Synthesis of D-fructose conjugated ligands via C6 and C1 and their corresponding [Ru(bpy)2(L)]Cl2 complexes

Article abstract of DOI:10.1016/j.carres.2017.04.020

A pyridyl triazole (pyta) modified sucrose ligand was prepared in a seven step synthesis using D-glucose as the protection group for D-fructose and starting from commercially available sucrose. After complexation with Ru(bpy)₂Cl₂ precursor, the sucrose-conjugated Ru complex of the general formula [Ru(bpy)₂(L)]Cl₂ was formed. Acidic cleavage of the D-glucose unit led to the first D-fructose conjugated metal complex via D-fructose C6 in literature. Additionally, pyta-modified D-fructose via C1 and the corresponding Ru complex were synthesized. All compounds were analyzed by R_f values, specific rotation, NMR, IR, UV/Vis and fluorescence spectroscopy, mass spectrometry and elemental analysis.

Full text of DOI:10.1016/j.carres.2017.04.020

Accepted Manuscript
Synthesis of D-fructose conjugated ligands via C6 and C1 and their corresponding
[Ru(bpy) (L)]Cl complexes
2
2
Michael Pröhl, Pascal D. Moser, Justyna A. Czaplewska, Patrick Hoffmann, Tanja
Bus, Anja Traeger, Helmar Görls, Ulrich S. Schubert, Michael Gottschaldt
PII:
S0008-6215(17)30108-8
10.1016/j.carres.2017.04.020
CAR 7370
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 13 February 2017
Revised Date: 24 April 2017
Accepted Date: 24 April 2017
Please cite this article as: M. Pröhl, P.D. Moser, J.A. Czaplewska, P. Hoffmann, T. Bus, A. Traeger,
H. Görls, U.S. Schubert, M. Gottschaldt, Synthesis of D-fructose conjugated ligands via C6 and C1
and their corresponding [Ru(bpy) (L)]Cl complexes, Carbohydrate Research (2017), doi: 10.1016/
2
2
j.carres.2017.04.020.
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ACCEPTED MANUSCRIPT
Synthesis of
D
-fructose conjugated ligands via C6 and C1 and their
corresponding [Ru(bpy)2(L)]Cl2 complexes
Michael Pröhl,†,ǂ Pascal D. Moser,†,ǂ Justyna A. Czaplewska,†,ǂ Patrick Hoffmann,†,ǂ Tanja Bus,†,ǂ Anja
Traeger,†,ǂ Helmar Görls,§ Ulrich S. Schubert,†,ǂ Michael Gottschaldt†,ǂ *
†
ǂ
§
Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena,
Humboldtstraße 10, 07743 Jena, Germany
Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743
Jena, Germany
Institute for Inorganic and Analytical Chemistry, Friedrich Schiller University Jena, Humboldtstraße
8, 07743 Jena, Germany
*corresponding author: michael.gottschaldt@uni-jena.de
Graphical Abstract

ACCEPTED MANUSCRIPT
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Synthesis of
D
-fructose conjugated ligands via C6 and C1 and their
corresponding [Ru(bpy)2(L)]Cl2 complexes
3
4
Michael Pröhl,†,ǂ Pascal D. Moser,†,ǂ Justyna A. Czaplewska,†,ǂ Patrick Hoffmann,†,ǂ Tanja Bus,†,ǂ Anja
Traeger,†,ǂ Helmar Görls,§ Ulrich S. Schubert,†,ǂ Michael Gottschaldt†,ǂ *
5
6
†
ǂ
§
Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena,
Humboldtstraße 10, 07743 Jena, Germany
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8
Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743
Jena, Germany
9
Institute for Inorganic and Analytical Chemistry, Friedrich Schiller University Jena, Humboldtstraße
8, 07743 Jena, Germany
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11
*corresponding author: michael.gottschaldt@uni-jena.de
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Electronical Supporting Information available: Crystallographic data (excluding structure factors) has
been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC-
1527070 for 2, CCDC-1527071 for 3, and CCDC-1527072 for 10. Copies of the data can be obtained free
of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [E-mail:
deposit@ccdc.cam.ac.uk].
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Abstract
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A pyridyl triazole (pyta) modified sucrose ligand was prepared in a seven step synthesis using
as the protection group for -fructose and starting from commercially available sucrose. After
complexation with Ru(bpy)2Cl2 precursor, the sucrose-conjugated Ru complex of the general formula
[Ru(bpy)2(L)]Cl2 was formed. Acidic cleavage of the -glucose unit led to the first -fructose conjugated
metal complex via -fructose C6 in literature. Additionally, pyta-modified -fructose via C1 and the
D-glucose
D
D
D
D
D
corresponding Ru complex were synthesized. All compounds were analyzed by Rf values, specific
rotation, NMR, IR, UV/Vis and fluorescence spectroscopy, mass spectrometry and elemental analysis.
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Keywords
D-fructose, sucrose, carbohydrates, metal complexes, click chemistry
1. Introduction
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The attachment of carbohydrates represents a strategy to enhance the hydrophilicity and selectivity of the
corresponding metal complexes due to their interaction with various biological structures.[1] Among a
diversity of sugars, which are extensively used for biomedical applications, D-fructose gained interest for

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the targeting of the GLUT5 receptor. In general, carbohydrates are entering into the cells by highly
selective transport proteins (GLUTs).[2] Among the thirteen known saccharide transporters, GLUT5 is
3
specific for D
-fructose and its structure was confirmed recently.[3] The incidence of GLUT5 is
4
controversially discussed in literature. Next to the existence in the kidney, colon and adrenal cells, it is
supposed to be overexpressed in more than 85% of 33 tested breast cancer cell lines,[4] whereas another
group claimed there is no GLUT5 overexpression in any breast cancer tissue.[5] Additionally, the GLUT5
receptor might be overexpressed in acute myeloid leukemia.[6] Since it is known that structural
5
6
7
8
modifications of the C1 as well as of the C6 position of the
transporter,[7, 8] there is intensive research in structural modification of
derivatives to various structures and in their biological properties. Therefore, nanoparticular formulations[9,
D
-fructose are tolerated by the GLUT5
9
D-fructose, the attachment of these
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10]
13]
as well as dyes,[11] micelles[12,
fructose to address various breast cancer cells lines. Also, low molar mass metal complexes conjugated
with various -fructose residues were used to investigate their interactions with the GLUT5 transporter.
For instance, Re complexes were functionalized with -fructose and their phosphorescence was used to
show the selective accumulation in breast cancer cell lines MCF-7 and MDA-MB-231 mediated by
GLUT5.[17]
-fructose conjugated Ir(III) complex exhibited a 3.7 higher uptake in MCF-7 than in non-
cancerous cells. In contrast to that, the
-fructose-free complex did not display any selectivity.[18] Also, the
natural compound bisdemethoxycurcumin was successfully labeled with -fructose by using Cu(I)-
and polymers[14-16] have been successfully functionalized with
D-
D
D
A
D
D
D
catalyzed “click” reaction between azides and alkynes and then complexed to Ru. Incubation of L929,
HepG2 and MDA-MB-231 revealed a high biocompatibility of these compounds due to the curcumin
moiety, but unfortunately, detailed uptake studies were not performed in this study.[19]
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The importance of the substitution position was shown very recently for a set of
platinum complexes. The C2-substituted -glucose Pt complex showed an enhanced accumulation in
various cancer cell lines, whereas the C3-substituted analogue was the least active complex.[20] Since the
C1 and the C3 position of -fructopyranose are easy to address due to commercially available starting
materials with protection groups, all presented studies focused on compounds, which were covalently
bound to these positions of the -fructose moiety, whereas modifications of the C6 position of -fructose
are rarely discussed. As a starting point, sucrose was used, since it contains a unit of -glucose, which is
α(1-2) covalently bound to -fructofuranose.
D-glucose conjugated
D
D
D
D
D
D
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Figure 1. Schematic representation of a sucrose molecule.

