Synthesis and anti-inflammation evaluation of new C60 fulleropyrrolidines bearing biologically active xanthine

Article abstract of DOI:10.1016/j.bmcl.2007.11.004

We designed and prepared the new C₆₀ fullerene hybrids bearing a xanthine moiety as potential double-action anti-inflammatory agents, capable of simultaneous inhibition of LPS-induced NO and TNF-α production. The 10 μM of fulleropyrrolidine-xanthine dyad 2a and b were effective in suppressing LPS-induced NO production by 55.1 ± 2.1% and 58.6 ± 2.6%, respectively, but only 2b was also effectively in suppressing LPS-induced TNF-α production by 34.0 ± 2.7%. We believed that the agents synthesized herein would hold promise for future development of a new generation of potent anti-inflammatory agents.

Full text of DOI:10.1016/j.bmcl.2007.11.004

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 99–103
Synthesis and anti-inflammation evaluation of new C60
fulleropyrrolidines bearing biologically active xanthine
a
b
c
Sheng-Tung Huang,a,b, Jian-Sheng Liao, Hsu-Wei Fang and Chun-Mao Lin
*
aGraduate Institute of Biotechnology, National Taipei University of Technology, Taipei, Taiwan
bDepartment of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei, Taiwan
cCollege of Medicine, Taipei Medical University, Taipei, Taiwan
Received 24 August 2007; revised 17 October 2007; accepted 1 November 2007
Available online 5 November 2007
Abstract—We designed and prepared the new C60 fullerene hybrids bearing a xanthine moiety as potential double-action
anti-inflammatory agents, capable of simultaneous inhibition of LPS-induced NO and TNF-a production. The 10 lM of fullero-
pyrrolidine-xanthine dyad 2a and b were effective in suppressing LPS-induced NO production by 55.1 2.1% and 58.6 2.6%,
respectively, but only 2b was also effectively in suppressing LPS-induced TNF-a production by 34.0 2.7%. We believed that
the agents synthesized herein would hold promise for future development of a new generation of potent anti-inflammatory agents.
ꢀ 2007 Published by Elsevier Ltd.
Research in the field of water-soluble C60 fullerene
derivatives has significantly increased due to the broad
range of biological activity that was found for these
compounds.1 However, the low water solubility of ful-
lerenes had always been an important issue for biologi-
cal use. One of the current approaches to overcome the
lack of fullerenes’ solubility in aqueous media is by
chemical modification of the fullerenes to incorporate
the polar functionalities such as carboxylate, polyethers,
polyols, and dendrons, so that they acquire solubility in
polar media.2 Recently, the preparation of novel water-
soluble fullerene hybrids bearing a variety of functional
moieties such as peptides,3 oligonucleotides,4 porphy-
rins,5 flavonoids,6 have attracted much attention. Such
dyad systems could amplify or alter the biochemical
characteristics of their components or even produce
compounds with new biological properties.
immune response. The cytokine responses to cell injury
are a regulated process and are usually beneficial to
the host, but overexpression of these cytokines can cause
serious diseases including, rheumatoid arthritis, multiple
sclerosis, asthma, and psoriasis.
Current therapeutic approaches to the treatment of
inflammatory diseases are centered on the suppression
of the NO or TNF-a production.8 It has been reported
that suppression of oxidative stress-mediated NO eleva-
tion might be beneficial in reducing the development of
inflammation.9 The intracellular second messenger,
cAMP, is also a very potent immunomodulator, exerting
generally suppressive effects on the function of inflam-
matory and immunocompetent cells.10 Activation of
the cAMP/PKA pathway inhibits the production of
pro-inflammatory cytokine TNF-a.11 The inhibitors
which inhibit the activity of cyclic adenosine monophos-
phate-phosphodiesterase (cAMP-PDE) are helpful in
the increased intracellular concentration of cAMP and
subsequent suppression of the production of pro-inflam-
matory cytokine TNF-a.11
The two pro-inflammatory cytokines, nitric oxide (NO)
and tumor necrosis factor a (TNF-a) have been recog-
nized as essential components in acute and chronic
inflammatory processes.7 The production of NO and
TNF-a serves to recruit other inflammatory cells, which
in turn release cytokines and subsequently amplify the
With this in mind, we desired to design a hybrid agent
which simultaneously inhibited the NO and TNF-a pro-
duction during inflammation. This hybrid agent would
be useful for the treatment of inflammatory diseases.
We envisioned that a hybrid agent, C60 fulleropyrroli-
dine-xanthine dyads 2a and b, would serve this purpose
(Fig. 1). The basic chemical architecture of dyads 2a and
Keywords: Anti-inflammation; C60 fulleropyrrolidine; TNF-a; Nitric
oxide; Xanthine.
*
Corresponding author. Tel.: +886 2 2771 2171x2525; fax: +886 2
2731 7117; e-mail: ws75624@ntut.edu.tw
0960-894X/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2007.11.004

