
3
Department of Biology and Chemistry
City University of Hong Kong, Tat Chee Avenue
Kowloon, Hong Kong (P.R. China)
Fax : (+852)3442-0522
hol glass at 77 K are probably due to the involvement of IL
(p!p*) (Me4-phen) character in its emissive state.[7]
Since the lectin concanavalin A (Con A) binds a-d-man-
nopyranoside and a-d-glucopyranoside,[8] the possible use of
the glucose complexes 1–3 as a luminescent sensor for this
lectin has been investigated.[9] Upon addition of Con A to a
E-mail: bhkenlo@cityu.edu.hk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101399.
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Chem. Eur. J. 2011, 17, 8304 – 8308

COMMUNICATION
Table 1. Results of emission titrations of complexes 1–3 with Con A in
potassium phosphate buffer (10 mm) at pH 8.5/methanol (9:1, v/v) with
CaCl2 (0.1 mm) and MnCl2 (0.1 mm) at 298 K.
Table 2. Lipophilicity, cellular uptake, and IC50 values of complexes 1–3,
1a–3a, and cisplatin.
Complex
LogPo/w
Amount of
IC50
[a]
[c]
Complex
I/Io
to
[ms][b]
t
Ka
[mꢁ1
nH
complex [fmol][a]
[mm][b]
[c]
[ms][b]
N
]
1
2
3
1a
2a
3a
cisplatin
0.57
2.73
3.44
0.77
2.94
1.10ꢂ0.09
2.15ꢂ0.03
3.02ꢂ0.10
1.64ꢂ0.13
4.73ꢂ0.22
6.61ꢂ0.33
N.A.
>150
1
2
3
1.8
2.0
3.2
0.39
0.64
0.40
1.15 (19%),
0.22 (81%)
4.32 (44%),
0.93 (56%)
2.04 (33%),
0.40 (67%)
4.5ꢁ105
5.8ꢁ105
4.4ꢁ105
2.0
2.3
2.5
90.0ꢂ7.6
68.9ꢂ2.3
22.8ꢂ5.2
7.7ꢂ0.6
2.8ꢂ0.4
27.6ꢂ1.8
4.03
ꢁ2.30[c]
[a] Io and I are the emission intensities of the complex (5 mm) in the pres-
ence of 0 and 5.5 mm Con A, respectively. [b] to and t are the emission
lifetimes of the complex (5 mm) in the presence of 0 and 5.5 mm Con A,
respectively. [c] Binding constants and Hill coefficients as determined by
the Hill equation.
[a] Amounts of rhenium associated with an average HeLa cell upon incu-
bation with the complexes (100 mm) in a glucose-free medium at 378C for
5 min as determined by ICP-MS. [b] HeLa cells, incubation in high glu-
cose Dulbecco’s modified Eagle’s medium (DMEM) for 48 h. [c] See
ref. [24].
buffer solution of the complexes, the emission intensities
were enhanced by ꢀ1.8 to 3.2 fold (Table 1) and the emis-
sion maxima were blueshifted by ꢀ5 to 15 nm. The emission
decay became biexponential with components of 0.22 to
0.93 ms and 1.15 to 4.32 ms (Table 1). The emission titration
curves for complexes 3 and 3a with Con A are shown in Fig-
ure S1 (see the Supporting Information). Since the glucose-
free complexes 1a–3a did not give similar observations, it is
likely that the changes exhibited by the glucose complexes
originated from the increased hydrophobicity and rigidity of
the local environment of the complexes after binding to
Con A. The binding has been analyzed by the Hill equation
and the binding constants (Ka =4.4ꢁ105 to 5.8ꢁ105 mꢁ1,
Table 1) are comparable to that of a ruthenium(II) glucose
complex L-[Ru(a-Glc-3-bpy)3]Cl2 (Ka =9.5ꢁ105 mꢁ1)[8b] but
one order of magnitude larger than that of p-nitrophenyl-a-
d-glucopyranoside (Ka =1ꢁ104 mꢁ1).[10] The higher binding
affinity has been attributed to the relatively hydrophobic
rhenium(I) polypyridine units.