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The glycosidically linked
D
-glucose avoids ring opening reactions of the D-fructofuranose and, therefore,
enables the selective modification of the C6’-position of the sucrose molecule. Sucrose is cultivated in
sugar beets to produce crystalline sugar.[21] Additionally, it is used for macroporous alumina ceramics,[22]
dye sensitized solar cells[23] and hollow carbon nanospheres.[24] Due to the renewable and biocompatible
properties of sucrose, it was also investigated regarding its use for polymers,[25-27] nanoparticles[28] and low
molar mass bioactive compounds.[29]
7
8
The Cu(I)- catalyzed “click” reaction between azides and alkynes provides a very effective tool for the
synthesis of five-membered heterocyclic systems, with good tolerance of other functional groups, simple
reaction conditions and a high selectivity.[30] The formation of 1,4-substituted triazoles enables various
features like hydrogen bonding and the attendance in dipol-dipol interactions, render them to isosteres of
amides, a key structure in various biological molecules.[31] Synthetic protocols of carbohydrate chemists
can easily introduce azide or alkyne functionalities into sugar residues.[32] The formation of carbohydrate-
conjugated triazoles can result in beneficial properties such as anticancerous and antiviral effects as well
as in fluorescent glycoprobes for diagnostics.[33, 34] Additionally, click reactions with other N-alkynes such
as 2-ethynyl pyridine result in potentially bidentate chelators and, therefore, the possibility to form various
metal complexes.[35, 36]
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There, we present the synthesis of pyridyl triazole (pyta) conjugated sugars using Cu(I) catalyzed click
reactions between azides and alkynes. In particular, this group was introduced to
four step synthesis and to the C6’ position of sucrose (which represents the C6 position of the
fructofuranose) in a seven step synthesis. The ligands were reacted with Ru(bpy)2Cl2 to form complexes
of the general formula [Ru(bpy)2(L)]Cl2 and in the case of sucrose-conjugated Ru complex, the -glucose
unit was cleaved to form the first -fructose-conjugated complex at C6. The cytotoxicity and uptake of the
complexes was evaluated as well.
D-fructose via C1 in a
D-
D
D
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2. Results and discussion
2.1 Synthesis and characterization
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6
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Figure 2. Schematic representation of the synthesis of the ligands. a) TBAF, CH3COOH, DMF / H2O, rt, 24 h; b) p-
toluenesulfonyl chloride, Et3N, CH2Cl2, 0 °C, 2 h; c) NaN3, 120 °C, 10 min (mw); d) 2-ethynyl-pyridine,
Cu(II)SO4
× 5H2O, sodium ascorbate, tert-BuOH / H2O, 60 °C, 25 min (mw); e) 1. NaOMe, CH3OH, rt, 24 h, 2.
DOWEX H+ to pH = 7; f) 2-ethynyl-pyridine, Cu(II)SO4
× 5H2O, sodium ascorbate, THF / H2O, 60 °C, 2 d; g) 2 M HCl,
EtOH/H2O, 1. 40 °C 12 h, 2. rt, 24 h.
9
10
11
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The aim was the synthesis of novel
D
-fructose derivatives substituted at C6. For modification of this
position of -fructose, sucrose was chosen as the starting molecule. Firstly,
D
D-fructose-moiety in sucrose
had to be modified selectively at the C6’ position (Fig. 2). Starting from acetylated and C6’-tert-butyl-
diphenl-silyl (TBDPS)-protected sucrose 1,[37, 38] the silylether was cleaved by a fluoride source. For this,
TBAF was used to form a hydroxyl group at C6’ to avoid HF or HF-pyridine as cleaving agent.[38] Due to
the migration and fluorolysis of the acetyl groups by using only TBAF, acetic acid was added to eliminate
these side reactions.[39] Following this procedure, the desired product 2 was obtained in moderate yield
16
(66%). Success of the reaction is shown by the disappearance of the tert-butyl (δ = 1.07 ppm) and the
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aromatic signals (δ = 7.30 to 7.78 ppm) in the 1H NMR spectrum as well as by the appearance of [M+Na]+
peak in the mass spectrum and the crystal structure (SI, Fig. S1 and S3). Reaction of mesylated sucrose
derivative[38] with NaN3 in DMF at 80 °C did not result in the desired product. Due to long reaction time,
poor yield and partial cleavage of protection groups, when applying 80°C in DMF, the route for the
synthesis of N3-functionalized sucrose was changed. Tosyl chloride was chosen to form tosylated sucrose
derivative 3 in quantitative yield. Appearance of signals in the 1H NMR at δ = 2.46 ppm (CH3) and δ = 7.36
to 7.8 ppm (phenyl moiety) as well as the [M+Na]+ signal in HR-MS (error: 3.4 ppm) proved the successful
introduction of the tosyl group (SI, Fig. S6 and S8). Reaction with an excess of sodium azide led to N3-
functionalized sucrose derivative 4 in quantitative yield. Disappearance of four tosyl-related peaks in the

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13C NMR (δ = 128 to 146 ppm and δ = 21.66 ppm) proved success of the reaction (SI, Fig. S12). Cu(I)-
catalyzed “click” reaction between sucrose-azide and 2-ethynyl-pyridine resulted in the sucrose derivative
5 with pyridyl triazole (pyta) functionality. Like for previously reported procedures,[38] microwave irradiation
of a mixture of tert-butanol and water as solvent and Cu(II)SO4 × 5H2O and sodium ascorbate as catalyst
3
4
1
5
forming pair offers a fast and easy approach for the synthesis. Triazole proton signal detected in H NMR
6
spectrum at δ = 8.26 ppm as well as [M+Na]+ signal in HR-MS (error: 0.3 ppm) confirms the structure of 5
(SI, Fig. S15 and S17). Standard deprotection procedure with NaOMe in methanol resulted in water
soluble pyta-functionalized sucrose 6 in quantitative yield. Cleavage of the acetyl groups was proven by
the disappearing of the signals in 1H NMR (δ = 2.01 to 2.18 ppm) and 13C NMR spectra
(δ = 20.48-20.67 ppm). Furthermore, the structure of the ligand was confirmed by the [M+Na]+ peak in HR-
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8
9
10
11
12
13
14
MS with an error of 4.0 ppm (SI, Fig. S20 to S22). To cleave off the
D-glucose, compound 6 was stirred
with 2M HCl at 40 °C in water for 12 h. Unfortunately, in this way only decomposition products were
observed. The alternative synthesis strategy was the cleavage of the
complex (Fig. 3).
D-glucose after conjugation to the Ru
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The synthesis of pyta-functionalized
azido-1-deoxy-2,3:4,5-di-O-isopropylidene-β-
azido-fructose 7 and 2-ethynyl-pyridine resulted in the pyta- conjugated
D
-fructose via C1 was utilized in a two-step synthesis started from 1-
-fructopyranose.[40] Cu(I)-catalyzed “click” reaction between
-fructose derivative 8 in high
D
D
yield (92%). Success of the reaction is proven by the appearance of signals in the aromatic region in the
1H NMR spectrum, which correspond to the triazole and pyridine protons (SI, Fig. S25). Additionally, the
[M+H]+ signal in the HR-MS spectrum (error: 0.3 ppm) confirms the structure of the desired compound (SI,
Fig. S27). Acidic cleavage of the isopropylidene groups of sugar 8 was performed by stirring with 2 M HCl
in the presence of water. The crude product was extracted with dry acetonitrile to remove most of the
NaCl, which was formed by neutralization with aqueous NaHCO3 solution. Disappearance of signals
related to isopropylidene groups in 1H NMR (δ = 0.87-1.50 ppm) as well as in 13C NMR spectra
(δ = 109.31 to 109.52 ppm and 24.05 to 26.35 ppm) and the [M+H]+ signal in HR-MS (error: 2.5 ppm)
confirm the formation of the desired compound 9 (SI, Fig. S30 to S32).
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Ligands 6, 9 and 10 were reacted with Ru(bpy)2Cl2 to form complexes of the general formula
[Ru(bpy)2(L)]Cl2 (Fig. 3), which are soluble in water, methanol and polar solvents.
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Figure 3. Schematic representation of the complex syntheses. a) Ru(bpy)2Cl2, Et3N, CH3OH, 60 °C, 12 h; b) 2 M HCl,
H2O, 40 °C, 16 h; c) Ru(bpy)2Cl2, DMF, 125 °C, 2 h (mw); d) Ru(bpy)2Cl2, CH3OH, 60 °C, 12 h.
4
5
Complexation reaction of 6 with Ru(bpy)2Cl2 was carried out in CH3OH at 60 °C and resulted in complex
11 in moderate yield. Triethylamine was added to avoid partial cleavage of D-glucose from the sucrose
6
ligand. Due to the charged character of the formed complex, a size exclusion column (Sephadex LH-20 in
H2O) was used to purify compound 11. Aromatic signals, which belong to the bpy-ligands of the complex,
appear in 1H (δ = 7 to 9 ppm) and 13C NMR spectra (δ = 120 to 160 ppm). Additionally, another signal with
7
8
1
9
the same intensity is appearing for each signal in H as well as in 13C NMR spectra, indicating the
10
existence of λ- and ∆-isomers (Fig. 4).
11
1
12
13
Figure 4. Details of A) 1H NMR spectrum of compound 11 in D2O; B) H NMR spectrum of compound 12 in D2O; C)
13C NMR spectrum of compound 11 in D2O; D) 13C NMR spectrum of compound 12 in D2O.
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Furthermore, the structure of complex 11 was proven by HR-MS as [M-2Cl]2+ with an error of 2.9 ppm (SI,
Fig. S36 to S38). Stirring at pH = 2 in water for 16 h at 40 °C resulted in the
D-fructose conjugated Ru
complex 12 via C6 in high yield. The structure of the desired complex was confirmed by the

