Synthesis and antitumor activity of novel 2′,3′-diethanethio- 2′,3′,5′-trideoxy-5′-triazolonucleoside analogues

Article abstract of DOI:10.1016/j.ejmech.2010.03.038

A series of novel 2′,3′-diethanethio-2′,3′, 5′-trideoxy-5′-triazoloribonucleosides was synthesized in excellent yields and their antitumor activity was evaluated. These nucleoside analogues with aromatic substituted triazole rings showed significantly improved activity towards a broad range of tumor cell lines and those without arene substitutes were inactive.

Full text of DOI:10.1016/j.ejmech.2010.03.038

European Journal of Medicinal Chemistry 45 (2010) 3219e3222
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis and antitumor activity of novel
20,30-diethanethio-20,30,50-trideoxy-50-triazolonucleoside analogues
,
a
a
a
a
Jin-Lan Yu a, Qin-Pei Wu a , Qing-Shan Zhang , Xiao-Dong Xi , Ning-Ning Liu , Yun-Zheng Li ,
*
Yan-Hong Liu b, Hong-Quan Yin a
a Department of Applied Chemistry and Pharmacy, Beijing Institute of Technology, Nandajie 5, Beijing 100081, P.R. China
b Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100080, P.R. China
a r t i c l e i n f o
a b s t r a c t
Article history:
A
series of novel 20,30-diethanethio-20,30,50-trideoxy-50-triazoloribonucleosides was synthesized in
Received 27 January 2010
Received in revised form
25 March 2010
Accepted 29 March 2010
Available online 3 April 2010
excellent yields and their antitumor activity was evaluated. These nucleoside analogues with aromatic
substituted triazole rings showed significantly improved activity towards a broad range of tumor cell
lines and those without arene substitutes were inactive.
Ó 2010 Elsevier Masson SAS. All rights reserved.
Keywords:
Antitumor
Nucleoside
Triazole
Targeted therapy
Cancer therapy
Numerous nucleosides and nucleotides analogues have been
developed for medicinal purposes [1]. Many of which have been
used in the clinic for the treatment of human immunodeficiency
virus (HIV) [2], hepatitis B virus (HBV) [3], herpes simplex virus
(HSV) [4], hepatitis C virus (HCV) [5] and various cancers [6] as
anticancer and antiviral drugs.
Within the last 10 years, targeted therapy has been explored
with the aim of developing highly specific inhibitors which act on
a single target. After the emergence of serious drug resistance and
the resulting relapse of one-target treatment plans in the clinic,
there is now general knowledge that most tumors depend on more
than one signaling pathway for their growth and survival. Thus,
molecules interfering simultaneously with multiple targets might
be more effective than single target agents [7]. A number of multi-
targeted compounds have been developed and have entered clin-
ical trials or clinical practice. These include both Gemcitabine and
2-chloro-2-deoxyadenosine 50-triphosphate (CldATP) which inhibit
DNA polymerase and potently inhibit ribonucleotide reductase
(RDPR) as well as Fludarabine 50-triphosphate (FaraATP) which
inhibits DNA and RNA polymerases, RDPR, DNA ligase 1 and DNA
leukemia and is currently being tested for combination therapy of
both leukemias and solid tumors. The mechanisms of its anticancer
activity involve a combination of direct inhibition of DNA synthesis
and ribonucleotide reductase and induction of apoptosis [8].
Ribonucleotide reductase (RDPR) is a well-recognized target for
cancer chemotherapeutic and antiviral agents [9]. RDPR inhibition
precludes DNA transcription and repair, and results in cell apoptosis.
The reduction of ribonucleotides into the corresponding 20-deoxyri-
bonucleotides is initiated by the conversion of cysteine residues
positioned at the active site of this enzyme into a cysteinyl free
radical. A series of 20-modified nucleoside analogues such as
20-methylene-20-deoxycytidine [10], 20-methylene-20-deoxy-uridine
[10], 20-O-allyl- -arabifuranosylcytosine [11] and 30-C-methylade-
D
nosine [12] have been shown to be effective mechanism-based
inhibitors of this enzyme and may be potential anticancer agents [13].
Furthermore, it is recognized that the replacement of the 20,30-
hydroxy function of nucleosides by a thiol group able to react with
reducing cysteine residues results in potent inhibitors of RDPR in
vitro [14]. Some 20,30-dideoxy-30-thionucleosides 2 (Fig. 1) [15] have
shown good anti-HIV activity and 20-deoxy-20-thiocytidine has
been proven to inhibit the proliferation of cancer cells [16]. A few
S6-nitrobenzyl mercaptopurine riboside analogues reported by
Gupte and Buolamwini [17] were shown to be inhibitors of nucle-
oside transporters, which are potential targets for chemotherapy in
cancer and viral infections [18].
primase [1d]. Clofarabine (Fig. 1),
a next-generation deoxy-
adenosine analogue, is effective against various subtypes of
* Corresponding author. Tel.: þ86 10 68918511; fax: þ86 10 68914009.
E-mail address: qpwu@bit.edu.cn (Q.-P. Wu).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.03.038

