A novel bitriazolyl acyclonucleoside endowed with dual antiproliferative and immunomodulatory activity

Article abstract of DOI:10.1021/jm300534u

A novel bitriazolyl acyclonucleoside was discovered to exhibit powerful antiproliferative effects on different cancer cell lines through caspase-dependent apoptosis and at the same time stimulate the immune response in dendritic cells via Toll-like receptor 7 (TLR7) signaling. This promising compound with dual anticancer and immunomodulatory activity may represent a new generation of highly efficacious drug candidates for use in cancer therapy.

Full text of DOI:10.1021/jm300534u

Brief Article
pubs.acs.org/jmc
A Novel Bitriazolyl Acyclonucleoside Endowed with Dual
Antiproliferative and Immunomodulatory Activity
Yi Xia,†,# Menghua Wang,†,‡,# Olivier Demaria,§,⊥ Jingjie Tang,‡ Palma Rocchi,∥ Fanqi Qu,‡
Juan L. Iovanna,∥ Lena Alexopoulou,§ and Ling Peng*,†
†Dep
‡State Key Laboratory of Virology, College of Chemistry and Molecular Sciences, Wuhan University, P. R. China
§CIML CNRS UMR 7280, UM2, INSERM U1104, Aix-Marseille Universite,
Marseille, France
∥CRCM UMR 1068 INSERM, Institut Paoli-Calmettes, Aix-Marseille Universite,
Marseille, France
́ ́
artement de Chimie, CINaM CNRS UMR 7325, Aix-Marseille Universite, Marseille, France
́
́
S
* Supporting Information
ABSTRACT: A novel bitriazolyl acyclonucleoside was discovered to exhibit powerful antiproliferative effects on different cancer
cell lines through caspase-dependent apoptosis and at the same time stimulate the immune response in dendritic cells via Toll-
like receptor 7 (TLR7) signaling. This promising compound with dual anticancer and immunomodulatory activity may represent
a new generation of highly efficacious drug candidates for use in cancer therapy.
INTRODUCTION
■
Cancer is one of the most difficult known diseases to treat
because of its high genetic heterogeneity and fast developing
drug resistance. The development of cancer therapies over the
past few decades has principally concerned chemotherapy
combined with other treatment modalities such as surgery,
radiotherapy, and targeted therapy. However, there is still an
urgent need for novel anticancer drug candidates able to induce
a more durable response and further facilitate tumor eradication
in cancer patients. Cancer immunotherapy has gained interest
based on the hypothesis that the progression of spontaneous
malignancies can be suppressed by the immune system.1,2
A
growing body of recent evidence suggests that the combination
of immunotherapy and chemotherapy holds enormous
potential to enhance clinical benefits due to its targeting of
different tumor-cell survival pathways and overcoming drug
resistance in advanced-stage cancers.3,4 At present, this
combined modality goal is mainly achieved by combining
cancer vaccines with chemotherapeutic drugs.3,4 However,
anticancer agents able to simultaneously stimulate tumor-
specific immune responses have attracted much attention
recently considering the potential that harnessing such a
synergic effect may have on more effectively combating tumor
progression.5
Nucleoside analogues represent a significant class of drugs
that elicit antimetabolic6 and immunostimulatory activity.7
Ribavirin (Figure 1), a triazole nucleoside currently recom-
mended in the treatment of the infection caused by hepatitis C
virus,8 is known to promote host T-cell-mediated immunity
against viral infection,9 while certain guanine ribonucleoside
analogues (isatoribine in Figure 1) have been reported to
potentiate immune responses via the activation of Toll-like
receptor 7 (TLR7).7 In our continuing efforts to develop novel
aryltriazole nucleosides imparted with biologically interesting
activities,10−12 we have focused much attention on nucleoside
analogues bearing a bitriazolyl moiety (1 and 2 in Figure 1).
Figure 1. Structures of ribavirin, isatoribine, and bitriazolyl
acyclonucleosides 1, 2, and 3.
