Synthesis and gelation property of a series of disaccharide triazole derivatives

Article abstract of DOI:10.1016/j.carres.2017.09.008

Low molecular weight gelators are important for the study of supramolecular chemistry and have useful applications for biomaterials. Glycomimetics that are easily accessible and have useful gelation properties are especially interesting molecules. In this

Full text of DOI:10.1016/j.carres.2017.09.008

Accepted Manuscript
Synthesis and gelation property of a series of disaccharide triazole derivatives
Ifeanyi S. Okafor, Guijun Wang
PII:
S0008-6215(17)30394-4
10.1016/j.carres.2017.09.008
CAR 7447
DOI:
Reference:
To appear in: Carbohydrate Research
Please cite this article as: I.S. Okafor, G. Wang, Synthesis and gelation property of a series of
disaccharide triazole derivatives, Carbohydrate Research (2017), doi: 10.1016/j.carres.2017.09.008.
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ACCEPTED MANUSCRIPT

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Synthesis and Gelation Property of a Series of Disaccharide Triazole
Derivatives
Ifeanyi S. Okafor and Guijun Wang*
Department of Chemistry and Biochemistry, Old Dominion University, Norfolk, VA 23529,
USA.
* Corresponding Author:
Guijun Wang, Ph.D., Professor
Department of Chemistry and Biochemistry
Old Dominion University
4541 Hampton Boulevard
Norfolk, VA23529-0126
Email: g1wang@odu.edu
Telephone: (757) 683-3781
Fax: (757) 683-4628
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Abstract
Low molecular weight gelators are important for the study of supramolecular chemistry and have
useful applications for biomaterials. Glycomimetics that are easily accessible and have useful
gelation properties are especially interesting molecules. In this research, nine per-O-acetyl
lactosyl- and thirteen per-O-acetyl maltosyl triazole derivatives were synthesized and analyzed.
Most of the maltosyl triazoles and one of the lactosyl derivatives were found to be effective
molecular gelators. The supramolecular gels were characterized using rheology and optical
microscopy and they exhibited morphologies ranging from fibers to planar sheets. The self-
assembling properties of selected lactosyl and maltosyl triazole derivatives were studied using 1H
NMR spectroscopy at different temperatures. The NMR studies revealed that the triazole moiety
in these compounds played an important role in the formation of the supramolecular assembly,
but the sugar moiety configurations are more influential towards gelation. Naproxen and
chloramphenicol were used as the model drugs to assess the potential of these compounds in
drug delivery applications. A pH responsive gelator showed faster delivery of chloramphenicol
at mild basic conditions than neutral conditions. The effective disaccharide triazole-based
molecular gelators are useful for the preparation of advanced soft materials that have potential
applications as matrix for immobilization of drugs or biomolecules.
Keywords: Organogelators, hydrogelators, disaccharides, maltose, lactose, click reaction,
triazole, glycolipids, self-assembly.
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Introduction
In recent years, functional molecular assemblies formed by small molecules have gained much
attention. Among these, low molecular weight gelators (LMWGs) are a class of small molecules
that are able to self-assemble and form reversible gels in organic solvents or aqueous solutions
[1-11]. The LMWGs form soft gel materials through non-covalent interactions such as hydrogen
bonding, π-π stacking, Van der Walls forces, hydrophobic interactions, etc. Several types of
relatively weak non-covalent interactions typically coexist and result in reversible yet stable gels
or supramolecular gels. These reversible organogels and hydrogels have many potential
applications. These include drug delivery, tissue engineering, protein binding and separation, and
nanofabrication of electronic devices [12-21]. Recently, supramolecular gels have also been
explored in the area of environmental chemistry for dye adsorption and oil spill recovery [16, 22-
25].
Numerous LMWGs were discovered by serendipity and the structural requirement for effective
gelation is still not well defined. However, extensive research in the area of molecular gelators
have shown that some general structural features can effect gelation. Molecules containing polar
functional groups that can form hydrogen bonds such as alcohols, ureas, esters, carboxylic acids
and amides are especially amenable for gelation. Compounds of biological origin including
natural products such as amino acids, peptides, carbohydrates, and nucleic acids have been
reported to be effective gelators [11, 26-32]. Among the various natural products, carbohydrates
are especially promising materials for preparing supramolecular gelators due to the fact that they
are renewable resources and have large structural diversity [11, 32-42]. The multiple hydroxyl
groups present in sugars can be regioselectively functionalized to afford sugar-based LMWGs.