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J.-L. Yu et al. / European Journal of Medicinal Chemistry 45 (2010) 3219e3222
NH2
N
the triazole ring with phenyl acetylene was initially carried out
NH2
N
with CuCl as the catalyst. To improve the yield, CuBr or CuI were
also employed as catalysts for this cycloreaction. However, the
isolated yields were all lower than 50%. Fortunately, the yield for
the desired product was higher than 80% when CueCuSO4 was used
to activate this 1,3-dipolar cycloaddition reaction at room temper-
ature [25]. In addition, the triazole structure was identified to be an
unambiguous 1,4-disubstituted cyclo-addition product according
to the NOE spectrum data of the final product 18 (Fig. 2).
N
N
N
N
N
HO
N
Cl
HO
HO
N
O
O
O
O
F
EtS
SEt
OH
SR
1
Clofarabine
2
3
R=H, SMe
Fig. 1. Molecular structures of nucleoside analogues 1 Clofarabine, 2 and 3.
Under the Silyl-Hilbert-Johnson glycosylation conditions [22,26],
trideoxy- -ribofuranose derivative 6 was treated with trimethylsi-
lylated uracil in the presence of trimethylsilyl trifluoromethane-
sulfate (TMSOTf) to give the corresponding nucleoside 16, which was
D
The structural diversity of nucleoside mimetics with antiviral
and anticancer activity suggests that any new nucleoside analogue
is worth exploring [19]. Recently, 1,2,3-triazoles have gained
significant interest in fields of drug discovery and bioconjugation
[20]. Introduction of a triazole ring into nucleosides to improve
their bioactivity for antitumor and/or antiviral applications has
become widespread in drug design practices [21].
Recently, we found that triazole nucleoside 3 showed enhanced
bioactivity against a broad spectrum of cancer cell lines in
comparison to the corresponding natural base nucleosides with an
isolated using column chromatography to afford the b-isomer in 51%
yield. Under the same reaction conditions, compounds 17e32 were
also successfully prepared in quite good yields. To remove the acetyl
protecting group in 32 methylamine was used to give the desired
nucleoside 33 in 94% yield (Scheme 1).
The stereochemistry of the final products was further elucidated
by NOE correlation experiments. In the NOE spectrum of 18, strong
NOE effects were observed between the anomeric proton H-10 (at
EC50 value of 5.96 mM in Hela cells [22]. Based on this interesting
d
5.97) and H-40 (at
the nucleoside is a
that the resonance signal of the triazole ring proton H-500 (at
interacts with both H-40 (at 4.34) and H-50 (at
4.82) further
d
4.34) and H-6 (at
-isomer (Fig. 2). Moreover, it was also observed
8.53)
d 7.57) which suggests that
result, we further synthesized and evaluated the bioactivity of
a series of novel 20,30,50-trideoxy-50-triazolonucleoside analogues
16e33 as described herein.
b
d
d
d
Compound 4 [22,23] effectively prepared in a large scale from
providing evidence that the substitute groups are at the 1- and
4-positions in the 1,2,3-triazole ring. The NOE effect observed
D
-xylose via a cascade reaction was smoothly converted into tosy-
late 5 [24] followed by treatment with sodium azide to give the
expected azido ribofuranoside derivative 6 in 74% yield for two
steps (Scheme 1). Under Huisge-Sharpless AzideeAlkyne cyclo-
addition reaction conditions, conversion of the azido group in 6 into
between the triazole ring proton H-500 (at
d
8.53) and the benzene
ring protons (at
d 7.78) might indicate that the triazole ring and the
benzene ring are coplanar or nearly coplanar in space (Fig. 2). These
N3
HO
OMe
TsO
OMe
SEt
OMe
O
b
O
O
a
c
EtS
SEt
EtS
EtS
SEt
6
4
5
16,
R = C6H5
O
17, R = 4-F-C6H4
18, R = 4-CH3O-C6H4
NH
N
N
N
19,
R = 2-CF3-C6H4
R
R
N
O
20, R = 4-CH3-C6H4
21,
O
R = 3-CH3-C6H4
N
22, R = -COOC2H5
N
N
23, R = -CH2OOCCH3
R
EtS
SEt
O
OMe
24,
R = thiophene-2-yl
O
EtS
SEt
25,
R = C6H5
d
NH
26, R = 4-F-C6H4
N
N
N
27, R = 4-CH3O-C6H4
N
O
28,
R = 2-CF3-C6H4
7
, R = C6H5
O
29, R = 4-CH3-C6H4
30,
8
, R = 4-F-C6H4
R = -COOC2H5
9, R = 4-CH3O-C6H4
10
31, R = thiophene-2-yl
, R = 2-CF3-C6H4
EtS
SEt
11, R = 4-CH3-C6H4
12
, R = 3-CH3-C6H4
, R = -COOC2H5
NHAc
N
NH2
13
14, R = -CH2OOCCH3
N
N
N
N
N
N
N
15
, R = thiophene-2-yl
Ph
Ph
N
O
N
O
e
O
O
EtS
SEt
Et
SEt
S
33
32
Scheme 1. Reagents and conditions: (a) TsCl, Et3N, CH2Cl2, rt, 87%; (b) NaN3, DMF, 105 ꢀC, 85%; (c) Alkyne, Cu, CuSO4, BuOH/H2O (1:1, v/v); (d) CH3CN, CF3SO2OSiMe3, silylated
bases; (e) MeNH2, EtOH, rt, 94%.