The FimH adhesin of E. coli type 1 pili is able to bind d-
mannosides and d-glucosides by virtue of a receptor-binding
domain.[11] Two E. coli strains ORN178 and ORN208 have
been used in this work to study the possible binding of the
glucose complexes to FimH. The ORN178 strain expresses
wild-type type 1 pili that exhibit monosaccharide-binding
properties, whereas the ORN208 strain is deficient of the
FimH gene and expresses abnormal type 1 pili that do not
show similar behavior.[12] Both E. coli strains were incubated
with the glucose complex 3 for 3 h and then imaged with
laser-scanning confocal microscopy. The emission intensity
of the ORN178 strain was 7.7 times that of ORN208 (n=
30) (See the Supporting Information, Figure S2). This obser-
vation has been ascribed to the binding of the glucose pend-
ant of the complex to the lectin expressed on the ORN178
strain. Both strains were also stained by the glucose-free
complex 3a but the emission intensities were very weak and
indistinguishable (See the Supporting Information, Fig-
ure S2), which further supports the specific binding of the
glucose moiety of complex 3 to FimH on the ORN178
strain.
lowed the orders: 1<2<3 and 1a<2a<3a (Table 2), which
are in accordance with the hydrophobic character of the dii-
mine ligands (phen<Me4-phen<Ph2-phen). Interestingly,
the glucose moiety reduced the logPo/w values of complexes
1–3 by ꢀ0.20 to 0.59 units with respect to the glucose-free
analogues 1a–3a. The somewhat high lipophilicity of com-
plexes 1–3 despite the polar glucose unit is probably a con-
sequence of the hydrophobic C6 spacer-arm. We have inves-
tigated the cellular uptake properties of the complexes
([Re]=100 mm with HeLa cells at 378C for 5 min) and their
cytotoxicity by ICP-MS and MTT assays, respectively. The
amounts of rhenium taken up by an average HeLa cell were
in the femtomole scale (Table 2), which is comparable to the
results from other cellular uptake studies.[13] The intracellu-
lar amounts in both series of rhenium complexes followed
the orders: 1<2<3 and 1a<2a<3a, which are in accord-
ance with their lipophilicity and cytotoxicity (Table 2). Since
the glucose complexes 1–3 showed lower cytotoxicity com-
pared to their glucose-free counterparts complexes 1a–3a
(Table 2), the incorporation of a glucose unit renders the
complexes more biocompatible.
To study the possible role of GLUTs on the internaliza-
tion of the glucose complexes, the cellular uptake properties
of complexes 3 and 3a towards two transformed cell lines,
HeLa and human breast adenocarcinoma (MCF-7), and two
non-transformed cell lines, human embryonic kidney cells
(HEK293T) and mouse embryonic fibroblast (NIH/3T3),
have been studied. In general, the intracellular amounts of
the glucose complex 3 were lower than those of the glucose-
free complex 3a among the cell lines studied (Table 3),
which is attributable to the lower lipophilicity of the former
complex. Interestingly, the uptake of complex 3 by HeLa
Table 3. Cellular uptake and IC50 values of complexes 3 and 3a towards
different cell lines.
Cell line
Amount [fmol][a]
IC50 [mm][b]
Complex 3
Complex 3a
Complex 3
Complex 3a
HeLa
MCF-7
HEK293T
NIH/3T3
2.92ꢂ0.36
2.33ꢂ0.37
0.86ꢂ0.04
0.33ꢂ0.03
6.29ꢂ0.06
4.30ꢂ0.31
3.73ꢂ0.68
4.43ꢂ0.08
62.9ꢂ1.7
20.3ꢂ2.0
40.9ꢂ1.6
3.20ꢂ0.70
2.94ꢂ0.14
4.94ꢂ0.54
2.80ꢂ0.56
>150
[a] [Re]=100 mm, incubation in glucose-free DMEM at 378C for 5 min.
[b] Incubation in high glucose DMEM for 48 h.
The lipophilicity (logPo/w) of all the complexes has been
measured by reversed-phase HPLC. The logPo/w values fol-
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K. K.-W. Lo et al.
and MCF-7 cells was at least 2.7 times that of HEK293T and
NIH/3T3 cells. This is possibly a result of the overexpression
of GLUTs in the transformed cell lines (HeLa and MCF-7)
rather than the non-transformed cell lines (HEK293T and
NIH/3T3).[2] In the case of complex 3a, the difference in cel-
lular uptake efficiency between the transformed and non-
transformed cell lines was much smaller (Table 3) and the
intracellular amount of rhenium in HeLa cells was slightly
higher than those in the other three cell lines. Also, the cyto-
toxicity of complexes 3 and 3a did not show any depend-
ence on the cell types (Table 3).
Glucose derivatives entering the cells through a GLUT-
mediated glucose-uptake pathway are competitively inhibit-
ed by d-glucose but not by l-glucose.[3c–e] The possible in-
volvement of GLUTs in the cellular uptake of complex 3
has been studied. HeLa cells were incubated with this com-
plex (100 mm) for 5 min in the absence or presence of 5 to
50 mm d-glucose or l-glucose in a glucose-free medium and
the intracellular rhenium associated with an average HeLa
cell has been determined. The addition of d-glucose to the
medium led to a decrease of cellular uptake of the complex,
but l-glucose gave no effects (Figure 1, top and middle),
which supports the argument that the internalization of this
complex occurred by a GLUT-mediated uptake pathway.