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S.-T. Huang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 99–103
inflammatory cytokine TNF-a by macrophage. In this
study, we also prepared the fulleropyrrolidine analogue
3 which lacked the xanthine moiety to evaluate its inhib-
itory effect on the LPS-induced NO and TNF-a produc-
tion. We believed that C60 fulleropyrrolidine-xanthine
dyads 2a and b could express synergistic immunomodu-
latory effects during inflammation.
The synthesis of fulleropyrrolidine-xanthine dyads 2a
and b is outlined in Scheme 1. The synthesis began with
the preparation of amide 6. Coupling the 1-pentonic
acid -3, 7-dimethylxanthine (4)15 with a known amine
salt 517 under standard peptide coupling conditions gave
the corresponding amide 6 in 77% yields. Removing two
protecting groups in 6 in a palladium-catalyzed hydro-
genation reaction furnished the N-alkylated glycine 7
in 91% yields. The fulleropyrrolidine moiety in 2 was
constructed by the 1–3 dipolar cycloaddition reac-
tions.17 Condensing the N-alkylated glycine 7 with
known aldehyde 8a17 or di-methoxyethoxymethyl
(MEM) protected ketone 8b18 formed the corresponding
azomethine ylide (not shown) which underwent the 1–3
dipolar cycloaddition reactions with C60 fullerene to
yield the desired C60 fulleropyrrolidine-xanthine dyads
2a and b, and the yields were 28% and 25%, respectively.
The chemical structures of both dyads 2a and b had been
characterized by 1H NMR, 13C NMR, and mass.19 Sev-
eral attempts to prepare 2c by cleaving the di-MEM pro-
tecting groups in 2b under various conditions (ZnBr2/
HCl, CBr4/IPA, HCl) were fruitless, and they gave
mostly unidentifiable products. The syntheses of the
C60 fulleropyrrolidine-xanthine dyads 2a and b were
completed in three steps from the known starting
materials.
Figure 1.
b is composed of 1-pentonic acid-3,7-dimethylxanthine
linked to the nitrogen of a C60 fulleropyrrolidine moiety
through ethylene glycol chains, and an additional polar
side chain was strategically positioned on the fullerene
spheroid of the dyads to provide the extra hydration
sites in order to enhance the solubility in the aqueous
media. The peculiar structure of C60 fullerene which is
capable of ‘adding’ multiple radicals per molecule serves
as a ‘radical sponge’.12 It was recently shown that a
number of water-soluble fullerene derivatives behaved
as potent antagonists of the basal and acetylcholine-
stimulated NO-mediated relaxation,13 and the possible
mechanism of these fullerene derivatives in the inhibi-
tion of NO-dependent relaxation was associated with
their radical scavenging and direct NO quenching activ-
ity.12b Xanthine analogues, caffeine and its major metab-
olite, paraxanthine, suppress neutrophil and monocyte
chemotaxis and also suppress production of the pro-
inflammatory cytokine TNF-a from human blood.14
Xanthine analogues, pentoxifylline (PTX), which is
widely used in the treatment of cerebrovascular and
peripheral vascular disease, and PTX analogue 115 were
known to posses anti-inflammation properties which are
related to their ability to suppress the synthesis of TNF-
a by macrophages through inhibition of the cAMP-PDE
activity. We postulated that the fulleropyrrolidine moi-
ety in 2 should be capable of reducing the NO released
by macrophages through scavenging the excess ROS
produced or by direct NO-quenching activity during
inflammation. Since, Tzeng et al. had shown that
water-soluble bis-malonate C60 derivatives did not exhi-
bit the inhibitory effects on LPS-induced TNF-a pro-
duction in microglia cells,16 we envisaged that the
xanthine moiety in 2 would act as an inhibitor of
cAMP-PDE thus suppressing the production of pro-
One of our goals in this study is to prepare the water-
soluble C60 fullerene derivatives. Both dyads 2a and b
were soluble in 1% DMSO aqueous solution with a max-
imum concentration of 1.5 · 10À5 M, and 1.0 · 10À5 M,
respectively.20 Recently, there are several papers describ-
ing the preparation of novel fulleropyrrolidine hybrids
bearing promising biological components, but their best
solubility in a 10% DMSO aqueous solution was re-
ported to be in the range of ꢀ10À5 M,21 and this pre-
sents a challenge to the further evaluation in a
mammalian cell culture model. The concentration of
DMSO exceeding 1% in cell media caused instability
of mammalian cells during culturing and biological eval-
uation. Both dyads 2a and b were soluble in 1% DMSO
aqueous solution, and they were suitable for evaluation
with a mammalian culture model.
We utilized the murine reticulum sarcoma cell line
J774A.1 with lipopolysaccharide (LPS) to simulate the
type of macrophages during inflammation for biological
evaluation.22 We first analyzed the cytotoxic effects of
both dyads 2a and b against a J774A.1 cell culture line-
age via MTT assay; and the cell viability results are
shown in Supplementary data. Cytotoxicity studies after
24 h of continuous exposure to the various concentra-
tions of dyads 2a and b with or without LPS stimulation
were measured with a colorimetric assay based on the
ability of mitochondria in viable cells to reduce MTT