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Previously we had studied the functionalization of a series of monosaccharide derivatives to
afford effective LMWGs [32-34, 37-38]. A general structure and gelation relationship of
monosaccharaide derivatives was established. We found that certain acyl derivatives of D-
glucose and D-glucosamine were effective gelators. For 4, 6-O-benzylidene acetal protected α-
D-methyl glucopyranosides, certain esters and carbamates of the 2-OH group afforded effective
molecular gelators. For similarly functionalized D-glucosamine derivatives, the carbamate,
amides and ureas obtained by functionalization at the 2-amino group were also effective
LMWGs. “Click” chemistry has been used extensively for the discovery of novel scaffolds and is
very important in biochemistry and glycoscience [43-52]. Recently, we synthesized a series of
peracetylated glucosyl triazole derivatives using the “Click” reaction and found that several
compounds are good organogelators and hydrogelators [48, 50]. As shown in Figure 1,
peracetylated glucosyl β-triazole derivatives 1-4 contain different substituents at the triazole 4-
poisition. These compounds formed gels in aqueous solutions and compound 4 also formed a
hydrogel at 0.4 wt%. From these encouraging results of monosaccharide derivatives from D-
glucose, we would like to find out the effect of replacing the monosaccharide moiety by a
disaccharide moiety. Maltose and lactose are important food based disaccharides and their
structures contain a common glucose unit, we anticipate that they may also form useful
molecular assemblies. Changing the monosaccharides to disaccharides will increase the scope of
the molecular gelators and also systematic studies using lactose and maltose will allow us to
obtain structural features necessary for common disaccharide derivatives to function as LMWGs.
Although a few disaccharide-based triazole-containing glycolipids have been reported to be
effective supramolecular hydrogelators [53, 54], systematic studies on peracetylated disaccharide
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triazole derivatives as molecular gelators have not been carried out. Our previous study showed
that peracetylated glycosyl triazole lipids are effective molecular gelators, here we would like to
study the influence towards gelation when adding another monosaccharide to the
monosaccharide triazole system (I and II).
Figure 1. Structures of glucosyl triazoles that are effective LMWGs [48] and the proposed
peracetylated disaccharide triazole derivatives I and II, R is an alkyl or aryl group, the structures
are shown in Scheme 1.
Results and Discussions
In this study, we aim to extend the study of gelation properties from monosaccharide to
disaccharide systems and understand whether the additional monosaccharide will affect the
molecular self-assembling behavior in different solvents. Two readily available disaccharides, D-
lactose and D-maltose, were selected for the study. As shown in Figure 1, the lactose derivatives
I and maltose derivatives II share a common glucosyl triazole scaffold with compounds 1-4. We
first synthesized a series of peracetylated lactosyl triazole derivatives with the general structure I
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as shown in Scheme 1. The precursor of the triazole, the lactosyl azide 6 was synthesized
following literature methods with slight modifications using D-lactose as the starting material
[55-57]. D-lactose was converted to the corresponding heptaacetate with the beta isomer as the
major product, which was directly used to synthesize the lactosyl bromide 5, afterwards the
bromide was displaced with azide to afford the compound 6. To prepare the triazole derivatives,
the peracetylated sugar azide 6 was treated with the corresponding terminal alkynes with
different functional groups respectively using a catalytic amount of copper sulfate and sodium
ascorbate. In order to understand the influence of structure on gelation, a series of lactosyl
triazole derivatives (7-15) with different substituents were synthesized. These include short alkyl
chain derivatives 7-8, chlorobutyl derivative 9, compounds containing a hydroxyl group (10-13),
a carboxyl group (14), and phenyl derivative 15.