This is also in accordance with the finding that the cellular
uptake of complex 3 by HeLa cells decreased with increas-
ing concentration of 2-deoxyglucose in the medium
(Figure 1, bottom) since 2-deoxyglucose is transported into
the cells in a similar manner to d-glucose.[3a] On the contra-
ry, the cellular uptake of the glucose-free complex 3a did
not show significant changes in the presence of d-glucose, l-
glucose, or 2-deoxyglucose (Figure 1). All these results re-
vealed that the glucose-dependent cellular uptake of com-
plex 3 originated from the specific recognition of the d-glu-
cose moiety of the complex by the cells. The possible in-
volvement of GLUTs in the cellular uptake properties of
complex 3 has been further examined. Since the expression
of GLUTs in HeLa cells can be upregulated by addition of
hypoxia-mimetic agents such as cobalt(II) chloride,[14] we
have incubated HeLa cells with this salt (250 mm) in the
growth medium for 2 h prior to treatment with complex 3
(100 mm) for 5 min. The results showed that the cellular
uptake was ꢀ1.5 fold higher than that of the control in
which cobalt(II) chloride was absent. Additionally, incuba-
tion of HeLa cells with two glucose-uptake inhibitors fasen-
tin (80 mm) and cytochalasin B (10 mm)[15] for 1 h reduced the
intracellular amounts of rhenium by ꢀ1.4 and 1.7 fold, re-
spectively. In contrast, complex 3a did not show significant
changes in uptake efficiency upon addition of cobalt(II)
chloride, fasentin, or cytochalasin B. These results support a
GLUT-mediated transport pathway for the glucose complex.
Incubation of HeLa cells with complexes 3 and 3a in a
glucose-free medium at 48C resulted in reduction of the in-
tracellular rhenium by ꢀ50%. Thus, the complexes appa-
rently entered the cells by an energy-dependent endocyto-
sis-like pathway.[16] Additionally, treatment of the cells with
sodium azide (3 mm) for 30 min at 378C before addition of
Figure 1. Relative cellular uptake of rhenium associated with an average
HeLa cell upon incubation with complexes 3 (shaded) and 3a (empty)
(100 mm) at 378C for 5 min in a glucose-free medium containing various
concentrations of d-glucose (top), l-glucose (middle), and 2-deoxyglu-
cose (bottom) (n=3).
the glucose-free complex 3a revealed a decrease of intracel-
lular rhenium by ꢀ1.6 fold, most likely due to the inhibition
of endocytic pathways by sodium azide through cellular
energy depletion.[16] In sharp contrast, HeLa cells treated
with sodium azide before incubation with the glucose com-
plex 3 led to an increase of the intracellular rhenium by
ꢀ2.5 fold. Since exposure of cells to azide is well known to
cause an immediate inhibition of oxidative phosphorylation
and a decline in cell ATP content resulting in a rapid stimu-
lation of glucose transport,[14] the increased uptake strongly
suggests that the internalization of complex 3 occurred
through a glucose-specific transport system.
Taxol is a genotoxin and a mitotic inhibitor that is used to
treat several types of cancers including ovarian, breast, and
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Rhenium(I) Polypyridine Complexes Appended with an a-d-Glucose
COMMUNICATION
non-small cell lung cancers.[17] Since genotoxic reagents are
known to lower the cellular metabolic rate and reduce the
glucose uptake in cancer cells,[18] the effects of taxol on the
cellular uptake of complexes 3 and 3a have been investigat-
ed. HeLa cells were incubated with taxol at various concen-
trations in the growth medium for 5 h, followed by treat-
ment with the glucose complex 3 or the glucose-free com-
plex 3a (100 mm) for 5 min before the determination of cel-
lular uptake efficiency (Figure 2). By using ꢃ125 nm of
taxol, the intracellular amount of complex 3 in an average
HeLa cell was reduced to ꢀ50% of that of the control (in
Figure 3. Laser-scanning confocal microscopy images of a HeLa cell upon
incubation successively with MitoTracker Deep Red FM (100 nm, 20 min,
lex =633 nm) and complex 3 (100 mm, 5 min, lex =405 nm) in a glucose-
free medium at 378C.
pendant of complex 3 plays a role in the accumulation of
the complex in mitochondria. Although a possible explana-
tion is the binding of the glucose complex to hexokinases
(the major proteins that phosphorylate glucose),[19] which
strongly associate with mammalian mitochondria,[20] we did
not observe phosphorylation of complex 3 in both in vitro
and in vivo experiments involving the isolated enzyme and
E. coli.[21] This is reasonable given the extremely rigid struc-
ture requirement of the enzyme for its substrates.[22] Never-
theless, other rhenium(I) polypyridine complexes have been
reported to show similar mitochondria-targeting proper-
ties.[23]
Figure 2. Relative cellular uptake of rhenium associated with an average
HeLa cell upon incubation with 100 mm of complexes 3 (solid squares)
and 3a (empty circles) at 378C for 5 min after exposure to taxol at vari-
ous concentrations for 5 h (n=3).