J.-L. Yu et al. / European Journal of Medicinal Chemistry 45 (2010) 3219e3222
3221
the least active towards the tested tumor cells. The results for
nucleosides 17 and 26 bearing a p-fluorophenyltriazole residue
indicated that the former had moderately active towards the four
tested cell lines, while the latter was active towards both HepG2
and Hela cells and inactive against lung A549 and LAC cells. EC50
values of 18, 19, 27 and 28 indicated that these compounds are
potential cytotoxic agents against a broad spectrum of cancer cells
and these compounds proved to be more active than 5-FU against
these tested four cell lines. Both 20 and 29 with a p-methyl-
phenyltriazole group displayed significant activity towards A549
O
HN
N
N
N
CH3O
O
O
6
H
N
5'
5''
H
1'
H
4'
H
H
SEt SEt
18
Fig. 2. Through space protoneproton interactions indicated by the NOE spectrum of
compound 18.
cells (6.78 and 12.32 mM, respectively) while both were inactive
against LAC cells. Additionally, 21 containing a m-methylbenzene
group similar to 20 and 29 in molecular structure also showed
remarkable activity against these four tested cell lines (Table 1).
Thiophen-2-yl triazole nucleosides, 24 and 31 was mostly inactive
towards these four cancer cell lines.
NOE spectroscopic data provide strong evidence for the b-anomeric
configuration assignments, the triazole ring structure as well as the
steric relationship between the triazole ring and the phenyl group.
The antitumor activity of these novel nucleosides devoid of
hydroxy groups was tested in vitro towards the following human
cancer cell lines: human hepatocellular liver carcinoma cell line
(HepG2), two types of non-small cell lung cancer: lung adenocar-
cinoma (LAC) and squamous subdivision of epithelial cells (A549),
and human cervical carcinoma cell line (Hela). Cytotoxic activity
was determined using the MTT assay, after exposure of cells to the
test compounds for 72 h. 5-Fluorouridine was used as the reference
compound and the results are summarized in Table 1.
As shown by the EC50 values listed in Table 1, most of these
nucleoside mimetics had good or moderate activity against three or
four of the tested tumor cell lines. Among these novel compounds,
compound 16 proved to be the most active and was cytotoxic
against three of the tested tumor cells, HepG2, A549 and Hela, with
Towards these four types of cancer cell lines evaluated,
compounds 22, 23 and 30 were inactive (EC50 ꢁ 100
mM). From the
EC50 values shown in Table 1, it is worthwhile to note that all nucle-
osides bearing an aromatic triazole ring display anticancer activities
and compounds lacking benzene substituents in the triazole rings are
inactive. Additionally, it should also be noted that the anticancer
activityof these analogues was improved compared with their parent
compounds without the triazole ring at the 50-position as reported
previously [22]. It is reasonable to speculate that the substituents in
the triazole ring playa pivotal role in the bioactivity, which may result
from the conjugation effects between the benzene ring and the tri-
azole moiety due to their coplanar relationship. Furthermore, this
interesting structureeactivity relationship was previously docu-
mented for 20,30-dideoxy-20,30-diethanthio-
D-ribofuranoside analo-
EC50 values ranging from 3.04 to 8.38 mM. These EC50 values were at
gues. For instance 3 wasstudied inwhich the natural base moiety was
replaced by a series of triazoles substituted with various groups [22].
Moreover, conjugation effects might enhance the hydrophobic
features of the triazole ring and might offer advantageous binding