D-maltose, another food based disaccharide, has two glucose units linked by an α (1-4)
glycosidic linkage. It shares the same glucose unit with D-lactose. We selected a similar series of
alkynes for the lactose derivatives to synthesize the maltose derivatives (Scheme 1 and S1).
These include straight chain alkyl derivatives 18-20, chlorosubstituted alkyl derivative 21,
terminal hydroxyl compounds 22-25, terminal carboxylic acid 26, and aromatic derivatives 27-
28. We also synthesized two dimeric triazole analogs 29 and 30, respectively, with four and five
carbon spacer. These compounds were then screened for their gelation properties using a variety
of solvents; the results are shown in Table 1.
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OAc
OAc
OAc
N
i
ii
N
N
O
O
O
XO
AcO
R
XO
AcO
XO
AcO
N3
OAc
AcO
OAc
Br
OAc
6
5
OAc
AcO
AcO
O
AcO
AcO
O
II X =
I
X=
Ac O
OAc
i: NaN3, DMF, 70 oC ii: Alkyne, CuSO4, sodium ascorbate, tBuOH:THF:H2O (1:1:1), rt, 24 h
Compound I: R:
Cl
OH
OH
7
8
9
11
10
80%
76%
85%
87%
79%
OH
O
OH
OH
Cl
13
14
15
12
70%
75%
85%
84%
Compound II: R:
OH
OH
18
20
71%
21
19
23
22
70%
81%
81%
83%
78%
OH
O
OH
OH
26
28
27
25
24
80%
81%
87%
82%
80%
29
79%
30
78%
Scheme 1. Synthesis of peracetylated lactosyl and maltosyl triazole derivatives 7-15 and 18-30.
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Table 1. Gelation test results for lactosyl and maltosyl triazole derivatives
Compound Toluene i-
EtOH H2O
DMSO: DMSO: EtOH:
EtOH:
No
PrOH
H2O
(1:1)
P
H2O
H2O
H2O
(1:2)
(1:2)
(1:1)
S
S
S
P
S
S
S
S
P
S
S
S
S
S
S
P
S
P
S
S
P
S
S
S
S
S
S
S
S
S
S
S
S
S
P
P
S
P
S
S
S
S
P
P
P
P
P
P
P
P
P
P
S
P
P
P
P
P
P
P
I
P
S
S
7
S
P
P
S
S
8
S
P
P
P
S
9
S
S
P
S
S
10
11
12
13
14
15
18
19
20
21
22
23
24
25
26
27
28
29
30
S
S
P
S
S
S
S
P
P
S
S
P
P
S
S
S
S
S
S
S
S
G 10
G 4.0
G 2.8
P
UG
G 4.0
G 2.8
P
UG
G 3.3
G 5.0
G 10
P
G 5.0
G 10
G 6.7
G 6.7
P
S
S
S
P
G 20
P
P
G 20
P
P
S
S
S
P
S
S
S
P
P
P
P
S
G 6.7
G 2.5
G 4.0
G 4.0
P
G 4.0
G 2.0
G 2.0
G 4.0
P
P
P
S
G 5.0
G 3.3
G 5.0
P
S
G 5.0
G 6.7
G 5.0
P
G 10 G 10
P
P
P
P
G 20
P
G 20
G 10
P
P
P
G, gel at room temperature; the number in the table are the minimum gelation concentrations in
mg/mL; I, insoluble; P, precipitate; S, soluble; UG, unstable gel at 20 mg/mL. All compounds
were insoluble in hexanes at 20 mg/mL.
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The gelation properties of the triazoles were tested using different solvents including hexane,
toluene, isopropanol, ethanol, water, DMSO:water mixtures, and ethanol:water mixtures as
shown in Table 1. These were also used in our previous studies for the peracetylated glucosyl
triazoles. We are more interested in the gelation results in water and in aqueous mixtures with
DMSO or ethanol due to their potential applications in drug delivery and biological studies.