This is because their more expanded aromatic surface and
increased rigidity of the nucleobase may favor interactions with
biological targets to induce potent anticancer and antiviral
activities.10−19 Here, we disclose a novel bitriazolyl acyclonu-
cleoside (3i in Figure 1) endowed with dual anticancer and
immunomodulatory activity. This compound belongs to a new
family of bitriazolyl acyclonucleosides (3 in Figure 1) which
were synthesized via the Cu(I) catalyzed Click process starting
from terminal alkyne-containing triazole acyclonucleoside and
various arylazides. 3i displayed potent antiproliferative activity
against different cancer cell lines and was able to activate
caspase-dependent apoptosis in the drug-resistant pancreatic
cancer MiaPaCa-2 cell line. Most importantly, this compound
was also able to stimulate the immune response in mouse
dendritic cells through the activation of TLR7. This dual-acting
anticancer and immunomodulating compound may constitute a
potentially interesting drug candidate for cancer therapy. We
present below the synthesis of this novel bitriazolyl
Received: April 15, 2012
© XXXX American Chemical Society
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Journal of Medicinal Chemistry
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acyclonucleoside and the evaluation of its anticancer and
immunomodulatory activity.
Investigation of the scope of substrate demonstrated that the
reaction between 6 and arylazides bearing electron-donating
groups usually gave quantitative yields (3b and 3c in Table 1),
while that concerning the electron-withdrawing azides was
associated with slightly lower yields (3d and 3e in Table 1).
This can be explained by the fact that the electron-withdrawing
group may impair the nucleophilicity of the azides and lead to
an unfavorable cycloaddition reaction. Noteworthy is that since
the pyrenyl group is relatively hydrophobic, increasing the ratio
of organic solvent in the reaction dramatically ameliorated the
yield of 3i (Table 1). Finally, the subsequent ammonolysis of 3
in NH3/MeOH furnished the desired products 3′ favorably
(Table 1).
CHEMISTRY
■
The motivation behind developing the bitriazolyl acyclonucleo-
sides 3 was based on our previous results obtained with the
bitriazolyl acyclonucleosides 1 and 2.15,16 Though compounds
1 have potent antiviral and anticancer activities,10 the linkage
between the two triazole units via a C−N bond makes this
family of compounds unstable and difficult to synthesize in
good yields at large quantities,15 thus limiting their potential
future application. By bridging of the 1,2,3-triazole ring to the
1,2,4-triazole system via a C−C bond, the stability of the
bitriazolyl acyclonucleosides 2 is significantly increased.16
However, the synthetic strategy does not afford this family of
compounds in their pure form of a 2(a) or 2(b) isomer but
rather a mixture of both. We therefore envisioned the novel
bitriazolyl acyclonucleosides 3, which could be conveniently
prepared via Huisgen reaction and obtained in straightforward
isomeric pure form with precise structure.
EVALUATION OF ANTIPROLIFERATION ACTIVITY
■
The initial biological screening of the bitriazolyl acyclonucleo-
sides 3 and 3′ was performed in human drug-resistant
pancreatic cancer MiaPaCa-2 cells by measuring their
antiproliferation activity using MTT (3-(4,5-dimethylthiazol-
2-yl)-2,5-diphenyltetrazolium bromide) assay. Of all the novel
compounds synthesized, 3i showed exceptional cell growth
suppressing activity that was superior to the currently
recommended anticancer drug gemcitabine (Figure 2A). To
The synthesis of 3 was adapted from that previously
reported15,16 and comprised a Cu(I)-catalyzed Huisgen
reaction by coupling the terminal alkyne bearing acyclonucleo-
side 6 with various arylazides followed by the deprotection
(scheme in Table 1). 6 was produced by a two-step reaction
Table 1. Synthesis of Compounds 3 and 3′
Figure 2. Inhibitory effect of compound 3i on different cancer cell
lines. (A) The indicated cell lines were left untreated (control) or
incubated with 50 μM 3i or 50 μM gemcitabine, and cell viability was
assessed 48 h later by MTT. (B) The indicated cell lines were
incubated with various concentrations of 3i, and cell viability was
assessed 48 h later by MTT. The values are the mean SE of three
independent experiments.
R2
3
yield, %
3′
yield, %
Ph
3a
3b
3c
3d
3e
3f
73
98
98
76
62
83
78
3′a
3′b
3′c
3′d
3′e
3′f
99
85
99
91
96
89
94
92
73
4-Me-Ph
4-OMe-Ph
4-CF3-Ph
4-NO2-Ph
CH3(CH2)11
benzyl
3g
3h
3i
3′g
3′h
3′i
further assess its activity against other cancers, 3i was
investigated across other cancer types using gemcitabine as
the reference control. As shown in Figure 2A, in addition to its
growth inhibitory effect on MiaPaCa-2 cells, 3i was able to
inhibit the proliferation of the human pancreatic cancer Capan-
2 and Panc-1, prostate cancer PC-3, cervical cancer HeLa, and
breast cancer MCF-7 cell lines. Moreover, a dose-dependent
assay with 3i in the above-mentioned cell lines conducted at 50
nM to 200 μM revealed a 50% growth inhibition (IC50) of most
cell lines at a dose of 10 μM or below (Figure 2B).