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disappearance of the
D
-glucose-related signals by 1H NMR (δ = 5.23 ppm and δ = 4.99 ppm) as well as by
HR-MS as [M-2Cl]2+ with an error of 1.9 ppm (SI, Fig. S42 and S44). Due to the cleavage of the
unit, the C2 position of the -fructose moiety is changed from full to semi acetal structure. This results in
the existence of stereoisomers of the -fructose, in particular the - and -fructofuranose and the open-
D-glucose
D
D
α
β-D
chained form, which is clearly visible in the appearance of additional signals in the 13C NMR spectrum
between 60 and 85 ppm, when measured in deuterated water (SI, Fig. S43). Those results are in
accordance to literature, where various
NMR.[14, 19]
D-fructose conjugated compounds revealed this behavior in
9
10
11
12
The reaction of 9 with Ru(bpy)2Cl2 in a similar manner to that of sucrose complex 11 was not satisfying
due to long reaction time (> 1 week) and formation of side products. Hence, complexation reaction of 9
was carried out in DMF at 125 °C for 2 h under microwave irradiation. After purification via size exclusion
column (Sephadex LH-20, water), complex 13 was obtained in moderate yield and high purity. Next to the
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product signal in HR-MS ([M-2Cl]2+
,
error: 0.2 ppm), additional signals in H NMR as well as in 13C NMR
spectra in the aromatic region in comparison to spectra of ligand 9 prove the successful formation of the
desired complex (SI, Fig. S48, S50 and S51). The appearance of various signals between δ = 9.3 ppm
and 9.7 ppm for the triazole proton of the pyta ligand (H-5ta) in 1H NMR spectrum showed the presence of
different forms of the
compound 13, when dissolved in deuterated DMSO, an approximate amount of 37.5% β-
27% β- -fructofuranose, 27% -fructofuranose and 8.5% of the open-chain -fructose was detected by
D
-fructose in solution and the existence of λ- and
∆-isomers (SI, Fig. S49). For
D-fructopyranose,
D
α
-
D
D
1H measurements. The equilibrium between the different forms is strongly dependent from pH,
temperature, solvent, presence of salts and others.[41-43]
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Since the rhenium (I) tricarbonyl complex of ligand 10 exhibited remarkable cytotoxicity in HepG2 cells,[36]
the corresponding Ru complex of 10 was synthesized. Complex 14 was prepared and purified in a similar
manner to that of sucrose complex 11. Success of the reaction is shown by the appearance of signals in
1H NMR as well as in 13C NMR spectrum, which belong to bipyridine groups of the complex (SI, Fig. S55
and S56).
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The absorbance and emission spectra of all compounds were measured in aerated methanol and are
summarized in the supporting information (Table S1). The absorption bands of compounds 5, 6, 8 and 9 at
λmax = 280 nm were associated with π→π* transitions of the ligands. For the Ru complexes 11 to 14 an
additional absorption maximum at around λmax = 440 nm was observed, which fits to the metal to ligand
charge transfer (MLCT) transition. The complexes revealed fluorescence in the visible region at around
λmax = 600 nm and when excited by about λex = 440 nm.
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Additionally, dynamic light scattering (DLS) experiments were conducted and revealed the formation of
particles with average sizes of 500 ± 37 nm (PDI = 0.146) for complex 14 dissolved in water, whereas for
all other complexes no well-defined correlation function was observable, indicating no particle formation.

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2.2 Cytotoxicity and cell-type dependent uptake studies
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To investigate the compounds regarding their cytotoxicity, non-cancerous cell line L929 and breast cancer
cell lines MCF-7 and MDA-MB-231 were treated with ligands 6, 9 and 10 and metal complexes 11 to 14 at
varying concentrations for 24 h in serum-containing media. As expected, none of the tested compounds
revealed significant cytotoxicity for the tested cell lines using these conditions (SI, Fig. S61 to S63).
6
7
Since studies showed an enhanced uptake of D-fructose conjugated metal complexes into breast cancer
cells,[17, 18] complexes 11 to 14 were also tested for their uptake behavior using flow cytometry and live-
cell CLSM (SI, Fig. S64 and S65). As also previously reported,[19, 44] the fluorescence of these kind of
complexes was quenched in aqueous media and therefore, no meaningful results regarding their uptake
could be obtained by these measurements (SI, Fig S60). To quantify the uptake of the complexes into
cells ICP-MS experiments were performed (SI, Fig. S66). ICP-MS revealed an increased, unspecific
uptake of sugar-free complex 14 in comparison to the other complexes into all tested cell lines. This might
be attributed to its decreased hydrophilicity and therefore, to the elevated diffusion through the cell
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membrane. The uptake of
D-fructose conjugated complexes 12 and 13 into breast cancer cell lines MDA-
MB-231 and MCF-7 was not significantly increased in comparison to sucrose bearing complex 11. In
contrast to other studies,[17, 18] the results here show that for this type of
complexes an enhanced GLUT5 mediated uptake is not observable.
D-fructose substituted metal
18
3. Conclusion
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In this work we presented the modification of sucrose in a seven step synthesis to modify the C6 position
of the -fructose unit exclusively with a pyridyl triazole (pyta) group. The -glucose unit acts as protection
group of the -fructofuranose. Using this approach, C6-modified -fructose derivatives are accessible in
high yields, since up to now -fructose derivatives were modified exclusively at the C1 or C3 position.
Additionally, pyridyl triazole modified -fructose via C1 was prepared in four-step synthesis, starting from
commercially available isopropylidene-protected -fructose. For both pyridyl triazole -fructose derivatives
D
D
D
D
D
D
D
D
as well as for pyta sucrose, Ru complexes of the general formula [Ru(bpy)2(L)]Cl2 were prepared. All
compounds were analyzed by Rf values, specific rotation, 1H NMR and 13C NMR, IR, UV/Vis and
fluorescence spectroscopy, mass spectrometry as well as by elemental analysis. No cytotoxic effects
could be detected for concentrations up to 100 µmol × mL-1 against L929, MDA-MB-231 or MCF-7 cells.
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4. Experimental part
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4.1 Materials and general experimental details: All reagents and solvents were commercial products
purchased from Sigma-Aldrich, Fluka, Across Organics, Strem, VWR or Alfa Aesar and were used without
further purification. Chromatographic separations were performed with NP silica RediSep Cartridges from
Teledyne Isco. The progress of the reactions was monitored by thin-layer chromatography (TLC) using
glass plates precoated with silica gel 60 (Merck). Microwave-assisted syntheses were performed in a
Initiator Sixty single-mode microwave synthesizer from Biotage equipped with a noninvasive IR sensor.

