Synthesis of novel carbohydrate based pyridinium ionic liquids and cytotoxicity of ionic liquids for mammalian cells

Article abstract of DOI:10.1039/d0ra01370f

The large pool of naturally occurring carbohydrates with their diversity in chirality and structure led to the idea of a systematic investigation of carbohydrate based ILs. To this end, we investigated the influence of different ether groups, mainly methyl or ethyl ether, on the secondary OH groups as well as different configurations on physical properties such as melting point, thermostability and especially the influence on cell toxicity. For this investigation we chose α- and β-methyl-, β-allyl- and β-phenyl d-glucopyranose as well as four 1-deoxy-pentoses. In order to be able to classify the results, more ionic liquids with different structural motives were examined for cytotoxicity. Here, we present data that confirm the biocompatibility of such ILs consisting of naturally occurring molecules or their derivatives. The synthesized carbohydrate based ILs were tested for their suitability as additives in coatings for medical applications such as drug-eluting balloons.

Full text of DOI:10.1039/d0ra01370f

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PAPER
Synthesis of novel carbohydrate based pyridinium
ionic liquids and cytotoxicity of ionic liquids for
mammalian cells†
Cite this: RSC Adv., 2020, 10, 14299
Melanie Reiß,a Andreas Brietzke,b Thomas Eickner,b Florian Stein,a
a
a
a
Christian Vogel,a Udo Kragl
and Stefan Jopp
*
Alexander Villinger,
The large pool of naturally occurring carbohydrates with their diversity in chirality and structure led to the
idea of a systematic investigation of carbohydrate based ILs. To this end, we investigated the influence of
different ether groups, mainly methyl or ethyl ether, on the secondary OH groups as well as different
configurations on physical properties such as melting point, thermostability and especially the influence
on cell toxicity. For this investigation we chose a- and b-methyl-, b-allyl- and b-phenyl D-glucopyranose
as well as four 1-deoxy-pentoses. In order to be able to classify the results, more ionic liquids with
different structural motives were examined for cytotoxicity. Here, we present data that confirm the
biocompatibility of such ILs consisting of naturally occurring molecules or their derivatives. The
synthesized carbohydrate based ILs were tested for their suitability as additives in coatings for medical
applications such as drug-eluting balloons.
Received 12th February 2020
Accepted 18th March 2020
DOI: 10.1039/d0ra01370f
rsc.li/rsc-advances
potential ILs with low cytotoxicity. While there have been a few
previous studies on carbohydrate based ILs,7–10 most of them
Introduction
focused on the synthesis. Examples of previous ILs based on
carbohydrates are shown in Fig. 1.
While the use of some of these carbohydrate based ILs as
solvents or for asymmetric induction9 has been studied, a study
for potential medical application has yet to be done.
In recent years, ionic liquids have aroused the interest of
scientists in the medical research eld due to their wide variety
of structures and potential applications.1 Current areas of
investigation include IL based drugs (Active Pharmaceutical
Ingredients-Ionic Liquids)2 as well as other applications of ILs
in the pharmacological eld such as drug delivery systems.1,3 In
such systems, the IL serves as a solvent or solvent promoter for
sparingly water-soluble drugs and can thus enhance pharma-
cokinetic and pharmacodynamic properties considerably.
Another interesting medical application are drug-eluting
balloons, which are typically used in re-stenotic lesions.4
Previous works of our group have shown that the ionic liquid
cetylpyridinium salicate [CetPyr][Sal] is a potential candidate for
such an application.5 This IL however, while showing good
properties in drug release and homogenous coating ability, is
not suited for an actual application due to cytotoxicity.
Results and discussion
Synthesis
The rst part of our strategy was the synthesis of four new ionic
liquids derived from pentoses. We chose the peracetylated
species of D-ribose 1a, D-lyxose 2a, D-xylose 3a and L-arabinose 4a
as starting materials, which were prepared by procedures
known from literature.11 Fig. 2 shows the general synthetic
pathway exemplary for D-ribose.
Starting from the peracetylated D-ribose 1a we investigated
a direct reduction of the anomeric center using TMSOTf and
Et3SiH.12 While this strategy successfully led to the 1-deoxy-
Thus we decided to further look into ILs based on natural
products like amino acids6 and carbohydrates7 Especially
carbohydrate based ionic liquids have piqued our interest as
aInstitute of Chemistry, University of Rostock, Albert-Einstein-Straße 3a, 18059
Rostock, Germany. E-mail: stefan.jopp@uni-rostock.de
bInstitute of Biomedical Engineering, University of Rostock, Friedrich-Barnewitz-Straße
4, 18119 Rostock, Germany
† Electronic supplementary information (ESI) available: Including experimental
data for all products as well as 1H, 13C and 19F NMR spectra for key
intermediates and all nal ionic products. CCDC 1914143 1916778 1916780. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/d0ra01370f
Fig. 1 Examples of carbohydrate based ILs from the literature.