However, almost none of the peracetylated lactosyl triazole derivatives I formed gels in these
tested solvents. They were soluble in ethanol and isopropanol, insoluble in hexane and
precipitated in water. Only the phenyl derivative 15 was able to form stable gels in DMSO:water
(v/v 1:1) and EtOH:water (v/v 1:1); apparently the phenyl functional group’s additional π-π
stacking interactions benefited gelation property. We were delighted to find that a majority of the
peracetylated maltosyl triazole derivatives II were effective gelators in at least one of the tested
solvents, in contrast to their lactosyl analogs. The performance of the maltose derivatives
resembled those of the monosaccharide glucosyl derivatives [48], but dimeric compounds 29 and
30 were not as effective as the monomeric derivatives 18-20 and the dimeric glucosyl triazoles.
The difference in the performance of these two disaccharide derivatives could be due to the
configuration differences of the sugar moiety, which led to different intermolecular forces and in
turn different gelation properties.
All compounds synthesized in Scheme 1 were insoluble in hexanes and many of them were
soluble in toluene. A majority of the maltose derivatives II were effective gelators in ethanol and
ethanol-water mixtures (Table 1). The phenyl derivatives 27 and 28 were good gelators for
ethanol and the aqueous mixtures. Compound 28 was also able to form a gel in isopropanol
while 27 did not. The long chain carboxylic acid compound 26 was an effective gelator in an
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ethanol-water mixture and DMSO-water mixtures. While the long chain hydroxyalkyl derivative
25 formed gels in aqueous DMSO solution, the short chain derivatives 22 and 23 did not form
gels in any of the tested aqueous mixtures but compound 22 was able to form a gel at 20 mg/mL
in ethanol. The long chain alkyl derivative 20 only formed gels in aqueous ethanol mixtures
while the shorter chain alkyl derivatives 18 and 19 were effective gelators in all the tested
aqueous mixtures. In contrast to the corresponding dimeric monosaccharide analogs, the dimeric
disaccharide derivatives 29 and 30 were less effective gelators. Most of the gels formed by the
maltosyl triazole series were transparent with some of them translucent; photographs of the gels
are shown in Figure 2.
In order to find out whether the acetyl protective groups are important towards gelation, we
deprotected gelators 19, 26, and 27 to obtain the corresponding deprotected triazole derivatives
31, 32 and 33 respectively (Supporting Information Part-I, Page S40) and tested their gelation
properties in the same solvents (Table S1). However the deacetylated compounds were soluble in
most of the tested solvents and none of them formed gels. This indicates that the acetyl groups
are important to maintain the gelation properties for these compounds.
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Figure 2. Photos of the gels formed by the gelators 18 (A, B), 19 (C), 28 (D), and 29 (E). A:
compound 18 in EtOH:H2O (v/v 1:2) at 3.3 mg/mL; B: compound 18 in DMSO:H2O (v/v 1:1) at
4.0 mg/mL; C: compound 19 in DMSO:H2O (v/v 1:2) at 2.8 mg/mL; D: compound 26 in
DMSO:H2O (v/v 1:2) at 2 mg/mL; E: compound 27 in EtOH:H2O (v/v 1:2) at 3.3 mg/mL.
The morphologies of the gels formed by compounds 18, 19, 26, 27, 28 and 30 were studied using
an optical microscope, the results are shown in Figure 3. The gels formed by these various
maltosyl triazole derivatives typically exhibited fibrous networks. The gel of compound 18 in
DMSO:H2O (v/v 1:1) at 4.0 mg/mL exhibited very long and uniform fibrous assemblies, with a
length of several hundreds of microns, and an estimated diameter of 0.5 µm (Fig. 3a). In contrast,
the hexyl derivative 19 formed shorter fibers (Fig. 3b) in DMSO:H2O (v/v 1:2), with estimated
lengths of 10-20 µm, and similar widths to that of compound 18. Figure 3c shows the gel
morphology of compound 26 in DMSO:H2O (v/v 1:2) at 2.0 mg/mL, this gel had different
features as it formed continuous film with some fibrous structures on the surface of the gels. The
gel morphology of the phenyl derivative 27 in EtOH:H2O (v/v 1:2) at 3.3 mg/mL (Fig. 3d)
exhibited similar morphologies to that of 26 as shown in Fig. 3c, with fibers separating from the
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gel matrix upon sample drying. The gel of compound 28 in EtOH:H2O (v/v 1:1) at 5.0 mg/mL
showed entangled fibrous networks with twisted fibers (Fig. 3e). The dimeric maltosyl triazole
30 exhibited similar filaments and fibrous assemblies similarly to those of compounds 26 and 27.