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FT-IR measurements were conducted utilizing a Brewster angle setup. Samples were prepared on clean
double side polished silicon wafers (p-type silicon wafers (100), resistivity 10 to 20 Ω cm obtained from
Siegert Wafer). Samples were dropcasted onto the wafer and the solvent was allowed to dry. Spectra
were obtained at a resolution of 4 cm-1 and 32 spectra were measured for each sample for averaging
purposes. Spectra were baseline corrected by the Bruker analysis software OPUS 5.5. The alamarBlue
solution for cytotoxicity studies was purchased from Thermo Fisher. Cell cultivation was performed at 37
°C in a humidified 5% CO2 atmosphere. L929 (CCL-1, ATCC), MDA-MB231 (HTB-26, ATCC) and MCF-
7(ATCC) cells were cultured in Dulbecco’s MEM (DMEM, Biochrom) supplemented with 10% fetal calf
serum (FCS, Capricorn Scientific), 100 µg mL-1 streptomycin and 100 IU mL-1 penicillin (Biochrom, Merck).
HUVEC cells were kindly provided by the Institute of Biochemistry, Friedrich Schiller University, group of
Prof. Mosig. Consumables for cell culture, like pipettes and cell culture plates (96-well) were obtained from
Corning (USA) and Greiner Bio-one (Austria/ Germany). Crystallographic data were corrected for Lorentz
and polarization effects; absorption was taken into account on a semi-empirical basis using multiple-
scans[45, 46] The structures were solved by direct methods (SHELXS) and refined by full-matrix least squares
techniques against Fo2 (SHELXL-97).[47] All hydrogen atoms (with exception of the methylene group of C23
from compound 3) were located by difference Fourier synthesis and refined isotropically. The hydrogen atoms
of the methylene group were included at calculated positions with fixed thermal parameters. All non-hydrogen
atoms were refined anisotropically.[47] Crystallographic data as well as structure solution and refinement
details are summarized in Table S2. MERCURY was used for structure representations.[48] Dynamic light
scattering experiments were carried out at 25 °C (λ = 633 nm) after an equilibration time of 120 s. The counts
were detected at an angle of 173°. Each measurement was performed in triplicate. The mean particle size
was approximated as the effective (Z-average) diameter and the width of the distribution as the polydispersity
index of the particles (PDI) obtained by the cumulants method assuming a spherical shape of the particles.
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4.2 Instrumentation: H NMR and 13C NMR spectra were measured with Bruker spectrometers (600,
500, 300 and 250 MHz). IR spectra were recorded with a Bruker Tensor 37 FT-IR spectrometer. UV/Vis
absorption spectra were measured with an AnalytikJenaAG Specord250 spectrometer and fluorescence
was recorded with a Jasco FP 6500 (298K, methanol, 10-5 M solutions). High Resolution electron spray
ionization mass spectrometry (HR-ESI-MS) was measured with a Bruker MicroQTof. Elemental analysis
was performed with a Leco CHN-932. The alamarBlue cell viability assay (Thermo Fisher) was performed
with an Infinite M200 PRO microplate reader (Tecan) according to supplier’s instructions. Specific rotation
was measured in a Jasco P-2000 polarimeter. Crystallographic data was collected on a Nonius KappaCCD
diffractometer using graphite-monochromated Mo-Kα radiation. For the uptake studies of HUVEC, MCF-7
and MDA-MB-231 cells a flow cytometer (Cytomics FC 500; Beckman Coulter, Krefeld, Germany) and a
confocal laser scanning microscope ELYRA PS1 LSM880 (Carl Zeiss, Jena, Germany) were used (see
below). ICP-MS measurements were performed using a XSeriesII (Thermo Fisher). Dynamic light
scattering was performed on a Zetasizer Nano ZS (Malvern Instruments, Herrenberg, Germany).
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4.3 Synthesis of the ligands

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4.3.1 6’-O-tert-Butyldiphenylsilyl-1’,2,3,3’,4,4’,6-hepta-O-acetyl-sucrose (1). Silylated sucrose
derivative was synthesized according to literature procedures.[37, 38]
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4.3.2 1’,2,3,3’,4,4’,6-Hepta-O-acetyl-sucrose (2). 19 g (21.72 mmol) of 1 were dissolved in 380 mL DMF
and a solution of 5.679 g (21.72 mmol) TBAF and 1.242 mL (21.72 mmol) CH3COOH in 27 mL H2O was
added dropwise. The reaction mixture was stirred for 24 h at room temperature. After TLC (SiO2,
EtOAc:n-hexane, v/v 2:1) indicated that no silylated sucrose was left, the solvent was evaporated. The
crude product was re-dissolved in 300 mL EtOAc, washed thrice with brine and the organic layer was
dried with Na2SO4. Purification by column chromatography (SiO2, EtOAc:n-hexane, v/v 2:1) resulted in
9.165 g (14.40 mmol) of a colorless oil. Yield: 66%. Crystals were obtained by slow diffusion of n-hexane
in a solution of the ligand in CHCl3. Rf 0.75 (SiO2, EtOAc); [α]20D = +139.8 (c 0.1, CHCl3); IR: ꢀꢁ = 2961
(ꢀꢂꢃ), 1749 (ꢀꢂꢄ) cm-1; 1H NMR (300 MHz, CDCl3): δ 5.66 (s, 1H, H-1), 5.48-5.37 (m, 3H, H-4, H-3, H-3’),
5.10 (t, 1H, J3 9.51 Hz, H-5), 4.87 (d, 1H, J3 10.41 Hz, H-2), 4.26-4.03 (m, 6H, H-6, H-1’, H-4’, H-5’), 3.84
(dd, 2H, J2 12.81 Hz, H-6’), 2.16-1.99 (m, 21H, H-Ac). 13C NMR (75 MHz, CDCl3): δ 170.68-169.47 (CO),
103.3 (C-2’), 90.07 (C-1), 81.64 (C-1’), 76.11 (C-3), 73.66 (C-3’), 70.25 (C-2), 69.37 (C-4), 68.74 (C-6),
67.96 (C-5), 63.89 (C-5’), 61.41 (C-4’), 61.14 (C-6’), 20.73-20.55 (CH3). Calcd. for C26H36O18
(636.56 g × mol-1): C, 49.06; H, 5.70. Found: C, 49.23; H, 5.71. ESI-MS found [2M+K]+ (7.5%) 1311.32,
[2M+Na]+ (33.6%) 1295.35, [M+K]+ (71.9%) 675.15, [M+Na]+ (100%) 659.18.
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4.3.3 1’,2,3,3’,4,4’,6-Hepta-O-acetyl-6’-O-tosyl-sucrose (3). 7.35 g (10.99 mmol) of 2 were dissolved in
60 mL dry CH2Cl2, 8 mL (57.71 mmol) of Et3N were added and a solution of 2.39 g (12.54 mmol) p-
toluenesulfonyl chloride in 20 mL dry CH2Cl2 was added dropwise at 0 °C under Ar. After 2 h stirring at
room temperature, TLC (SiO2, EtOAc:n-hexane, v/v 2:1) indicated that no starting material remained. The
solution was washed thrice with saturated, aqueous NaHCO3 solution, dried with Na2SO4 and purified by
column chromatography (SiO2, EtOAc:n-hexane, v/v 2:1) to obtain 8.8 g (11.13 mmol) of a colorless oil.
Yield: 96%. Crystals were obtained by slow diffusion of n-hexane into a solution of the ligand in CHCl3.
Rf 0.23 (SiO2, EtOAc:n-hexane, v/v, 1:1); [α]20D = +168.2 (c 0.1, CHCl3); IR: ꢀꢁ = 1751 (ꢀꢂꢄ), 820 (δ CH) cm-
1; 1H NMR (600 MHz, CDCl3): δ 7.80 (d, 2H, J3 8.22 Hz, H-2’’), 7.36 (d, 2H, J3 8.28 Hz, H-3’’), 5.42 (d, 1H,
J3 6.12 Hz, H-1), 5.39-5.36 (m, 2H, H-3’, H-3), 5.22 (t, 1H, J3 5.82 Hz, H-4’), 4.98 (t, 1H, J3 9.90 Hz, H-4),
4.79 (dd, 1H, J3 10.44 Hz, 3.60 Hz, H-2), 4.32-4.19 (m, 4H, H-5, H-6, H-1’), 4.11-4.03 (m, 4H, H-5’, H-1’,
H-6’), 2.46 (s, 3H, H-5’’), 2.13-2.00 (m, 21H, H-Ac). 13C NMR (100 MHz, CDCl3): δ 170.69-169.58 (CO),
145.18 (C-1’’), 132.66 (C-4’’), 129.94 (C-3’’), 128.08 (C-2’’), 103.86 (C-2’), 89.85 (C-1), 78.81 (C-1’), 75.23
(C-3), 74.78 (C-3’), 70.03 (C-2), 69.47 (C-4), 69.33 (C-6), 68.47 (C-5), 68.26 (C-5’), 62.53 (C-4’), 62.23 (C-
6’), 21.66 (C-5’’), 20.67-20.45 (CH3). Calcd. for C33H42O20S (790.74 g × mol-1): C, 50.12; H, 5.35; S, 4.06.
Found: C, 50.29; H, 5.38; S, 4.16. HR-ESI-MS m/z calcd. for C33H42O20SNa [M+Na]+: 813.1882; found:
813.1855 (error: 3.4 ppm).
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4.3.4 1’,2,3,3’,4,4’,6-Hepta-O-acetyl-6’-azido-6’-deoxy-sucrose (4). 5.673 g (7.17 mmol) of 3 were
dissolved in 10 mL DMF, 2.8 g (43.07 mmol) of NaN3 were added and the suspension was stirred for
10 min in the microwave at 120 °C. After cooling to room temperature the solvent was removed and the