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Fig. 3 Synthesis of alternative 1-deoxy-ribose ILs with varying 2- and
3-O-groups. (a) 2,2-Dimethoxy propane, camphorsulfonic acid,
acetone, r.t., 1.5 h; (b) Tf2O, pyridine, DCM, 0 ꢀC, 10 min; (c) pyridine,
reaction at rotary evaporator, 700 mbar, 40 ꢀC; (d) AcOH (70%), r.t.,
20 min; (e) NaH, ethyl or allyl bromide, DMF, 0 ꢀC $ r.t., overnight; (f)
AcOH (70%), 70 ꢀC, 45 min; (g) Pd(OH)2, MeOH, H2-atmosphere, r.t.,
12 h; (h) Tf2O, pyridine, DCM, 0 ꢀC, 10 min; (i) pyridine, reaction at
rotary evaporator, 700 mbar, 40 ꢀC; *yield over two steps.
Fig. 2 Synthesis of 1-deoxy-ribose based ionic liquid 1i; the same
synthetic strategy was applied for lyxose (2a–i), xylose (3a–i) and
arabinose (4a–i). (a) Thiophenol, BF3$OEt2, DCM, 0 ꢀC $ r.t., 2 h; (b)
Bu3SnH, AIBN, toluene, reflux, 2.5 h; (c) MeOH, Na, r.t., 4 h; (d) trityl
chloride, NEt3, DMAP, DCM, r.t., overnight; (e) NaH, MeI, DMF, 0 ꢀC $
r.t., overnight; (f) AcOH (70%), 70 ꢀC, 45 min; (g) Tf2O, pyridine, DCM,
0
ꢀC, 10 min; (h) pyridine, reaction at rotary evaporator, 700 mbar,
40 ꢀC; *yield over two steps.
By changing the reagent used for the introduction of the
ether groups starting from 1e, ethyl and allyl ethers 1l and 1p
have also been synthesized successfully (Fig. 3e). By further
reducing the allyl group to a propyl group and carrying on with
the already established strategy of introduction of the triate
followed by quarternization with pyridine, products 1o, 1s and
1v were achieved.
All nine new pyridine salts derived from pentoses are shown
in Fig. 5. These ionic structures all classify as ionic liquids, as
further shown under “Thermal analysis”.
Our second synthetic goal was to apply the established
strategy for 1-deoxy-pentoses on different glucosides. Our
starting materials were b-D-methyl, allyl and phenyl glucosides
5–7a as well as a-D-methyl glucoside 8a. Fig. 6 shows the general
synthetic pathway exemplary for the b-D-methyl glucoside 5a.
The 5-step reaction starts with the introduction of the 6-O-
trityl group (Fig. 6a). This step was performed with yields from
66% when using the b-D-allyl glucoside up to 87% for the b-D-
methyl glucoside. The follow-up reactions are, similar to the
synthesis shown in Fig. 2, the introduction of the methyl ether
groups and aerwards the 6-O-trityl deprotection. These two
ribose derivative 1c in a high yield of 92%, it could not be
applied for the other three starting materials 2–4a. The yields
were low and the products impure. Thus we switched to a two-
step strategy of rst introducing a thiophenyl group at the
anomeric center followed by reduction with tributyltin hydride
(Fig. 2a and b). This strategy could be applied for all four
products in yields from 50 to 85%.
The next four steps were the deprotection of the acetyl groups,
5-O-tritylation, introduction of the methyl ether groups on the
secondary OH groups and lastly deprotection of the 5-O-trityl
group, leading to the products 1–4g (Fig. 2c–f). These steps were
generally performed with high yields ranging from 80 to 95%.
Our strategy was nalized by converting the unprotected
5-OH group into a triate, directly followed by the quarter-
nization reaction with pyridine, yielding the products 1–4i in
overall high yields aer an 8-step synthesis (Fig. 2g and h).
By using 1d and 1e as starting materials in a similar pathway
as shown in Fig. 1 we were furthermore able to produce four
additional 1-deoxy-ribose based ILs with varying groups in
positions 2 and 3.