Due to the higher concentration of the gel (20 mg/mL isopropanol), the gel of dimer 30 appeared
long fibers and some planar films like morphology (Fig. 3f).
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Figure 3. Optical micrographs of the gels formed by several compounds. a) compound 18 in
DMSO:H2O (v/v 1:1) at 4.0 mg/mL; b) compound 19 in DMSO:H2O (v/v 1:2) at 2.8 mg/mL; c)
compound 26 in DMSO:H2O (v/v 1:2) at 2.0 mg/mL; d) compound 27 in EtOH:H2O (v/v 1:2) at
3.3 mg/mL; e) compound 28 in EtOH:H2O (v/v 1:1) at 5.0 mg/mL, f) compound 30 in
isopropanol at 20.0 mg/mL.
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The stability and elastic properties of the gels were studied using a rheometer and the results are
shown in Figure 4 (and SI-II Figure S17). For the gels formed by compounds 18, 25 and 26 their
G′ storage moduli were greater than G′′ loss moduli. Compound 26 had the highest G′ and G′′
values among the three gels, indicating that the mechanical strength of the gel was the greatest
among these three. But all three tested gels were stable based on their rheological properties.
Figure 4. The rheology properties of the gels formed by compound 18 in DMSO:H2O (v/v 1:1)
at 4.0 mg/mL; 25 in DMSO:H2O (v/v 1:2) at 4.0 mg/mL; and 26 in DMSO:H2O (v/v 1:2) at 2.0
mg/mL.
In order to understand the molecular interactions and the self-assembling process, we performed
1H-NMR studies at different temperatures for the gelators with polar terminal substituents, 23,
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25, 26 and phenyl derivatives 27, 28 in CDCl3 as the solvent. For structural comparison
1
purposes, we also obtained the H NMR spectra for the lactose derivatives 11, 13, and 14 at
different temperatures, these compounds contain the same triazole 4-substituents as compounds
1
27, 29, and 30, respectively. The structures of compounds 13 and 25 and their H NMR spectra
at different temperatures are shown in Figures 5-7; the others are included in the Supporting
Information Part II (SI-II, Figures S1-S9).
For the maltose series, the 1H-NMR spectra of compound 23 at temperatures ranging from 30 °C
to 60 °C are shown in SI –II Figure S4. At elevated temperature, the signal of the triazole proton
shifted slightly upfield from 7.49 ppm at 30 °C to 7.46 ppm at 60 °C. The splitting patterns of
signals in 3.90-4.30 ppm region, which are corresponding to the hydrogens on C-5 and C-6 of
both sugars, changed significantly; these indicated that the disaccharide moiety played an
important role towards molecular self-assembly and gelation. Besides these two regions, other
signals including the two anomeric protons didn’t show noticeable changes. Similar trends were
observed for the other three maltose derivatives 25 (Figure 6a), 27 and 28 (SI-II Figure S8-S9).
The triazole signals in these three compounds all exhibited a 0.02 ppm upfield shift when
temperature was increased from 30 °C to 60 °C. Interestingly the carboxylic acid derivative 26
didn’t follow the same trend at different temperatures, the triazole signal stayed at 7.43 ppm for
all tested temperatures. However the regions corresponding to the disaccharides on C-5 and C-6
from 3.90-4.40 ppm changed considerably in splitting patterns and chemical shifts (SI-II Figure
S6). In CDCl3, the triazole signals for lactosyl derivatives 11, 13, and 14 showed similar trends
as for the corresponding maltose derivatives (SI-II Figures S1-S3).
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We selected two compounds (13 and 25) to analyze their 1H NMR spectra in a different solvent.
Since many compounds formed gels in DMSO and water mixtures, using DMSO-d6 as the
solvent may allow us to probe the intermolecular forces more accurately than using CDCl3.
