Water gelation abilities of alkylbenzyltriazole-appended 2′-deoxyribonucleoside and ribonucleoside

Article abstract of DOI:10.1039/b617559g

Effective hydrogelators based on alkylbenzyltriazole-appended 2′-deoxyribonucleioside and ribonucleoside nucleobase-modified uridine were prepared and the dependence of gelation properties on the nature of single hydroxyl group was investigated. The nucleosides were synthesized by modifying the position of the uracin base with alkylbenzyltriazole units. The small molecular-based gelators of organic and aqueous solvents were prepared from amino acids, bis-ureas, sugars, nucleic acid, and steroids. It was found that the balance between the hydrophilic and hydrophobic characteristics and the nature of the gelators' interactions proved to be an important factors for the small molecular hydrogelators. It was also found that the uridine-based hydrogelators exhibited gelation behavior different to that of corresponding 2-deoxyuridine based systems. The results show that they possess relatively higher minimum gelation concentrations (MGC).

Full text of DOI:10.1039/b617559g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Water gelation abilities of alkylbenzyltriazole-appended
2ꢀ-deoxyribonucleoside and ribonucleoside†
Sun Min Park, Yongcun Shen and Byeang Hyean Kim*
Received 1st December 2006, Accepted 5th January 2007
First published as an Advance Article on the web 17th January 2007
DOI: 10.1039/b617559g
Alkylbenzyltriazole units covalently bonded onto uridine
nucleosides were synthesized and their suitability for water
gelation compared with 2ꢀ-deoxyuridine derivatives was
tested.
Various types of small molecule-based gelators of organic and
aqueous solvents have been investigated to determine their
essential characteristics for gelation.1 These systems, which have
been prepared from amino acids,2 bis-ureas,3 sugars,4 nucleic
acids,5,6 and steroids,7 are designed to self-assemble through
aggregation mediated by hydrophobic, dipole–dipole, van der
Waals, p–p, and hydrogen bonding interactions.1 For the small
molecule hydrogelators in particular, the balance between their
hydrophilic and hydrophobic characteristics and the nature of the
gelators’ interactions with water are important factors.8 Hydrogels
are receiving an increasing amount of attention from both
academia and industry because of their potential applications9
and, therefore, it remains necessary to establish the design rules
for preparing hydrogelators effectively.
Fig. 1 2ꢀ-Deoxyuridine (1a–d)- and uridine (2a–d)-based hydrogelators.
We are interested in developing chemically modified nucleoside-
based hydrogelators that will behave as delivery systems. Although
a few examples of nucleic acid-based hydrogelators are known,
they do not appear to follow any common design rules.5a,6 In this
paper, we report the preparation of effective hydrogelators based
on nucleobase-modified uridine and describe how the gelation
properties depend crucially on the nature of a single hydroxyl
group.
In a previous paper,5a we reported that the alkylbenzyl triazole-
appended 2ꢀ-deoxyuridines 1a–d form gels in water; the best gelator
of that series was the ethylbenzyltriazole-appended 2ꢀ-deoxy-
uridine 1c. In this study, we investigated the corresponding series
of uridine derivatives, i.e., systems that exhibit one extra hydroxyl
group and, therefore, possess somewhat increased hydrophilicity
(Fig. 1). We introduced the same appending units, alkylbenzyl-
triazole groups, to compare how the hydrophilic/hydrophobic
balance affects each system. We synthesized the four nucleosides
by modifying the 5-position of the uracil base with alkylbenzyltri-
azole units using methods similar to those we described previously
(Scheme 1).5a
Scheme 1 Synthesis of alkylbenzyltriazole-appended uridines. Reagents
and conditions: (a) acetic anhydride, triethyl amine, 1,4-dioxane, rt;
(b) iodine, ammonium cerium(IV) nitrate, MeCN, 80 ◦C, 1 h; (c) TM-
S-acetylene, Pd(PPh3)2Cl2, CuI, triethylamine–THF (3 : 1), 45–50 ◦C;
(d) TBAF, THF, rt; (e) 1. alkylbenzylazide, Na-ascorbate, CuSO4·5H2O,
tert-BuOH–H2O (1 : 1), rt, 2. K2CO3, MeOH–H2O (1 : 1), rt.
minimum gelation concentrations (MGCs), with three of them
(2a–c) forming unstable partial gels in water (Table 1); in addition,
these systems required more than 5 min to establish hydrogelation.
Table 1 Gelation properties of 1a–d and 2a–d in water at room
temperaturea
As expected, the uridine-based hydrogelators exhibited gelation
behavior different to that of the corresponding 2ꢀ-deoxyuridine-
based systems. In general, they possessed relatively higher
1
2
a
b
c
G (0.3)
G (0.6)
G (0.2)
G (0.8)
UG (2.5)
PG (4.0)
PG (4.0)
G (1.0)
Laboratory for Modified Nucleic Acid Systems, Department of Chemistry,
BK School of Molecular Sciences, Pohang University of Science and Tech-
nology, Pohang, 790-784, Korea. E-mail: bhkim@postech.ac.kr; Fax: +82
54 279 3399; Tel: +82 54 279 2115
† Electronic supplementary information (ESI) available: Experimental
procedures and characterization details. See DOI: 10.1039/b617559g
d
a G: Stable gel; UG: unstable gel; PG: partial gel. Minimum gelation
concentrations (MGCs) are provided in parentheses (wt%).
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Fig. 2 SEM images of the xerogels formed from hydrogels. The white scale bars are 2 lm long in 2a and 1d, 200 nm long in 2b and 1c, and 500 nm long
in 2c and 2d.
The hydrogels formed by the modified uridines were less opaque