a
1-naphthalenyl
1-methylpyrenyl
83, 97
a
44, 99
a
The experiment was performed in THF/H2O = 3/1.
sequence including the Sonogashira reaction of 5-bromotriazole
acyclonucleoside 4 with trimethylsilylacetylene (TMSA) and
the subsequent deprotection of the trimethylsilyl (TMS) group
in the presence of KF (scheme in Table 1).17,20 The synthesis
of 3 involved the Huisgen reaction of 6 with arylazides in the
presence of CuSO4/sodium ascorbate using THF/H2O as
solvent, which gave good to excellent yields (Table 1).
Considering the potent anticancer activity shown by 3i, we
performed a structure−activity relationship analysis (Figure 3
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propidium iodide (PI) staining of the cellular DNA represents
an efficient method to monitor cell cycle distribution. As can be
seen in Figure 4A, in contrast to the untreated or gemcitabine-
Figure 3. Structural analogues of 3i.
and Supporting Information Figure S1) using pancreatic cancer
MiaPaCa-2 cells as the test model. Compound 3′i (Figure 3),
the deprotected form of 3i, showed significantly decreased
activity, and the ribonucleoside analogue 7 (Figure 3) was
devoid of any notable activity. This implies that alteration of the
sugar part of 3i was detrimental to anticancer activity. We then
turned our attention to the contribution of the pyrene group to
the anticancer activity of 3i and prepared compounds 8 and 9
bearing naphthalenyl and anthracenyl groups (Figure 3), both
of which are less bulky comparatively. Both 8 and 9 as well as
3g containing a benzyl group (Figure 3) showed reduced
anticancer activity, indicating the importance of the pyrene
system. To verify the contribution of the bitriazolyl motif, we
further synthesized the non-bitriazolyl compounds 10−12
(Figure 3 and Scheme S1), employing an alkynyl group, alkyl
chain, or amine functionality21 to replace the 1,2,3-triazole ring
and connect the 1,2,4-trizole with the pyrenyl moiety. The
considerably reduced activity exhibited by all these analogues
compared with 3i confirmed the pivotal role of the bitriazolyl
motif in the anticancer activity displayed by 3i. Finally, 13 (the
constitutional isomer of 3i) and 14, in which the CH2 group
between the pyrenyl group and the 1,2,3-triazole ring has been
removed (Figure 3), failed to elicit any notable activity,
indicating the detrimental effect of even minor structural
variation in 3i.
Figure 4. Apoptosis induction in pancreatic cancer MiaPaCa-2 cells
after 48 h treatment with 3i using gemcitabine (Gem) and no
treatment (Ctrl) as reference control. (A) DNA histograms from
control and treated cells. Proportion of cells in sub-G1/G0 phase
represents cells undergoing apoptosis. (B) Apoptosis but not necrosis
was induced following treatment of 3i, using flow cytometry to
quantify the cells undergoing apoptosis (annexin V positive cells) and
necrosis (7-AAD positive cells). (C) ELISA test for detection of
DNA/histone release. (D) Caspase-3/7 activity measurement. All the
experiments were done in triplicate.