Interestingly the maltose derivative 25 showed very different patterns in DMSO (Figure 6b), the
triazole signal showed more significant change, which shifted from 8.03 to 7.96 ppm, with 0.07
ppm upfield shift for higher temperature in comparison to 0.02 ppm difference when using
CDCl3 (Figure 6a). The anomeric proton (H-1 next to triazole) signal also showed a 0.02 ppm
upfield shift, but in CDCl3 the H-1 signal didn’t change. Moreover, the second anomeric proton
(H-1′) signal didn’t change with increasing temperature for either solvents. The NMR chemical
shift changes in DMSO-d6 reflected the gelation trend and indicated that in this solvent, the
triazole heterocycle is more responsible for the intermolecular interactions which resulted in
gelation. However the different properties of the functional groups in different solvents also
imply that the gelation properties are very much correlated to the solvents used.
For the lactose derivative 13, the triazole region showed similar trends to that of compound 25 in
both solvents. In CDCl3, the triazole proton and the anomeric proton remained the same at
different temperatures (Figure 7 and SI-II Figures S2), but the lactose derivative 13 showed more
pronounced change for H-1′ proton signal, which shifted from 4.52 to 4.56 at 60 °C. This effect
is quite different from that of maltose derivative 25, which showed no chemical shift change for
the anomeric proton H-1′. In DMSO-d6, compound 13 showed similar patterns to that of 25 for
the triazole proton and anomeric protons. The quite different responses at the anomeric H-1′ with
increasing temperatures indicated that the sugar moiety’s configuration is important in the
molecular packing to form gels.
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At higher temperatures the chemical shift changes are due to the change of the Van der Waals
interactions among the sugar headgroup and the π-π stacking of the triazoles. However the
configuration of the second monosaccharide seems to play an important role in forming the
molecular assemblies.
Figure 5. Structures of compounds 13 and 25, the chemical shifts are labeled for CDCl3 as
solvent at 30 °C.
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Figure 6a. 1H-NMR spectra of compound 25 in CDCl3 of at different temperatures. The triazole
peak shifted from 7.42 at 30 °C to 7.40 ppm at 60 °C, anomeric H-1 δ 5.85 ppm (d, J = 9.3 Hz)
and H-1′ δ 5.44 ppm, (d, J = 3.5 Hz) remained the same.
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Figure 6b. 1H-NMR spectra of compound 25 in DMSO-d6 at different temperatures, the
anomeric H-1 δ 6.23ppm (d, J = 9.2 Hz), H-1′ δ5.36 ppm (d, J = 3.9 Hz), note the 0.07 ppm
change for triazole signal.
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Figure 7a. 1H-NMR spectra of compound 13 in CDCl3 at different temperatures, anomeric proton
H-1 δ5.79, H-1′ δ4.52 (d, J = 7.9Hz), the H-1′ signal shifted from 4.52 to 4.56 ppm at 60 °C,
while the rest of the signals remained almost the same.
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Figure 7b. 1H-NMR spectra of compound 13 in DMSO-d6 at different temperatures, anomeric
proton H-1 δ 6.20 (d, J = 8.8 Hz); and H-1′ δ 4.83 (d, J = 8.0 Hz).
1
We also acquired the H NMR spectra at different concentrations at 30 °C for compound 26, as
1
shown in SI-II Figure S7. In contrast to the H NMR spectra at different temperatures (SI-II
Figure S6), the triazole ring showed a slight upfield shift at higher concentration. The upfield
shift of the triazole proton signal at higher concentration indicated that the glycosyl triazole
compound self-assembled in solution via π-π stacking [58].
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After the characterization of these gelators, next we analyzed their effectiveness for
immobilizing drug compounds and the diffusion rate of the drug molecule from the gel to
aqueous phase. The delivery rate of naproxen from gel to solution phase was monitored using
UV-Vis spectrometry. As shown in Figure 9, in 6 h about 40% of naproxen was released from
the gels, and 60% was released in 12 h. After 3 days about 87% naproxen was released. When
the solution was changed to pH = 10, the release profile was similar to the neutral pH during the
first 24 h (Supporting information II Figure S10). In three days at the basic condition 95%
naproxen was released, which was a little higher than the released amount at pH 7. These results
indicated that compound 27 is stable at mild basic conditions, and sustained release from the gels
to aqueous solution was observed. The UV spectra of the gelator 27 and the gel photographs are
shown in the SI figures S11 and S12. For Figure 9, the observed signals were due to naproxen’s
absorption only and not affected by the gelator’s background absorption.