The isopropylidene protection of 1d (Fig. 3a) allows the
production of ionic liquid 1k, which has free OH groups in the
positions 2 and 3. Due to the instability of the isopropylidene
group under acidic conditions, the synthesis of an iso-
propylidene protected 1-deoxy-ribose based IL was not possible
at rst. Said group was partly cleaved during the introduction of
the 5-O-triate group, thus a full cleavage of the isopropylidene
group was performed aer quarternization (Fig. 3b–d). We were
however able to produce the isopropylidene protected 1-deoxy-
ribose based IL 1x by using mesylate instead of triate (Fig. 4).
Fig. 4 Synthesis and ORTEP13 of 1x. (a) Mesyl chloride, pyridine, r.t.,
12 h; (b) pyridine, 125 ꢀC, 5 h; *yield over two steps.
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Fig. 5 Overview of 1-deoxy-pentose based ILs.
Fig. 7 Overview of glucoside-based pyridinium salts and ORTEPs13 of
7f and 5j.
Biocompatibility
For biocompatibility measurements, several commonly known
ILs, whose cytotoxicity has already been thoroughly explored,14
have been studied in comparison to the new carbohydrate
based ILs we synthesized. A few examples of these additionally
tested ILs are shown in Fig. 8.
Cell viability assay revealed a strong impact on cell viability
at 0.1 mol Lꢁ1 molar concentration for the predominant share
of the evaluated ionic liquids (Fig. 9A–F). According to that only
[AlaC1][Lac], choline dihydrogenphosphate and sodium chlo-
ride, which was tested for comparison, exhibit no zytotoxic
effects. Due to the natural occurrence of these substances in
cells, this meets our expectations.
Besides that, further discriminations between the ionic
liquids presented herein can be made. Comparison between the
different glucose derivatives (Fig. 9A) shows almost no viability
for any substance at c ¼ 0.1 mol Lꢁ1, whereas major differences
Fig. 6 Synthesis of ionic liquid 5f from b-D-methyl glucoside 5a; the
same strategy was applied for b-allyl glucoside (6a–f), b-phenyl
glucoside (7a–f) and a-methyl glucoside (8a–f). (a) Trityl chloride,
NEt3, DMAP, DCM, r.t., overnight; (b) NaH, MeI, DMF, 0 ꢀC $ r.t.,
overnight; (c) AcOH (70%), 70 ꢀC, 45 min; (d) Tf2O, pyridine, DCM, 0 ꢀC,
10 min; (e) pyridine, reaction at rotary evaporator, 700 mbar, 40 ꢀC;
*yield over two steps.
steps were generally performed in high yields up to 94% (Fig. 6b
and c). The resulting free 6-OH group of the products 5–8d was
then converted into a triate group followed by quarternization
with pyridine, leading to the carbohydrate-based pyridinium
triate salts 5–8f (Fig. 6d and e).
By following the same idea as applied before for the 1-deoxy-
pentoses, the methyl ether groups were also changed to ethyl
ether groups on the b-D-methyl glucoside structure. This leads
to product 5j (Fig. 7). Lastly, two further salts were derived from
5d by changing the leaving group to mesylate or tosylate,
leading to 5l and 5n, respectively (Fig. 7).
All seven new pyridine salts derived from glucosides are
shown in Fig. 7. Most of these new products classify as ionic
liquids, as further shown under “Thermal analysis”.
Fig. 8 Examples of additional ILs used in cell viability assay.
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over the whole concentration range. There are no signicant
differences between the different anions.
In contrast amino acid derivatives from alanine and glycine
as cations exhibit no cytotoxic effects at a concentration of
10ꢁ2 mol Lꢁ1 (Fig. 9E). There is also no difference between
methoxy- or ethoxy esters in the glycine derivatives. According
to the counter ion no signicant differences between nitrate
and acetate can be found.
Hence, using naturally occurring substances and their
derivatives to generate the cation opens up new elds of
application, such as biomedical applications. It is worth noting
that the IL [AlaC1][Lac] shows good viability already at concen-
trations of 0.1 mol Lꢁ1, but compared to the other [AlaC1]
derivatives a slightly worse impact on the biocompatibility at
lower concentrations. Further studies have to be performed to
shed light on this phenomenon (Tables 1 and 2).
Thermal analysis
The analysis of the melting points of our 16 new carbohydrate
based pyridinium salts allows the categorization into the class
of ionic liquids, ꢀwhich are per denition salts with a melting
point under 100 C.
As such, only bPhGluMePyrOTf 7f, bMeGluEtPyrOTf 5j and
bMeGluMePyrOTs 5n do not qualify as ionic liquids, while all
other glucoside- and 1-deoxy-pentose products exhibit melting
points under 100 ꢀC, with many of them even being room
temperature ionic liquids (Tables 3 and 4).