Finally, we have examined the photostability of complex
3. The 2-deoxyglucose analogue 2-(N-(7-nitrobenz-2-oxa-
1,3-diazol-4-yl)-amino)-2-deoxy-d-glucose (2-NBDG) is
a
fluorescent indicator for direct glucose-uptake measure-
ments and has been applied in tumor imaging and the ex-
amination of GLUT-related cell metabolism.[3c] However,
the fast photobleaching rate of this organic compound limits
its applications in prolonged exposure to the light source or
time-lapse imaging experiments. We have compared the
photostability of the glucose complex 3 and 2-NBDG. Con-
focal microscopy images and irradiation time-dependence
emission intensity of HeLa cells treated with complex 3
(100 mm, 5 min, lex =405 nm, 25 mW) or 2-NBDG (100 mm,
5 min, lex =488 nm, 15 mW) are illustrated in Figure S4 (see
the Supporting Information) and Figure 4, respectively. The
emission intensity of 2-NBDG decreased much more rapidly
compared to that of the glucose complex upon laser irradia-
which taxol was absent). However, the presence of taxol did
not cause a similar effect to the glucose-free complex 3a
(Figure 2). Thus, the incorporation of a glucose unit into the
complex renders its uptake to be regulated by an anticancer
reagent. Since the cellular uptake of the luminescent com-
plex can be readily assessed by fluorescence spectroscopy
and microscopy (see below), these findings could form the
basis of new cell-viability assays.
The intracellular localization of complex 3 upon internali-
zation by HeLa cells has been investigated by laser-scanning
confocal microscopy. The complex was diffusely distributed
in the cytoplasm with punctate staining (see the Supporting
Information, Figure S3). The nucleus gave much weaker or
no emission, indicative of negligible nuclear uptake. Similar
intracellular distribution has been observed for other lumi-
nescent rhenium(I) polypyridine complexes.[5c,d] In addition
to the perinuclear region, the complex was concentrated in
specific compartments of the cells, which appeared to be the
mitochondria. Thus, HeLa cells pretreated with MitoTracker
Deep Red FM (100 nm, 20 min, lex =633 nm), whose spec-
tral properties do not interfere, were incubated with com-
plex 3 (100 mm, 5 min, lex =405 nm). The fluorescence stain-
ing pattern showed that the mitochondria of a typical HeLa
cell have been co-stained by the fluorescent dye and the
rhenium(I) complex (Figure 3). The intracellular localization
of the complex 3 is different to that of its glucose-free com-
plex 3a, which did not show granular appearance, but a dif-
fused staining of the whole cytoplasm.[5c] Thus, the glucose
Figure 4. Irradiation time-dependence of the emission intensity of HeLa
cells upon incubation with complex 3 (solid squares) and 2-NBDG
(empty circles) under exposure to 405 nm (25 mW) and 488 nm (15 mW)
laser excitation, respectively.
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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K. K.-W. Lo et al.
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to only ꢀ10% of its initial value, whereas the emission in-
tensity of the glucose complex was maintained at ꢀ70% of
its initial value after irradiation at a shorter wavelength
(405 nm) for the same period (Figure 4). This much higher
photostability renders this class of luminescent rhenium(I)
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In summary, we have designed three luminescent rhe-
nium(I) polypyridine glucose complexes and investigated
their photophysics, biomolecular binding, bacterial staining,
and cellular-uptake properties. Various experimental results
have indicated that GLUTs play a very important role in
the cellular uptake of the complexes. We anticipate that
these complexes can serve as new imaging reagents and glu-
cose-uptake indicators for mammalian cells.
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Acknowledgements
We thank The Hong Kong Research Grants Council (Project No. CityU
102109) and City University of Hong Kong (Project No. 7002697) for fi-
nancial support. M.W.L acknowledges the receipt of a Postgraduate Stu-
dentship, a Research Tuition Scholarship, and an Outstanding Academic
Performance Award administered by City University of Hong Kong. We
thank Prof. Paul E. Orndorff for providing the E. coli strains, Dr. David
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Mr. Michael Wai-Lun Chiang, and Mr. Ho-Hang Chan for their assis-
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Keywords: biological probes
agents · luminescence · rhenium
· carbohydrates · imaging
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Received: May 7, 2011
Published online: June 28, 2011
8308
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