properties to the corresponding biological targets. The nature of this
interaction between the arene substituted triazole groups in these
trideoxy nucleoside analogues and biological targets may be elec-
trostatic, hydrophobic and/or include aromatic ring stacking. Weak
interactions such as these between agents and targets are the
essential requirement for multi-target agents [27]. On the other hand,
the nucleoside analogues without hydroxy groups cannot apparently
be phosphorylated by deoxycytidine kinase to form natural nucleo-
sides and thus they likely act as antimetabolic agents interacting with
targets via specific modes of action [21c,28], but further studies will
be needed to address these hypotheses.
least 6-fold higher than those for the reference 5-FU against tumor
cells (Table 1). The thymidine derivative 25 showed higher activity
against Hela cells (1.89 mM) than against HepG2 and A549 tumor
cells. Compared with 16 and 25, the cytosine compound 33 showed
Table 1
Cytotoxicity of compounds 16e33 against cancer cell lines.a
b
Compound
EC50
(
mM)
HepG2
A549
LAC
Hela
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
33
5-FU
8.38
3.04
n/a
6.59
22.57
16.21
30.28
19.92
18.26
ꢁ100
ꢁ100
91.82
64.98
22.72
22.78
22.09
21.61
ꢁ100
ꢁ100
57.10
52.43
22.87
16.78
19.38
6.78
12.17
ꢁ100
ꢁ100
ꢁ100
31.69
ꢁ100
38.83
7.23
12.32
ꢁ100
37.28
64.03
ꢁ100
72.37
24.33
81.14
ꢁ100
99.00
ꢁ100
ꢁ100
86.49
n/a
ꢁ100
25.88
50.61
ꢁ100
ꢁ100
ꢁ100
n/a
37.41
27.68
32.82
46.69
18.79
ꢁ100
ꢁ100
ꢁ100
1.89
39.51
65.95
54.33
77.53
ꢁ100
54.86
33.47
79.79
In conclusion, a small library of novel 20,30,50-trideoxy-20,30-
diethanethio-50- triazoloribonucleosides were prepared in 46e68%
overall yields in four steps (Scheme 1). The molecular structure
analysis indicated the potential coplanar relationship between the
phenyl moiety and the triazole ring which results in the conjugate
effects. Some of these compounds with aromatic substituents in the
triazole ring showed excellent anticancer activity and most of them
were potential inhibitory agents towards a broader range of tumor
cell lines. Some trideoxy nucleoside analogues without the phenyl
group were inactive against all four tested tumor cells. These results
might suggest that the conjugation effects of the triazole ring with
the aromatic system may be essential for bioactivity. Further
structureeactivity studies investigating the capacity of these
compounds to act as multi-target candidates are currently
underway in our laboratory.
43.73
n/a means the EC50 values were not recorded as the sample was contaminated by
accident during testing.
a
Cancer cells (2000 cells/0.1 mL) were cultured under standard conditions in 96-
well plates. Twenty-four hours later, a series of concentrations of compounds was
added and further incubated at 37 ꢀC in 95% air and 5% CO2 for 72 h. To the wells 20
m
L of MTT reagent was added and further incubated for 4 h and the absorbance was
measured at 490 nm. The fifty percent growth inhibitory concentration (EC50) was
Acknowledgments
calculated based on the observed growth inhibition.
b
EC50 is the concentration of compound required to inhibit the cell growth by
We would like to thank Dr. Claire Simons (Cardiff University) for
her useful advices. Financial supports of this work by the Ministry
50% compared with an untreated control. Compounds were tested up to a concen-
tration of 100 mM.

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J.-L. Yu et al. / European Journal of Medicinal Chemistry 45 (2010) 3219e3222
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