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crude product re-dissolved in 200 mL EtOAc. The organic layer was washed thrice with saturated,
aqueous NaHCO3 solution, dried with Na2SO4 and purified by column chromatography (SiO2, EtOAc:n-
hexane, v/v 3:2) to obtain 4.704 g (7.11 mmol) of a colorless oil. Yield: 99%. Rf 0.32 (SiO2, EtOAc:n-
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hexane, v/v, 1:1); [α]20D = +108 (c 0.1, CHCl3); IR: ꢀꢁ = 2104 (ꢀꢅꢆꢇꢈꢉ), 1753 (ꢀꢂꢄ) cm-1; H NMR (300 MHz,
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CDCl3): δ 5.63 (d, 1H, J3 3.60 Hz, H-1), 5.50-5.43 (m, 2H, H-3’, H-3), 5.31 (t, 1H, J3 6.17 Hz, H-4’), 5.09 (t,
1H, J3 9.80 Hz, H-4), 4.91 (dd, 1H, J3 10.41 Hz, 3.63 Hz, H-2), 4.31-4.10 (m, 6H, H-5, H-6, H-5’, H-1’),
3.74-3.47 (m, 2H, H-6’), 2.16-2.01 (m, 21H, H-Ac). 13C NMR (75 MHz, CDCl3): δ 170.67-169.56 (CO),
103.89 (C-2’), 90.35 (C-1), 80.15 (C-5’), 75.73 (C-3’, C-4’), 70.20 (C-2), 69.42 (C-3), 68.56 (C-5), 68.24
(C-4), 62.73 (C-1’), 61.99 (C-6), 52.88 (C-6’), 20.70-20.48 (CH3). Calcd. for C33H42O20S (661.57 g × mol-1):
C, 47.20; H, 5.33; N, 6.35. Found: C, 47.49; H, 5.37; N, 5.96. ESI-MS found [M+K]+ (26.9%) 700.16,
[M+Na]+ (100%) 684.18.
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4.3.5 1’,2,3,3’,4,4’,6-Hepta-O-acetyl-6’-deoxy-6’-(4-(2-pyridyl)-1,2,3-triazole-1-yl) sucrose (5). 4.704 g
(7.11 mmol) of 4 and 1.077 mL (10.7 mmol) 2-ethynyl-pyridine were dissolved in 5 mL degassed tert-
butanol under Ar. 585 mg (2.95 mmol) of sodium ascorbate and 383 mg (1.53 mmol) of Cu(II)SO4 × 5H2O
in each 2.5 mL degassed H2O were added and the mixture was heated at 60 °C for 25 min under
microwave irradiation. After TLC (SiO2, EtOAc:n-hexane, v/v 1:1) indicated that no starting material
remained, the solvent was evaporated and the crude product was re-dissolved in 250 mL of EtOAc and
washed thrice with each 100 mL of aqueous ammonia solution (25%) and once with 200 mL brine. The
organic layer was dried with Na2SO4 and purified by column chromatography (SiO2, EtOAc) to obtain
4.493 g (5.88 mmol) of a colorless oil. Yield: 83%. Rf 0.57 (SiO2, EtOAc); [α]20D = +119.8 (c 0.1, CHCl3);
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UV-Vis: λ (CH3OH, ε × 10-3 / M-1 cm-1): 280 (14.97) nm; IR: ꢀꢁ = 1751 (ꢀꢂꢄ) cm-1. H NMR (300 MHz,
CDCl3): δ 8.58 (d, 1H, J3 4.29 Hz, H-6py), 8.26 (s, 1H, H-5ta), 8.17 (d, 1H, J3 7.92 Hz, H-3py), 7.80 (t, 1H,
J3 7.74 Hz, H-4py), 7.25 (m, 1H, H-5py), 5.65 (d, 1H, J3 3.54 Hz, H-1), 5.56-5.41 (m, 3H, H-3’, H-3, H-4),
5.08 (t, 1H, J3 9.86 Hz, H-4’), 4.97-4.75 (m, 3H, H-2, H-6), 4.54-4.49 (m, 1H, H-5), 4.35-4.29 (m, 1H, H-5’),
4.25-3.93 (m, 4H, H-1’, H-6’), 2.18-2.01 (m, 21H, H-Ac). 13C NMR (75 MHz, CDCl3): δ 170.51-169.53
(CO), 150.00 (C-6py), 149.31 (C-2py), 148.37 (C-4ta), 137.00 (C-5py), 123.33 (C-5ta), 122.94 (C-3py), 120.34
(C-4py), 103.79 (C-2’), 90.26 (C-1), 79.53 (C-5’), 75.51 (C-3), 74.93 (C-3’), 69.94 (C-2), 69.35 (C-4’), 69.04
(C-5), 68.32 (C-4), 62.63 (C-1’), 62.31 (C-6), 53.04 (C-6’), 20.67-20.48 (CH3). Calcd. for C33H40N4O17
(764.69 g × mol-1): C, 51.83; H, 5.27; N, 7.33. Found: C, 51.96; H, 5.43; N, 7.16. HR-ESI-MS m/z calcd.
for C33H40N4O17Na [M+Na]+: 787.2281; found: 787.2278 (error: 0.3 ppm).
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4.3.6 6’-Deoxy-6’-(4-(2-pyridyl)-1,2,3-triazole-1-yl) sucrose (6). 4.493 g (5.88 mmol) of 5 were dissolved
in 100 mL dry CH3OH and 76.4 mL of a 0.5 M NaOMe solution (38.2 mmol) in CH3OH were slowly added
under argon. The mixture was stirred for 24 h at room temperature and Amberlite IR-120 (H+) resin was
added until the pH value changed to 7. The resin was filtered, washed with CH3OH and the solvent was
evaporated. The crude product was re-dissolved in water and washed thrice with CHCl3. Then, the
aqueous layer was freeze-dried to obtain 2.72 g (5.78 mmol) of a colorless oil. Yield: 98%. Rf 0.22 (SiO2,
CH3CN:H2O:KNO3(aq), v/v, 40:4:1); [α]20D = +69.6 (c 0.1, CH3OH); UV-Vis: λ (CH3OH, ε × 10-3 / M-1 cm-1):