S.-T. Huang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 99–103
101
Scheme 1. Reagents and conditions: (a) EDCI, HOBT, Et3N, DMF, rt, 16 h, 77%; (b) H2 (60 psi), Pd/C, 18 h, 91%; (c) toluene, reflux.
as described previously.23 The J774A.1 cells pretreated
with 10 lM of either2a or b in the presence of 1 lg/ml
of LPS for 24 h had a viability close to 95% with respect
to the control. One interesting observation was that we
observed a slight increase in the cells viability when
J774A.1 incubated with 10 lM of either 2a or b without
LPS stimulation. Both dyads 2a and b were not cyto-
toxic to the J774A.1 cell culture lineage.
a synthesis (Fig. 2B). The J774A.1 pretreated with 10 lM
of either PTX or 2a exhibited a slight reduction of the
TNF-a, and the concentration of TNF-a detected in cell
medium were, 28.3 0.05 ng/ml and 26.7 1.5 ng/ml,
respectively, and those were 7.5 0.6% and
12.7 3.6% reduction with respect to the control. Once
again, dyads 2b exhibited an impressive effect on sup-
pressing the TNF-a production by the LPS-induced
TNF-a synthesis at either 1 or 10 lM of the pretreat-
ments; the concentration of TNF-a detected in the cells
medium were 25.8 0.5 ng/ml and 20.2 0.9 ng/ml,
respectively, and those were 15.6 + 0.6% and
34.0 2.7% reduction with respect to the control. The
fulleropyrrolidine-xanthine dyad 2a and b were equally
effective in suppressing LPS-induced NO production.
PTX and 2a exhibited weakly inhibition effect on the
LPS-induced TNF-a production, but only dyad 2b also
exhibited significant inhibition effect on LPS-induced
TNF-a production by the macrophages JA774A.1.
We evaluated the influence of both dyads on the LPS-
activated macrophages J774A.1 by determining the
amount of NO and TNF-a released into the cell superna-
tants. The J774A.1 cells were pretreated with either PTX
or two different concentrations of 2a and b (10, and
1 lM) for 3 h, followed by stimulating them with LPS
(1 lg/ml) for 24 h. The J774A.1 stimulated with LPS
alone was the control. The amount of NO was deter-
mined by measuring the nitrite concentrations in the cell
supernatants after 24 h treatment.24 The concentration
of TNF-a was determined by the ELISA method as de-
scribed according to prior known art.25 The results are
shown in Figure 2. The macrophages J774A.1 pretreated
with 10 lM of either 2a or b for 24 h in the absence of
LPS stimulation did not induce any NO or TNF-a pro-
duction by the cells (shown in Supplementary data).
All tested agents, PTX, 2a and b, showed an inhibitory
effect on LPS-induced NO production (Fig. 2A). The
J774A.1 pretreated with 10 lM of either the PTX or
the 2a exhibited a reduction of the NO produced, and
Because dyad 2b was the most effective agent tested
herein, we were interested in evaluating the effect of
dyad 2b without the xanthine moiety on J774A.1 after
the LPS stimulation. We designed and synthesized 3, a
structural analogue of 2b which lacked the xanthine
moiety. The synthesis of 3 was similar to that for dyad
2b, and it was also completed in 3 steps from the known
starting materials with overall yield of 18%.19 We evalu-
ated the influence of 3 on the LPS-activated J774A.1 by
determining the amount of NO and TNF-a released in
the cell medium, and the results are also shown in Figure
2. The 10 lM of fulleropyrrolidine 3 effectively inhibited
on LPS-induced NO production by 52.1 2.3%, but it
had little influences on the LPS-induced TNF-a produc-
tion by the macrophages. These results suggested that
the C60 fulleropyrrolidine moiety alone was unable to in-
hibit the LPS-induced TNF-a production by cells in a
simulated inflammation cell model.
the
concentrations
of
NO
produced
were
24.4 0.05 lM and 16.6 0.7 lM, respectively, and
those were 33.9 0.2% and 55.1 2.1% reduction with
respect to the control. In contrast, the dyad 2b was a po-
tent agent for reducing the NO released, and the concen-
trations of NO detected in the cell supernatants were
15.3 1.1 lM and 19.4 1.3 lM when the cells were
pretreated with 10 lM and 1 lM of 2b, respectively,
and those were 58.6 2.6% and 47.5 2.7% reduction
with respect to the control. All agents tested herein had
no quenching effect on the Griess reagent at the concen-
trations used. On the other hand, 10 lM of either PTX or
2a exhibited little inhibitory effect on LPS-induced TNF-
The 2b was more effective then PTX in inhibiting the
LPS-induced NO production by the macrophage, and
the chemical structure of 2b is a combination of PTX