than those of 2ꢀ-deoxyuridine-based hydrogelators despite their
higher MGCs. Compound 2a began to precipitate from the gel
after 1 h; of this series of uridine-derived compounds, 2d formed
the most stable hydrogel and had the lowest MGC. We used
scanning electron microscopy (SEM) to examine the nano- or
meso-scale structures of these uridine-based hydrogels. Fig. 2
displays the SEM images of the xerogels (freeze-dried gels)
prepared from the hydrogels. Interestingly, the xerogels formed
from 2b and 2d had fibrous morphologies, unlike the lamellar
structures observed for their corresponding 2ꢀ-deoxyuridine-based
congeners. With the exception of the xerogel prepared from 2a,
these systems all possessed more densely intertwined, but thinner,
nanofibers (the individual fibers had diameters of ca. 10–30 nm)
than we had observed previously (note in Fig. 2 that the xerogel
prepared from 1c possesses nanofibers having an average diameter
of ca. 30–50 nm).
To evaluate the different gelation behavior in more detail, we
measured the FTIR spectra of the gel and solid phases of the four
compounds that exhibited the best gelation ability, namely the
pairs of ethylbenzyltriazole- and butylbenzyltriazole-substituted
systems. We carefully monitored the signals in the FTIR spectra in
the range of 1500–1700 and 3000–3500 cm−1; Table 2 summarizes
the results.
The peaks in the wavenumber range from 1500 to 1700 cm−1
represent the amide I and amide II bands. For 2c, 2d, and 1d, the
wavenumbers of both of these bands increased upon proceeding
from the solid phase to the gel phase. This finding indicates
a change in the hydrogen bonding pattern—namely stronger
and weaker hydrogen bonds for the carbonyl and NH units,
respectively, in the gel phase.10 In the case of 1c, however, the
wavenumber of the amide I band increased while that of the
amide II band decreased slightly, suggesting that the hydrogen
bonding interactions of the carbonyl and NH units were the main
interactions in both phases.
We monitored the hydrogen bonding of the hydroxyl groups by
observing their peaks in the range 3000–3500 cm−1. The signals for
the hydroxyl groups of hydrogelators 2c and 2d were much broader
in both the gel and solid phases relative to those of 1c and 1d.
Because the uridine-based hydrogelators in series 2, both have an
additional hydroxyl group in their sugar moieties, it is not surpris-
ing that they would be more hydrophilic (i.e., interact to a greater
degree with water molecules) than the compounds in series 1.
The FTIR spectroscopic signals correlate with the values of
MGC and the stabilities of the hydrogels. For example, the best
hydrogelator, compound 1c, exhibited a different signal pattern for
its amide I and II bands; both the carbonyl and NH moieties of
the uracil base participated in intermolecular hydrogen bonding
interactions. In the cases of 2c, 2d and 1d, however, only the
carbonyl moieties took part in hydrogen bonding interactions.
That is to say, hydrogelator 1c self-assembled into fibers through
the action of its additional hydrogen bonding unit; its balance
between hydrophilicity and hydrophobicity in water resulted in
the formation of a stable hydrogel. Although the NH moieties
of the hydrogelators 2c and 2d were not involved in hydrogen
bonding, these compounds possess the additional hydroxyl group,
which enables favorable additional intermolecular interactions. As
a result, they also exhibited fibrous self-assembled microstructures
in their SEM images. Nevertheless, the presence of the additional
hydroxyl group results in these compounds interacting to a greater
extent with the solvent (water).
Table 2 Wavenumbers (cm−1) for the IR absorption signals of the
hydroxyl groups and amide I & II bands
Hydroxyl group
Amide I band
Amide II band
1c
1d
2c
2d
KBr
Gel
KBr
Gel
KBr
Gel
KBr
Gel
3452
3250
3477
3250
3352 (br)
3394 (br)
3350 (br)
3394 (br)
1680
1697
1647
1695
1650
1652
1650
1653
1543
1542
1511
1542
1515
1540
1511
1541
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Therefore, most of the uridine-based hydrogelators did not
form stable hydrogels. Of the uridine-based hydrogelator systems,
the best balance of hydrophilicity and hydrophobicity—i.e., the
best gelation behavior—was that of compound 2d; the extra hy-
drophilicity imparted by the additional hydroxyl group in the sugar
moiety was offset by the hydrophobicity of the butylbenzyl group
in the base moiety to provide the most effective hydrogelation. The
validity of this design rule is presently under further investigation.
In summary, we have studied the properties of new uridine-
based hydrogelators in comparison with their 2ꢀ-deoxyuridine-
based congeners, which we had reported previously. As expected,
these two series of nucleoside-based gelators displayed differ-
ent gelation properties. For example, the butylbenzyltriazole-
appended hydrogelator 2d was the most effective gelator of the
uridine series, but its mode of self-assembly leading to hydrogela-
tion was different from that of the ethylbenzyltriazole-appended
hydrogelator 1c, the best system among the 2ꢀ-deoxyuridine series.
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Acknowledgements
We are grateful to KOSEF for financial support through the
National Research Laboratory Program (Laboratory for Modified
Nucleic Acid Systems) and Gene Therapy R & D program
(MA0534000011-05N3400-01110).
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