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281 (13.19) nm. IR: ꢀꢁ = 3333 (ꢀꢄꢃ) cm-1. H NMR (300 MHz, CDCl3): δ 8.45-8.08 (m, 2H, H-5ta, H-6py),
7.85-7.57 (m, 2H, H-3py, H-4py), 7.22 (s, 1H, H-5py), 5.32 (d, 1H, J3 3.60 Hz, H-1), 4.8-4.6 (m, 2H, H-3, H-
4), 4.19-4.00 (m, 3H, H-4’, H-6), 3.86-3.40 (m, 7H, H-5, H-1’, H-3’, H-5’, H-6’), 3.31 (t, 1H, J3 9.45 Hz, H-
2). 13C NMR (75 MHz, CDCl3): δ 148.91 (C-2py), 144.68 (C-6py), 138.39 (C-3py, C-4py, C-5py), 124.46 (C-4ta,
C-5ta), 104.05 (C-2’), 92.22 (C-1), 79.02 (C-5’), 76.19 (C-3), 75.60 (C-3’), 72.77 (C-2), 72.53 (C-4’), 70.99
(C-5), 69.48 (C-4), 61.14 (C-1’), 60.61 (C-6), 52.98 (C-6’). Calcd. for C19H26N4O10 × 2.5 H2O
(515.48 g × mol-1): C, 44.27; H, 6.06; N, 10.87. Found: C, 44.44; H, 5.77; N, 10.84. HR-ESI-MS m/z calcd.
for C19H26N4O10Na [M+Na]+: 493.1501; found: 493.1481 (error: 4.0 ppm).
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4.3.7 1-Azido-1-deoxy-2,3:4,5-di-O-isopropylidene-β-D-fructopyranose (7). The azide was synthesized
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as previously reported.[40]
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4.3.8 1-(4-(2-Pyridyl)-1,2,3-triazole-1-yl)-1-deoxy-2,3:4,5-di-O-isopropylidene-β-D-fructopyranose (8).
6.777 g (23.8 mmol) of 7 and 2.88 mL of 2-ethynyl pyridine (28.5 mmol) were dissolved in 100 mL
degassed THF. 471 mg (2.4 mmol) of sodium ascorbate and 297 mg (1.2 mmol) of Cu(II)SO4 × 5H2O in
each 5 mL degassed H2O were added and the mixture was heated to 60 °C for two days. After TLC (SiO2,
EtOAc:n-hexane, v/v 1:2) indicated that no starting material remained, the solvent was evaporated and the
crude product was re-dissolved in 300 mL EtOAc and washed thrice with each 100 mL of aqueous
ammonia solution (25%) and once with 200 mL of brine. The organic layer was dried with Na2SO4, filtered
and the solvent was evaporated. The crude product was re-crystallized from a mixture of EtOAc and n-
hexane (EtOAc:n-hexane, v/v 1:4) to obtain 8.521 g (5.88 mmol) of a colorless oil. Yield: 92%. Rf 0.22
(SiO2, EtOAc:n-hexane, v/v, 1:1); [α]20D = +42 (c 0.1, CHCl3); UV-Vis: λ (CH3OH, ε × 10-3 / M-1 cm-1): 279
(8.90); 238 (14.79) nm. IR: ꢀꢁ = 3159 (ꢀꢊꢂꢃ); 1605 (ꢀꢂꢊꢂ); 1421 (ꢋꢊꢂꢃ); 1045 (ꢋꢊꢂꢃ); 1011 (ꢋꢊꢂꢃ); 980
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(ꢋꢊꢂꢃ) cm-1. H NMR (300 MHz, CDCl3): δ 8.60 (d, 1H, J3 4.80 Hz, H-6py), 8.30 (s, 1H, H-5ta), 8.19 (d, 1H,
J3 7.96 Hz, H-3py), 7.80 (td, 1H, J3 1.68 Hz, 1H, H-4py), 7.24 (m, 1H, H-5py), 4.81 (d, 1H, J2 14,31 Hz, H-1),
4.68-4.60 (m, 2H, H-4, H-1), 4.52 (d, 1H, J3 2.73 Hz, H-3), 4.27 (m, 1H, H-5), 3.95-3.78 (m, 2H, H-6),
1.50-0.87 (4s, 12H, CH3). 13C NMR (75 MHz, CDCl3): δ 150.32 (C-6py), 149.40 (C-2py), 148.16 (C-4ta),
136.81 (C-4py), 124.80 (C-5ta), 122.77 (C-5py), 120.29 (C-3py), 109.52 (Cq), 109.31 (Cq), 100.81 (C-2),
70.78 (C-3), 70.58 (C-5), 70.11 (C-4), 61.89 (C-6), 55.34 (C-1), 26.35-24.05 (CH3). Calcd. for C33H40N4O17
(388.42 g × mol-1): C, 58.75; H, 6.23; N, 14.42. Found: C, 58.80; H, 6.27; N, 14.46. HR-ESI-MS m/z calcd.
for C19H25N4O5 [M+H]+: 389.1819; found: 389.1818 (error: 0.3 ppm).
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4.3.9 1-(4-(2-Pyridyl)-1,2,3-triazole-1-yl)-1-deoxy-β-D-fructopyranose (9). 515 mg of 8 (1.33 mmol)
were dissolved in 10 mL of ethanol and 5 mL of an aqueous 2 M HCl solution were added slowly. After
10 mL of water were added, the solution was heated to 40 °C for 12 h and stirred at rt for additional 24 h.
After TLC (SiO2, EtOAc) indicated that no starting material remained, the solution was neutralized with
NaHCO3 and lyophilized. The crude residue was thrice suspended in 100 mL of dry acetonitrile and
filtered. The organic layers were combined and the solvent was evaporated to obtain 360 mg (1.17 mmol)
of a colorless oil. Yield: 88%. Rf 0.42 (SiO2, CH3CN:H2O:KNO3(aq), v/v, 40:4:1); [α]20D = -24 (c 0.1, CH3OH);