Figure 8. Model drugs used for the study of release profile by the supramolecular gels
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Figure 9. Naproxen release from the gels formed by compound 27 monitored by UV absorption
at different times at pH 7. The gel was formed by compound 27 at 2 mg/mL in DMSO:H2O
(v/v1:2) and 0.5 mg of naproxen sodium. Then 3 mL of water (pH 7) was added on top of 1 mL
gel and the amount of naproxen released was measure by UV absorbance.
Compound 26 has a free carboxylic acid functional group, the resulting gels could be responsive
towards increasing pHs. To avoid the influence of naproxen’s formation of carboxylate anion at
basic pHs, we chose a neutral drug molecule for the controlled release study. As shown in Figure
10, under neutral conditions, chloramphenicol was slowly released from the gels. About 40% of
the drug was released to the aqueous phase after 6 h and about 80% was released after 24 h. In
comparison to the basic conditions, about 70% chloramphenicol was released in 6 h and in 10 h
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almost 85% of the drug was released. Under basic condition, the drug was released more rapidly;
this can be rationalized based on the structure of the gelator. The carboxylic acid in compound
26 was deprotonated at pH = 10 and this allowed the faster release of the trapped
chloramphenicol from the gel matrix. The photographs of the drug release study corresponding
to Figure 10 are shown in SI section II Figures S13 and S14. At neutral conditions, the gels were
stable even after 36 h standing time, but at basic conditions, the gels degraded significantly after
24 h. The observed signals in Figure 10 are only due to chloramphenicol absorption and not
interfered by the gelator’s background absorption. The UV spectra of the gelator 26 and the gel
photos are shown in SI-II Figures S15 and S16.
Figure 10. Chloramphenicol release from the gels formed by compound 26 monitored by UV
absorption at different times at pH 7 and pH 10. The gels were formed by 4 mg of compound 26,
0.2 mg of chloramphenicol in 0.9 mL of DMSO:H2O (v1:2) solvent. Then 3 mL of the buffer
solution was added on top of the gels and the UV spectra of the aqueous phase were recorded at
different times.
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The gelators 26 and 27 and their co-gels with drug compounds showed that these gelators are
effective to entrap the drug compounds in the gel matrix. The pH responsive gelator 26 showed
rapid delivery of chloramphenicol at mildly basic conditions due to partial formation of
carboxylate anion which resulted in destabilization of the gel matrix. The phenyl triazole gelator
27 doesn’t contain an ionizable functional group, the resulting gels exhibited similar rate of
release of entrapped naproxen from gel to solution phase at different pHs (Supporting
information II Figure S10). These results indicated that the supramolecular gelators could be
utilized for controlled release drug delivery, especially the pH responsive gelator.
Conclusions
In summary, we have synthesized and analyzed two series of hepta-acetyl disaccharide triazole
derivatives using lactose and maltose as the starting materials via click chemistry. We found that
most of the peracetylated maltosyl β-triazole derivatives were effective low molecular weight
gelators but the peracetylated lactosyl β-triazole derivatives were not effective gelators for the
tested solvents. The difference in gelation properties of the two disaccharide derivatives was
attributed to the configuration of the sugar moiety. We also showed that the acetyl protected
groups on the sugar moieties are important for gelation properties for the maltose triazole
derivatives. The self-assembling properties were studied using 1H NMR spectroscopy at different
temperatures and it indicated that the triazole heterocycle played an important role in the
molecular assemblies together with hydrogen bonding from polar substituents. Moreover, the
influences of the various substituents on the triazole ring of the maltose derivatives were also
examined. Typically hydrophobic substituents including alkyl and aryl groups showed enhanced
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gelation tendencies. The gels formed by several maltosyl triazole derivatives were characterized
using optical microscopy and rheology. We also analyzed the drug immobilization and release
using two gelator molecules 26 and 27. These compounds exhibited sustained release of the
entrapped drug molecules, their structures could be optimized to obtain a more effective gel
matrix in the future applications as advanced soft materials and for controlled or sustained
release of drugs.