treated condition, 3i treatment caused a much stronger
accumulation of apoptotic cells (the cells in sub-G0/G1
phase), indicating that the main mode of antiproliferative
activity shown by 3i was the induction of apoptosis. We went
on to test whether the 3i-treated cells underwent apoptosis and
necrosis by flow cytometry analysis using annexin V-FITC and
7-aminoactinomycin (7AAD) staining, respectively. In 3i-
treated cells, the percentage of apoptotic cells was increased
by more than 20-fold while no significant fraction of necrotic
cells (<0.5%) was observed even after 48 h of treatment,
suggesting the predominant role of apoptosis in 3i induced cell
death (Figure 4B). Early events in apoptosis can also be
revealed by DNA fragmentation and the subsequent release of
DNA/histone nucleosomes into the cytoplasm. We therefore
used an enzyme linked immunosorbent assay (ELISA) to
detect cytoplasmic nucleosomes, and a remarkable 15-fold
increase in DNA/histone nucleosome release was observed
after treatment with 3i compared with nontreated cells, which
was significantly greater than that caused by gemcitabine
(Figure 4C). We also examined the ability of 3i to induce
caspase-3/7 activation, the final molecular step leading to
apoptosis execution. Our data demonstrate that 3i treatment
could promote a significant increase in caspase-3/7 activity
compared with untreated or gemcitabine treated cells (Figure
APOPTOSIS-INDUCED ANTIPROLIFERATION
ACTIVITY
■
Altogether the obtained results highlighted 3i as possessing the
highest antiproliferative activity among all the newly synthe-
sized compounds described in this work. We therefore
evaluated its ability to induce apoptosis in the drug-resistant
pancreatic cancer cell line MiaPaCa-2. We first assessed the
proapoptosis effect of 3i using fluorescence-activated cell
sorting (FACS) flow cytometry. The FACS analysis based on
C
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Journal of Medicinal Chemistry
Brief Article
4D). Taken together, these results suggest that 3i has the ability
to induce apoptosis and may therefore constitute a potential
anticancer drug lead.
induce an immune response further highlights the promising
role of 3i as a lead of drug candidate for cancer therapy.
CONCLUSION
■
IMMUNOMODULATORY ACTIVITY
We have synthesized a novel family of bitriazolyl acyclonucleo-
sides 3 via a Huisgen reaction with remarkably improved yields
in mild reaction conditions. Among the synthesized com-
pounds, 3i exhibited the most powerful antiproliferative effects
on numerous cancer cell lines. This anticancer activity was
shown to be principally the result of caspase-dependent
apoptosis. Most interestingly, 3i also has the capacity to
stimulate the immune response in dendritic cells via TLR7
signaling, demonstrating the dual anticancer and immunomo-
dulatory activity of this lead compound. We believe our
discovery of the dual-acting 3i will provide a new perspective
and advancement of our program on triazole nucleosides in the
continuing quest for more potent candidates to treat cancer or
other life-threatening diseases in which the immune system has
an impact on the therapeutic outcome.
■
It is known that the triazole nucleoside ribavirin and the
guanine derivative isatoribine are the representative nucleoside
compounds capable of stimulating immune response in cells,
some of which act through TLR7 signaling.7,9 Since 3i is a
bitriazolyl nucleoside and triazole nucleosides are reported to
structurally mimic guanine nucleosides,9,22 we wanted to test
whether 3i also possessed immunomodulatory activity in
addition to its anticancer activity. To do so, bone marrow
dendritic cells derived from wild-type mice were stimulated
with two doses of 3i, and the production of interleukin-6 (IL-6)
in culture supernatants was measured 24 h later by ELISA. As
shown in Figure 5A, 3i induced the production of IL-6 in a
dose-dependent manner, indicating that 3i is able to induce an
immune response.
EXPERIMENTAL SECTION
■
All compounds were determined to be >95% pure by HPLC.
Synthesis of 3i. Compound 6 (26.7 mg, 0.10 mmol),
CuSO4·5H2O (1.3 mg, 0.005 mmol), and sodium ascorbate (9.9 mg,
0.05 mmol) were dissolved in a mixed solvent system (THF/H2O, 3:1,
4 mL) under argon. The 1-(azidomethyl)pyrene (30.8 mg, 0.12 mmol)
was added. The yellow mixture was stirred at 45 °C until complete
consumption of 6. Column chromatographic purification (petroleum
ether/ethyl acetate, 1:1) afforded the product 3i in a yield of 99%
(52.2 mg).
Figure 5. Compound 3i exhibited immunostimulatory activity through
TLR7 signaling. (A) Wild-type bone marrow dendritic cells were left
untreated or stimulated with two doses of 3i, and 24 h later the
production of IL-6 in culture supernatants was measured by ELISA.
Data are the mean SD of four mice per group. (B) Bone marrow
dendritic cells from wild-type (WT), TLR3−/−, TLR7−/−, and
TLR9−/− mice were left untreated or stimulated with different doses
of 3i, and 24 h later the production of IL-12p40 in culture
supernatants was measured by ELISA.