Fig. 9 Relative cell viability of L929 mouse fibroblasts after 48 h
cultivation in a dilution series of the ionic liquids compared to the pure
cell culture medium control (n ¼ 4, mean ꢂ SEM). (A) Glucoside based
ILs; (B) 1-deoxy-pentose based ILs; (C) imidazolium based ILs; (D) ILs
While most of the 1-deoxy-pentose based ILs are liquid at
based on tetrabutylphosphonium cation and amino acids as anion; (E) room temperature (Table 4) and such don't allow a direct
ILs based on amino acids as cation; (F) further natural salts and ILs.
comparison of the impact of conguration and varying groups
on the melting point, such comparisons can be made for the
glucoside based products (Table 3).
can be found at a concentration of 10ꢁ2 mol Lꢁ1. A change of the
The type and conguration of the group at the anomeric
anomeric form from b-glucose to a-glucose results in
a decreased viability.
center has a high inuence on the melting point. A trend of
bOMe < bOAll # bOPh was found for the glucosides 5–7f. The
double bonds of allyl and phenyl groups allow more interac-
tions between the cations than the methyl group, leading to this
trend. Furthermore, bMeGluMePyrOTf 5f is liquid at room
Moreover, results indicate a major impact of the sort of
anion on biocompatibility. For bMeGluMePyr+ viability rises for
following anions in the order: ꢁOTs < ꢁOTf < ꢁOMs. This effect
is supported by redXylMePyr+ with the counterions ꢁOTf <
ꢁOMs (Fig. 9B). Surprisingly, the substitution of the methyl
group by an allylic group at the anomeric center diminishes the
cytotoxicity of the triate anion.
Table 1 Relative cell viability of L929 mouse fibroblasts with carbo-
hydrate based ILs
For 1-deoxy-pentoses different viabilities could be observed
in the following order: lyxose # xylose < arabinose < ribose.
Ribose derivatives are naturally found in all nucleotides (DNA,
RNA) and hence in all cells, while lyxose can be found in the cell
walls of few bacteria and xylose and arabinose in the poly-
saccharides of plants. Hence, ribose derivatives should be
tolerated better by cells with mammalian origin.
Thus, the use of substances with biological origin such as
carbohydrates and amino acids is a promising approach for
improving the biocompatibility of ionic liquids. To test this,
a common tetrabutylphosphonium cation [P4444] was countered
with four different anions derived from proteinogenic hydro-
phobic amino acids: proline, valine, glycine and leucine
(Fig. 9D). The resulting ionic liquids exhibit cytotoxic effects
No.
Cation
Anion
EC50 [mmol Lꢁ1
]
1i
2i
3i
4i
1k
1v
5f
6f
7f
8f
5l
5n
redRibMePyr
redLyxMePyr
redXylMePyr
redAraMePyr
redRibOHPyr
redRibPrPyr
bMeGluMePyr
bAllGluMePyr
bPhGluMePyr
aMeGluMePyr
bMeGluMePyr
bMeGluMePyr
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OMs
OTs
46.40
25.19
38.65
40.37
54.80
136.62
41.73
36.40
n.m.a
49.88
57.60
51.49
a
7f was not measured due to its very poor solubility in water.
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Table 2 Relative cell viability of L929 mouse fibroblasts with several
The decomposition points of the glucoside products vary
from 205 to 250 ꢀC, while the 1-deoxy-pentose products have
higher values with 297 to 345 ꢀC. In general, these new products
have a good thermal stability.
ILs15–18
Cation
Anion
EC50 [mmol Lꢁ1
]
Glass transition temperatures we measured for the 1-deoxy-
pentose based IL's to acquire further information of the inu-
ences of conguration and varying groups on physical proper-
ties. Here we see a trend of lyxose 2i < arabinose 4i < xylose 3i <
ribose 1i. The impact of the varying groups in positions 2 and 3
on the glass transition temperature is small, with the methyl
ether product 1i having the highest and the free OH group
product 1k the lowest Tg in direct comparison.
P4444
P4444
P4444
P4444
GlyC1
GlyC2
AlaC1
AlaC1
Pro
Val
Gly
Leu
NO3
NO3
NO3
Lac
H2PO4
Br
0.575
0.775
0.875
0.725
35
20
20
25
30
Choline
Amim
15
C2mim
C2mim
C4mim
BF4
SCN
Cl
4
8
10
Methods
Cell viability assay
C4mim
PF6
Cl
—
—
Sal
7
C10mim (demim)
Ammoeng 110®
Ammoeng 110® purif.
Cetpyr
0.035
1.07
3.08
0.038
51.85
In order to evaluate the biocompatibility of the carbohydrate-
based ILs cytotoxicity was tested with Cell Viability Assay Kit
(BioAssay systems, Hayward, CA, USA).