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UV-Vis: λ (CH3OH, ε × 10-3 / M-1 cm-1): 280 (36.38); 240 (57.27) nm. IR: ꢀꢁ = 3537 (ꢀꢄꢃ), 3493 (ꢀꢄꢃ), 3360
(ꢀꢄꢃ), 3176 (ꢀꢄꢃ) cm-1. 1H NMR (250 MHz, DMSO-d6): δ 8.60 (d, 1H, J3 2.04 Hz, H-6py), 8.51-8.37 (m, 1H,
H-5ta), 8.05 (d, 1H, J3 8.04 Hz, H-3py), 7.92 (t, 1H, J3 7.69 Hz, H-4py), 7.35 (t, 1H, J3 5.80 Hz, H-5py),
6.22-4.75 (m, 4H, 2-OH, 3-OH, 4-OH, 5-OH), 4.68-4.41 (m, 2H, H-1), 3.91-3.35 (m, 5H, H-3, H-4, H-5, H-
6). 13C NMR (75 MHz, DMSO-d6): δ 150.67 (C-2py), 150.60 (C-2py), 150.48 (C-2py), 150.04 (C-6py), 150.01
(C-6py), 147.38 (C-4ta), 147.26 (C-4ta), 147.17 (C-4ta), 137.64 (C-4py), 137.61 (C-4py), 124.77 (C-5ta),
124.67 (C-5ta), 124.62 (C-5ta), 123.36 (C-5py), 123.27 (C-5py), 123.23 (C-5py), 119.81 (C-3py), 119.77 (C-
3py), 103.19 (C-2), 100.67 (C-2), 97.17 (C-2), 96.60 (C-2), 83.09 (C-3), 82.75 (C-3), 82.53 (C-3), 77.50 (C-
5), 76.58 (C-5), 75.16 (C-5), 69.98 (C-4), 69.20 (C-4), 68.78 (C-4), 64.24 (C-6), 63.10 (C-6), 61.69 (C-6),
55.22 (C-1), 54.78 (C-1), 54.61 (C-1). Calcd. for C13H16N4O5 (308.29 g × mol-1): C, 50.65; H, 5.23; N,
18.17; found: C, 50.37; H, 5.15; N, 18.15. HR-ESI-MS m/z calcd. for C13H17N4O5 [M+H]+: 309.1193; found:
309.1186 (error: 2.5 ppm).
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4.3.10 2-(1-(4-(tert-Butyl)benzyl)-1H-1,2,3-triazole-4-yl)pyridine (10). The ligand was synthesized like
previously reported.[49] Crystals were obtained by slow diffusion of n-hexane into a solution of the ligand in
CHCl3.
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4.4 Synthesis of the complexes
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4.4.1 6’-Deoxy-6’-(4-(2-pyridyl)-1,2,3-triazole-1-yl) sucrose bis(2,2’-bipyridine) ruthenium(II)
dichloride (11). To a solution of 200 mg (0.43 mmol) of 6 in 25 mL CH3OH, 206 mg (0.43 mmol) of
Ru(bpy)2Cl2 in 25 mL CH3OH and 60 µL (0.43 mmol) Et3N were added. The mixture was stirred for 12 h at
60 °C. After cooling to room temperature the mixture was concentrated and was purified by a sephadex
LH-20 column in H2O to obtain 198 mg (0.25 mmol) of a red oil. Yield: 58%. Rf 0.1 (SiO2,
CH3CN:H2O:KNO3(aq), v/v, 40:4:1); [α]20D = +60.2 (c 0.1, CH3OH); UV-Vis: λ (CH3OH, ε × 10-3 / M-1 cm-1):
444 (11.97), 287 (54.07) nm. Fluorescence (CH3OH, λex = 444 nm): λem = 599 nm. IR: ꢀꢁ = 3343 (ꢀꢄꢃ), 1643
(ꢀꢂꢊꢌ) cm-1. 1H NMR (300 MHz, D2O): δ 8.81 (m, 2H, H-5ta), 8.43 (m, 8H, H-3bpy, H-3’bpy), 8.08 (m, 2H, H-
6py), 7.96-7.71 (m, 18H, H-3py, H-4bpy, H-4’bpy, H-6bpy, H-6’bpy), 7.62 (m, 2H, H-4py), 7.36-7.10 (m, 10H, H-
5py, H-5bpy, H-5’bpy), 5.23 (m, 1H, H-1), 4.99 (m, 1H, H-1), 4.11-3.14 (m, 26H, H-2, H-3, H-4, H-5, H-6, H-1’,
H-3’, H-4’, H-5’, H-6’). 13C NMR (125 MHz, D2O): δ 157.61-156.95 (C-2bpy, C-2’bpy), 152.04-151.43 (C-6py,
C-6’py), 150.59 (C-2py), 148.20 (C-6py), 148.17 (C-6py), 137.94 (C-4ta), 137.65-137.32 (C-4py, C-4bpy, C-
4’bpy), 127.16-125.65 (C-3py, C-3bpy, C-3’bpy), 123.94 (C-5ta),123.66-122.63 (C-5py, C-5bpy, C-5’bpy), 103.98
(C-2’), 103.83 (C-2’), 92.18 (C-1), 91.86 (C-1), 78.59 (C-5’), 78.47 (C-5’), 76.04 (C-3), 75.92 (C-3), 75.69
(C-3’), 75.63 (C-3’), 72.83 (C-2), 72.62 (C-2), 72.51 (C-4’), 72.44 (C-4’), 70.99 (C-5), 70.93 (C-5), 69.60
(C-4), 69.57 (C-4), 60.93 (C-1’), 60.87 (C-1’), 60.71 (C-6), 60.59 (C-6), 54.37 (C-6’), 54.26 (C-6’). HR-ESI-
MS m/z calcd. for C39H42N8O10Ru [M-2Cl]2+: 442.1028; Found: 442.1021 (error: 2.9).
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5
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4.4.2 6’-(4-(2-Pyridyl)-1,2,3-triazole-1-yl)-6’-deoxy-D-fructofuranose bis(2,2’-bipyridine) ruthenium(II)
dichloride (12). 118 mg (0.12 mmol) of 11 were dissolved in 40 mL H2O and 20 mL 2 M HCl were added
and the resulting mixture was stirred for 16 h at 40 °C. After TLC (SiO2, CH3CN:H2O:KNO3(aq), v/v, 40:4:1)
indicated that no starting material remained, the solution was neutralized with aqueous 2 M NaOH
solution. The solution was concentrated and purified by a Sephadex LH-20 column in H2O to obtain 50 mg
(0.06 mmol) of a red oil. Yield: 51%. Rf 0.14 (SiO2, CH3CN:H2O:KNO3(aq), v/v, 40:4:1); [α]20D = +39.2 (c 0.1,
CH3OH); UV-Vis: λ (CH3OH, ε × 10-3 / M-1 cm-1): 443 (12.26), 286 (56.24), 239 (31.20) nm. Fluorescence
(CH3OH, λex = 444 nm): λem = 600 nm. IR: ꢀꢁ = 3379 (ꢀꢄꢃ), 1607 (ꢀꢂꢊꢌ), 779 (δbpy) cm-1. 1H NMR (500 MHz,
D2O): δ 8.89 (m, 2H, H-5ta), 8.46-8.34 (m, 8H, H-3bpy, H-3’bpy), 8.1 (m, 2H, H-6py), 8.01-7.69 (m, 18H, H-3py,
3
H-4bpy, H-4’bpy, H-6bpy, H-6’bpy), 7.61 (t, J = 4.63 Hz, 2H, H-4py), 7.39-7.15 (m, 10H, H-5py, H-5bpy, H-5’bpy),
4.67-2.60 (m, 14H, H-1’, H-3’, H-4’, H-5’, H-6’). 13C NMR (125 MHz, D2O): δ 157.47-156.93 (C-2bpy, C-
2’bpy), 151.89-151.43 (C-6bpy, C-6’bpy), 150.62-150.56 (C-2py), 147.92 (C-6py), 147.88 (C-6py), 137.94 (C-
4ta), 137.72-137.31 (C-4py, C-4bpy, C-4’bpy), 127.31-126.47 (C-3py, C-3bpy, C-3’bpy), 125.65 (C-5ta),
123.96-122.66 (C-5py, C-5bpy, C-5’bpy), 105.12 (C-2’), 104.61 (C-2’), 102.15 (C-2’), 101.97 (C-2’), 81.26 (C-
5’), 81.11 (C-5’), 79.24 (C-3’), 78.42 (C-3’), 77.86 (C-5’), 77.68 (C-5’), 77.16 (C-4’), 76.60 (C-4’), 75.13 (C-
3’), 75.06 (C-3’), 74.64 (C-4’), 74.62 (C-4’), 62.86 (C-1’), 62.45 (C-1’), 62.27 (C-1’), 62.20 (C-1’), 53.50 (C-
6’), 52.71 (C-6’), 52.33 (C-6’), 46.66 (C-6’). HR-ESI-MS m/z calcd. for C33H32N8O5Ru [M-2Cl]2+: 361.0764;
found: 361.0775 (error: 1.9 ppm).