ASSOCIATED CONTENT
* Supporting Information
Synthesis of 3−14, their NMR spectra, HPLC analysis, and
biological assays. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
Since guanine derivatives such as isatoribine act as agonists of
TLR7,9 we also explored whether 3i could induce the TLR-
mediated immune response, an answer to which would allow us
to better understand the mechanism behind the 3i-induced
immune response. To do so, we focused on TLR7, TLR3, and
TLR9, since all three TLRs are located in endosomes, detect
microbial nucleic acids, and are involved in viral recognition
that has also been implicated in cancer development.23 Bone
*Phone: +33 4 91 82 91 54. Fax: +33 4 91 82 93 01. E-mail:
ling.peng@univmed.fr.
Present Address
⊥Immuno-Dermatologie, CHUV, Lausanne 1011, Switzerland.
Author Contributions
#These authors contributed equally.
marrow dendritic cells derived from wild-type, TLR3−/−
,
Notes
TLR7−/−, and TLR9−/− mice were left untreated or stimulated
with 3i. After 24 h, the culture supernatants were collected and
the protein levels of IL-12p40 assessed by ELISA. The
production of IL-12p40 by wild-type, TLR3−/−, and TLR9−/−
cells increased upon 3i treatment compared with untreated cells
(Figure 5B). Interestingly, TLR7−/− cells were totally
unresponsive even upon stimulation with 10 μM 3i (Figure
5B), suggesting that 3i acts through TLR7 signaling. Although
TLRs are best known for their ability to control host defense
upon infection, emerging evidence suggests that TLRs can
serve as negative regulators of cancer through various
mechanisms including the stimulation of adaptive immune
system.24 Among the different TLRs, TLR7 has received the
most attention in cancer biology because of the robust
anticancer activity of small-molecule agonists that act through
TLR7.25 Thus, the fact that 3i can signal through TLR7 to
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project is supported by the National Mega Project on
Major Drug Development (Grant 2009ZX09301-014), Wuhan
University, CNRS, INSERM, la Fondation pour la Recherche
Med
́
icale (Y.X.) and la bourse d’excellence Eiffel (M.W.). We
thank Joel Tardivel-Lacombe for cell culture, and Drs. Gilles
̈
́ ́
Quelever and Emily Witty for manuscript reading.
REFERENCES
■
(1) Mellman, I.; Coukos, G.; Dranoff, G. Cancer immunotherapy
comes of age. Nature 2011, 480, 480−489.
(2) Sharma, P.; Wagner, K.; Wolchok, J. D.; Allison, J. P. Novel
cancer immunotherapy agents with survival benefit: recent successes
and next steps. Nat. Rev. Cancer 2011, 11, 805−812.
D
dx.doi.org/10.1021/jm300534u | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Brief Article
(3) Ramakrishnan, R.; Antonia, S.; Gabrilovich, D. Combined
modality immunotherapy and chemotherapy: a new perspective.
Cancer Immunol. Immunother. 2008, 57, 1523−1529.
(22) Wu, J. Z.; Lin, C.-c.; Hong, Z. Ribavirin, viramidine and
adenosine-deaminase-catalysed drug activation: implication for nucleo-
side prodrug design. J. Antimicrob. Chemother. 2003, 52, 543−546.
(23) Morris, J. D. H.; Eddleston, A. L. W. F.; Crook, T. Viral
infection and cancer. Lancet 1995, 346, 754−758.
(4) Proietti, E.; Moschella, F.; Capone, I.; Belardelli, F. Exploitation
of the propulsive force of chemotherapy for improving the response to
cancer immunotherapy. Mol. Oncol. 2012, 6, 1−14.
(24) Rakoff-Nahoum, S.; Medzhitov, R. Toll-like receptors and
cancer. Nat. Rev. Cancer 2009, 9, 57−63.
(5) Galluzzi, L.; Senovilla, L.; Zitvogel, L.; Kroemer, G. The secret
ally: immunostimulation by anticancer drugs. Nat. Rev. Drug Discovery
2012, 11, 215−233.
(25) Schon, M. P.; Schon, M. TLR7 and TLR8 as targets in cancer
therapy. Oncogene 2008, 27, 190−199.
(6) Herdewijn, P. Modified Nucleosides in Biochemistry, Biotechnology
and Medicine; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim,
Germany, 2008.
(7) Lee, J.; Chuang, T. H.; Redecke, V.; She, L.; Pitha, P. M.; Carson,
D. A.; Raz, E.; Cottam, H. B. Molecular basis for the
immunostimulatory activity of guanine nucleoside analogs: activation
of Toll-like receptor 7. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 6646−
6651.
(8) Clercq, E. D. The design of drugs for HIV and HCV. Nat. Rev.