L929 mouse broblasts (CCL-1, ATCC) were cultured in
DMEM (PAN BIOTECH, Aidenbach, Germany) with 4.5 mg
glucose and 10% fetal calf serum (FCS), 1% Penicillin/
Streptomycin and 3.7 g Lꢁ1 NaHCO3.
Na
Cl
Table 3 Melting points and decomposition points of glucoside based
products
For screening tests 2 ꢃ 104 L929 mouse broblasts were
seeded in a 96-well microtiter plate with 200 mL culture medium
per well and incubated under cell culture conditions (37 ꢀC, 5%
CO2) for 24 hours.
To proof cell viability CellQuanti-Blue Cell Viability Assay Kit
(BioAssay systems, Hayward, CA, USA) was implemented. 10%
CellQuanti-Blue supplement was added to the wells followed by
an incubation of another 2 hours under same conditions. The
reductive activity of the cells conducts the metabolic turnover
from resazurin to the uorescent resorun (absorption 544 nm,
emission 590 nm) which was detected with the Fluostar optima
(BMG LABTECH, Ortenberg, Germany).
No.
Cation
Anion
mp [ꢀC]
dp [ꢀC]
5f
6f
7f
8f
5j
5l
5n
bMeGluMePyr
bAllGluMePyr
bPhGluMePyr
aMeGluMePyr
bMeGluEtPyr
bMeGluMePyr
bMeGluMePyr
OTf
OTf
OTf
OTf
OTf
OMs
OTs
Liquid at r.t.
66–70
225
205
225
242
215
250
242
164–168
95–100
118–120
60–63
135–138
Table 4 Melting points, decomposition points and glass transition
temperature of 1-deoxy-pentose based products
Thermal analysis
Melting points were determined with a micro heating stage
(Mikroheiztisch BOETIUS, Dresden, Germany).
No.
Cation
Anion
mp [ꢀC]
dp [ꢀC]
Tg [ꢀC]
Decomposition points have been measured via thermogra-
vimetric analysis using a Labsys 1600 TGA-DSC (SETARAM
Instrumentation, Caluire, France).
The differential scanning calorimetry using a Pyris 1 DSC
(PerkinElmer, Waltham, USA) allowed the analysis of glass
transition temperatures.
1i
2i
3i
4i
1o
1s
1v
1k
1x
redRibMePyr
redLyxMePyr
redXylMePyr
redAraMePyr
redRibEtPyr
redRibAllPyr
redRibPrPyr
redRibOHPyr
redRibIsoPyr
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OMs
48–51
Liquid at r.t.
32–36
Liquid at r.t.
Liquid at r.t.
Liquid at r.t.
Liquid at r.t.
Liquid at r.t.
92–94
345
325
345
340
316
301
235
297
296
ꢁ18
ꢁ41
ꢁ28
ꢁ38
ꢁ26
n.m.
ꢁ27
ꢁ30
n.m.
Conclusion
In this work we presented a reproducible strategy to synthesize
new carbohydrate based pyridinium salts. Said synthetic
pathway was successfully applied on 4 different 1-deoxy-
pentoses as well as 4 different glucosides, leading to overall
16 new products with varying congurations and groups.
Thermal analysis shows that 13 of these new carbohydrate
based pyridinium salts qualify as ionic liquids per denition,
with most of them even being room temperature ionic liquids.
temperature, while aMeGluMePyrOTf 8f has a melting point
close to 100 ꢀC, showing that the conguration of the anomeric
center alone has a high impact on the melting point. The
change of methyl ether groups in 5f to ethyl ether groups in 5j
also heightens the melting point signicantly. Lastly the cor-
responding anion also has a high inuence, showing a clear
trend of OTf < OMs # OTs.
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Further biocompatibility tests have proven that these ionic
liquids are suitable for biomedical applications, as they exhibit
a much higher viability than common imidazolium or phos-
phonium based ILs, which have been tested in comparison. A
potential application currently under testing is the usage of
these new carbohydrate based ionic liquids as additives in
coatings for drug-eluting balloons.
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
We thank Prof. H. Ohno for providing us the four tetrabutyl-
phosphonium ILs paired with amino acid anions, which we
used in the biocompability tests. We also thank Prof. Schick of
the University of Rostock for conducting DSC with our sam-
ples.This work was supported by the European Union (ESF/14-
BM-A55-0048/16) as well as by the Federal Ministry of Educa-
tion and Research (BMBF) project REMEDIS (FKZ:03IS2081).
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14304 | RSC Adv., 2020, 10, 14299–14304
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