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S.-T. Huang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 99–103
details of the molecular pharmacological studies involv-
ing dyad 2b are underway.
In conclusion, we successfully prepared new C60 fullero-
pyrrolidines bearing biologically active xanthine, 2a and
b. Our preliminary biological evaluation using a cell
lineage to simulate the type of macrophages present dur-
ing inflammation had identified that 10 lM of dyad 2b
was the most potent agent to reduce both NO and
TNF-a released into cells medium. Furthermore, inte-
gration of a xanthine onto a C60 fulleropyrrolidine
exhibited an inhibitory effect on LPS-induced TNF-a
production. The present study has demonstrated that a
C60 fulleropyrrolidine hybrid bearing xanthine could
be a potent agent to inhibit LPS-induced NO and
TNF-a production. We believed that the agents synthe-
sized herein would hold promise for future development
of a new generation of potent anti-inflammatory agents.
Acknowledgment
This work was supported by Nation Science Council
(NSC 94-2113-M-027-004).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2007.11.004.
References and notes
Figure 2. Inhibition of nitrite and TNF-a production by PTX, 2a, b,
and 3 in LPS-stimulated murin macrophage cell in J774A.1. (A) Nitrite
production in J774A.1 cells were pretreated with the indicated
concentration of PTX, 2a, b, and 3 for 3 h. The cells were activated
with LPS (1 lg/ml). Control cells were incubated with DMSO alone.
Culture supernatants were collected after a 24 h activation. (B) TNF-a
production in J774A.1 cells were pretreated with the indicated
concentration of PTX, 2a, b, and 3 for 3 h. The cells were activated
with LPS (1 lg/ml). Control cells were incubated with 1% DMSO
alone. Culture supernatants were collected after a 24 h activation.
Error bars represent standard error of mean (n = 3). *Significant
difference (P < 0.01) compared with the control treated with LPS.
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