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4.4.3
1-(4-(2-Pyridyl)-1,2,3-triazole-1-yl)-1-deoxy-β-
D
-fructopyranose
bis(2,2’-bipyridine)
ruthenium(II) dichloride (13). 85 mg of 9 (0.28 mmol) and 134 mg of Ru(bpy)2Cl2 (0.28 mmol) were
dissolved in 15 mL DMF and were stirred at 125 °C for 2 h in the microwave. After cooling to room
temperature, the solvent was evaporated in vacuo. The crude product was redissolved in 3 mL of H2O,
filtered and was purified by a Sephadex LH-20 column in H2O to obtain 106 mg (0.13 mmol) of a red oil.
Yield: 48%. Rf 0.14 (SiO2, CH3CN:H2O:KNO3(aq), v/v, 40:4:1); [α]20D = -21 (c 0.1, CH3OH); UV-Vis: λ
(CH3OH, ε × 10-3 / M-1 cm-1): 440 (9.14); 285 (53.24); 240 (24.92) nm. Fluorescence (CH3OH, λex = 439
3
4
5
6
7
1
8
nm): λem = 604 nm. IR: ꢀꢁ = 3402 (ꢀꢄꢃ), 1603 (ꢀꢂꢊꢌ), 779 (δbpy) cm-1. H NMR (400 MHz, DMSO-d6):
9
δ 9.67-9.37 (m, 2H, H-5ta), 8.94-8.48 (m, 10H, H-6py, H-3bpy, H-3’bpy), 8.23-8.07 (m, 10H, H-3py, H-6bpy, H-
6’bpy), 7.91-7.39 (m, 20H, H-4py, H-5py, H-4bpy, H-4’bpy, H-5bpy, H-5’bpy), 6.55-6.18 (m, 2H, 3-OH), 5.98-5.67
(m, 2H, 5-OH), 5.46-5.34 (m, 4H, 5-OH, 4-OH), 5.11-4.99 (m, 2H, 4-OH), 4.96-4.68 (m, 2H, 2-OH),
4.69-4.33 (m, 4H, H-1), 4.02-3.21 (m, 10H, H-3, H-4, H-5, H-6). 13C NMR (75 MHz, CDCl3):
δ 157.74-157.08 (C-2bpy, C-2’bpy), 152.23-151.58 (C-6bpy, C-6’bpy), 151.29 (C-2py), 151.11 (C-2py), 147.19
10
11
12
13
14
15
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20
(C-6py), 147.07 (C-6py), 138.80 (C-4ta), 138.32-138.09 (C-4py, C-4bpy, C-4’bpy), 128.26-126.61 (C-3py, C-3bpy
,
C-3’bpy), 126.52 (C-5ta), 125.02 (C-5ta), 124.89-123.22 (C-5py, C-5bpy, C-5’bpy), 102.72 (C-2), 102.54 (C-2),
100.34 (C-2), 100.11 (C-2), 96.84 (C-2), 96.40 (C-2), 83.58 (C-3), 82.99 (C-3), 82.59 (C-3), 82.36 (C-3),
82.17 (C-3), 79.09 (C-5), 78.49 (C-5), 76.63 (C-5), 75.35 (C-5), 70.16 (C-4), 70.00 (C-4), 69.46 (C-4),
69.30 (C-4), 69.10 (C-4), 64.43 (C-6), 62.99 (C-6), 61.42 (C-6), 61.19 (C-6), 57.99 (C-1), 57.38 (C-1),
57.17 (C-1), 56.86 (C-1). HR-ESI-MS m/z calcd. for C33H32N8O5Ru [M-2Cl]2+: 361.0764; Found: 361.0769
(error: 0.2 ppm).
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4.4.4 2-(1-(4-(tert-Butyl)benzyl)-1H-1,2,3-triazole-4-yl)pyridine bis(2,2’-bipyridine) ruthenium(II)
dichloride (14). 195 mg (0.40 mmol) of Ru(bpy)2Cl2 precursor complex were dissolved in 10 mL CH3OH
and 118 mg (0.40 mmol) of ligand 10 in 20 mL CH3OH were slowly added. The mixture was stirred for
12 h at 60 °C. After cooling to room temperature the mixture was concentrated and purified by a
Sephadex LH-20 column in CH3OH to obtain 262 mg (0.34 mmol) of a red oil. Yield: 85%. Rf 0.42 (SiO2,
CH3CN:H2O:KNO3(aq), v/v, 40:4:1); [α]20D = -7.2 (c 0.1, CH3OH); UV-Vis: λ (CH3OH, ε × 10-3 / M-1 cm-1): 443
(12.11); 287 (54.57) nm. Fluorescence (CH3OH, λex = 444 nm): λem = 600 nm. IR: ꢀꢁ = 1608 (ꢀꢂꢊꢌ), 777
1
(δbpy) cm-1. H NMR (500 MHz, DMF-d7): δ 10.05 (s, 1H, H-5ta), 9.16 (m, 2H,H-3bpy), 9.08 (m, 2H, H-3’bpy),
8.72 (d, 1H, J3 7.90 Hz, H-6py), 8.31 (m, 3H, H-4bpy, H-4’bpy), 8.24 (t, 1H, J3 3.43 Hz, H-4’bpy), 8.19 (m, 3H,
H-6bpy, H-6’bpy), 8.10 (d, 1H, J3 5.45 Hz, H-3py), 8.04 (t, 1H, J3 4.88 Hz, H-5py), 7.88 (d, 1H, J3 5.49 Hz, H-
6bpy), 7.68 (m, 3H, H-5bpy, H-4py), 7.60 (m, 1H, H-5’bpy), 7.53 (m, 1H, H-5’bpy), 7.40 (m, 2H, H-3Bn), 7.21 (m,
2H, H-2Bn), 5.89 (q, 2H, J3 24.01 Hz, CH2), 1.29 (s, 9H, CH3) ppm. 13C NMR (125 MHz, DMF-d7): δ 157.98
(C-2bpy), 157.62 (C-2bpy), 157.53 (C-4Bn), 157.28 (C-1Bn), 152.37 (C-5py), 152.29 (C-6bpy), 152.00 (C-3py),
151.79 (C-6bpy), 151.51 (C-2py), 151.16 (C-2’bpy), 148.07 (C-5ta), 138.46 (C-6’bpy), 138.07 (C-5py), 137.87
(C-4’bpy), 131.89 (C-4ta), 127.91 (C-4py), 127.84 (C-2Bn), 127.44, 127.16 (C-5’bpy), 126.28 (C-5’bpy), 125.81
(C-3Bn), 124.94 (C-5bpy), 124.89 (C-3bpy), 124.44 (C-3’bpy), 124.15 (C-3’bpy), 123.26 (C-6py), 54.85 (CH2),
48.78 (Cq), 30.80 (CH3).

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4.5 Biological studies
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3
4.5.1 Determination of cytotoxicity. Cytotoxicity studies were performed with L929, MCF-7 and MDA-
MB-231 cells. Cells were seeded at 104 cells per well in a 96-well plate and incubated for 24 h.
Afterwards, the test substances (6 and 9 to 14) at indicated concentrations (25, 50, 100 µmol L-1) were
added to the cells and the plates were incubated for further 24 h. Subsequently, the medium was replaced
by a mixture of fresh culture medium and alamarBlue solution (Thermo Fisher), prepared according to the
manufacturer’s instructions. After a further incubation of 4 h at 37 °C, the fluorescence was measured at
λex = 570 nm / λex = 610 nm, with untreated cells on the same well plate serving as negative controls. The
negative control was standardized as 0% of metabolism inhibition and referred as 100% viability. Data are
expressed as mean ± SD of three independent determinations.
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4.5.2 Uptake studies. HUVEC, MCF-7 and MDA-MB-231 cells were cultured as described above.
Subsequently, cells were seeded at a density of 105 cells per mL in 24-well plates and cultured for 24 h.
One hour prior to the addition of the complexes, the medium was replaced by fresh culture medium. The
plates were incubated for 1 h at 37 °C under 5% CO2 atmosphere. Metal complexes were added to the
cells at indicated concentrations for 1 h. Afterwards the cells were washed, harvested and 10% trypan
blue was added to quench the outer fluorescence of the cells. To determine the relative uptake of the
metal complexes, 10,000 cells were measured by flow cytometry using a Cytomics FC 500 (Beckman
Coulter). Dead cells were identified via counterstaining with propidium iodide. The experiments were
performed at least three times independently. Live cell imaging was additionally performed for uptake
studies. In detail, cells (105 cells mL-1) were seeded on glass-bottomed dishes (Greiner, Germany) and
cultivated for 24 h in a humidified atmosphere. One hour prior to the metal complex addition, the cells
were rinsed with phosphate buffered saline (PBS) and the medium was changed to fresh culture medium.
The metal complexes were added to the cells and incubated for one additional hour. Imaging was
performed with LSM880, ELYRA PS.1 system (Zeiss, Oberkochen, Germany) applying a 63× 1.4 NA plan
apochromat oil objective. The excitation wavelength was λex = 488 nm and the fluorescence was detected
from λ = 553 to 650 nm. Since the complexes showed no measurable fluorescence in aqueous media,
ICP-MS studies were performed. Cells were grown to 50% confluency in a 6-well plate. Unless specified,
the cells were incubated with the Ru complexes 11 to 14 (50 µM) in D-fructose-free medium at 37°C under
a 5% CO2 atmosphere for 1 h. The medium was then removed and cells were washed gently with PBS.
The cells were trypsinized and harvested. The harvested cells were digested with 65% HNO3 at 60°C in
an ultrasonic bath for 1 h and afterwards incubated at room temperature over night to ensure complete
digestion. The samples were then diluted with MilliQ water to a final concentration of 2% HNO3 and
measured by ICP-MS.
34
5. Acknowledgement
35
36
The authors gratefully thank Carolin Fritzsche for the accomplishment of the cytotoxicity assays, Gabi
Sentis for NMR measurements and Dr. Dirk Merten for ICP-MS measurements. This project was funded

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by the German Federal Ministry of Education & Research (BMBF, #031A518B Vectura) and by the
German Research Council (DFG, GO 1100/4-1). Furthermore, the Carl-Zeiss Foundation (JCSM
Strukturantrag) is gratefully acknowledged for financial support. The LSM880 ELYRA PS.1 was further
funded with a grant from the German Research Council (DFG).
5

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ACCEPTED MANUSCRIPT
Synthesis of
D
-fructose conjugated ligands via C6 and C1 and their
corresponding [Ru(bpy)2(L)]Cl2 complexes
Michael Pröhl,†,ǂ Pascal D. Moser,†,ǂ Justyna A. Czaplewska,†,ǂ Patrick Hoffmann,†,ǂ Tanja Bus,†,ǂ Anja
Traeger,†,ǂ Helmar Görls,§ Ulrich S. Schubert,†,ǂ Michael Gottschaldt†,ǂ *
†
ǂ
§
Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena,
Humboldtstraße 10, 07743 Jena, Germany
Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743
Jena, Germany
Institute for Inorganic and Analytical Chemistry, Friedrich Schiller University Jena, Humboldtstraße
8, 07743 Jena, Germany
*corresponding author: michael.gottschaldt@uni-jena.de
Highlights
-
-
Sucrose can be used as a starting material for the modification of the C6 position of
D
-fructose
Pyridyl triazole (pyta) was introduced to the C1 and to the C6 position of
potential chelating ligand
D-fructose to form a
-
D-fructose conjugated pyta form complexes of the general formula [Ru(bpy)2(L)]Cl2, when reacted
with Ru(bpy)2Cl2