Experimental Section:
General methods:
All reactions, unless otherwise noted, were carried out in oven dried glassware under nitrogen
atmosphere. Solvents and reagents were purchased from Sigma-Aldrich, VWR, Acros and Fisher
and used directly without further purifications. Chromatography was carried out using 100-200
or 230-400 mesh silica gel. Thin-layer chromatography (TLC) analysis was performed with TLC
plates from Sigma-Aldrich and visualized using UV lamp at 254 nm and stained with PMA
1
13
ethanol solution. H NMR and proton-decoupled C NMR spectra were obtained with Bruker
400 MHz spectrometers in CDCl3. Proton and carbon spectra chemical shifts were reported using
CDCl3 as internal standard at 7.26 ppm and at 77.00 ppm respectively. HRMS analyses were
completed with positive electrospray ionization on a Bruker 12 Tesla APEX -Qe FTICR-MS
with an Apollo II ion source. The optical rotations were measured on a Jasco P-2000 polarimeter,
using a wavelength of 589 nm and tungsten light source and a 10 mm glass cuvette. The specific
T
rotation was cacluated using the formula, [α]D = α/(l x c), l is path length in dm, and c is
concentration in g/mL.
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Gelation test:
In general, about 2 mg of the compounds were tested in a 1 dram vial with a rubber lined screw
cap. To this vial, solvents were added in a 0.1 mL increment. A starting concentration of 20
mg/mL was used. The mixture was heated and sonicated until the sample was fully dissolved.
The mixture was then allowed to cool at room temperature for 30 mins. The vial was then
examined visually. If it appeared as a homogenous solid, the vial was then inverted; and if after
being inverted, no solvent flows, then the gel is called a stable gel. If the semi-solid like material
fell apart while being inverted, it is called an unstable gel. A serial dilution is performed on the
stable gel formed until the resulting gel is no longer stable. The concentration prior to the
formation of the unstable gel was recorded as the minimum gelation concentration (MGC).
Optical microscopy:
A small amount of gel was transferred to a clean glass slide using a spatula or pipette and was
observed directly under an optical microscope. Some of the gels were left drying in a desiccator
for a few hours if too much liquid prevented imaging. The gels were observed using the
Olympus BX60M optical microscope and the Olympus DP73-1-51 high performance 17MP
digital camera with pixel shifting and Peltier cooled. The imaging software for image capturing
was CellSens 1.11.
Rheological analysis:
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The elasticity and stability of the gels were determined using rheological analysis. The rheology
experiment was performed on HR-2 Discovery hybrid rheometer by TA instrument, operating in
an oscillatory mode, with a 25 mm stainless steel parallel plate geometry. The Peltier
temperature controller was set to maintain a temperature of 25 °C during the measurement.
Typically 0.5-1 mL of gels were transferred quickly to the center of the Peltier plate, the gel
samples were analyzed immediately with a gap of 100 µm, and dynamic frequency sweep was
performed from 0.1 to 100 rad/s with 5% strain. An amplitude sweep was also done from 0.1-
10% oscillation strain.
Naproxen release analysis:
A gel was prepared in a 1 dram vial using compound 27 (2 mg) and naproxen sodium (0.5 mg) in
1 mL DMSO:H2O (v/v 1:2). After a stable gel was formed, aqueous solution (3 mL) at different
pHs was added on top of the gel carefully. The amount of naproxen released from the gel phase
to aqueous phase was recorded using UV-vis spectrometer at different time. After each
measurement, the aqueous solution was carefully transferred back to the same vial and placed on
top of the gel again till the next measurement. The UV spectra collected were plotted and shown
in Figure 10, the λmax = 331 nm was used for estimating the concentration of naproxen. The UV
spectra of naproxen and gelator standard in the solvent systems were also recorded. The
chloramphenicol release study was done similarly as described above, the detailed procedure and
figures are included in the supporting information.
Synthesis of peracetylated lactosyl β-azide 6:
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