Drug Discovery 2007, 6, 1001−1018.
(9) Ogawa, K.; Hige, S.; Nakanishi, M.; Yamamoto, Y.; Chuma, M.;
Nagasaka, A.; Asaka, M. Immunological and mutagenic actions of
ribavirin monotherapy preceding combination therapy with interferon
for patients with chronic hepatitis C. Antiviral Ther. 2009, 14, 513−
522.
(10) Xia, Y.; Qu, F.; Peng, L. Triazole nucleoside derivatives bearing
aryl functionalities on the nucleobases show antiviral and anticancer
activity. Mini-Rev. Med. Chem. 2010, 10, 806−821.
(11) Wan, J.; Xia, Y.; Liu, Y.; Wang, M.; Rocchi, P.; Yao, J.; Qu, F.;
Neyts, J.; Iovanna, J. L.; Peng, L. Discovery of novel arylethynyltriazole
ribonucleosides with selective and effective antiviral and antiprolifer-
ative activity. J. Med. Chem. 2009, 52, 1144−1155.
(12) Xia, Y.; Liu, Y.; Wan, J.; Wang, M.; Rocchi, P.; Qu, F.; Iovanna,
J. L.; Peng, L. Novel triazole ribonucleoside down-regulates heat shock
protein 27 and induces potent anticancer activity on drug-resistant
pancreatic cancer. J. Med. Chem. 2009, 52, 6083−6096.
(13) Wang, M.; Xia, Y.; Qu, F.; Peng, L. Novel triazole nucleoside
analogs with anticancer activity. Chin. J. Med. Chem. 2010, 20, 562−
370.
(14) Xia, Y.; Li, W.; Qu, F.; Fan, Z.; Liu, X.; Berro, C.; Rauzy, E.;
Peng, L. Synthesis of bitriazolyl nucleosides and unexpectedly different
reactivity of azidotriazole nucleoside isomers in the Huisgen reaction.
Org. Biomol. Chem. 2007, 5, 1695−1701.
(15) Li, W.; Xia, Y.; Fan, Z.; Qu, F.; Wu, Q.; Peng, L. Bitriazolyl
acyclonucleosides with antiviral activity against tobacco mosaic virus.
Tetrahedron Lett. 2008, 49, 2804−2809.
(16) Wang, M.; Zhu, R.; Fan, Z.; Fu, Y.; Feng, L.; Yao, J.; Maggiani,
A.; Xia, Y.; Qu, F.; Peng, L. Bitriazolyl acyclonucleosides synthesized
via Huisgen reaction using internal alkynes show antiviral activity
against tobacco mosaic virus. Bioorg. Med. Chem. Lett. 2011, 21, 354−
357.
(17) Zhu, R.; Wang, M.; Xia, Y.; Qu, F.; Neyts, J.; Peng, L.
Arylethynyltriazole acyclonucleosides inhibit hepatitis C virus
replication. Bioorg. Med. Chem. Lett. 2008, 18, 3321−3327.
(18) Liu, Y.; Xia, Y.; Li, W.; Cong, M.; Maggiani, A.; Leyssen, P.; Qu,
F.; Neyts, J.; Peng, L. S-Aryltriazole acyclonucleosides: synthesis and
biological evaluation against hepatitis C virus. Bioorg. Med. Chem. Lett.
2010, 20, 3610−3613.
(19) Wang, M.; Xia, Y.; Fan, Y.; Rocchi, P.; Qu, F.; Iovanna, J. L.;
Peng, L. A novel arylethynyltriazole acyclonucleoside inhibits
proliferation of drug-resistant pancreatic cancer cells. Bioorg. Med.
Chem. Lett. 2010, 20, 5979−5983.
́
(20) Dyrager, C.; Borjesson, K.; Diner, P.; Elf, A.; Albinsson, B.;
̈
Wilhelmsson, L. M.; Grøtli, M. Synthesis and photophysical
characterisation of fluorescent 8-(1H-1,2,3-triazol-4-yl)adenosine
derivatives. Eur. J. Org. Chem. 2009, 2009, 1515−1521.
(21) Fan, Y.; Xia, Y.; Tang, J.; Rocchi, P.; Qu, F.; Iovanna, J.; Peng, L.
Ligand-mediated highly effective and selective C−N coupling for
synthesizing bioactive N-aryltriazole acyclonucleosides. Org. Lett. 2010,
12, 5712−5715.
E
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