Synthesis and antitumor activity of novel 2′,3′-dideoxy-2′,3′-diethanethionucleosides bearing 1,2,3-triazole residues

Article abstract of DOI:10.1016/j.bmcl.2009.10.127

A series of novel 2′,3′-dideoxy-2′,3′-diethanethioribonucleosides and those modified with a triazole ring were prepared in excellent yields and their antitumor activity was evaluated. Nucleosides with a triazole ring, 16a-16c, showed significantly improved activity towards a broad range of tumor cell lines.

Full text of DOI:10.1016/j.bmcl.2009.10.127

Bioorganic & Medicinal Chemistry Letters 20 (2010) 240–243
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antitumor activity of novel 20,30-dideoxy-20,30-diethane
thionucleosides bearing 1,2,3-triazole residues
a
b
a
a
Jin-Lan Yu a, Qin-Pei Wu a, , Qing-Shan Zhang , Yan-Hong Liu , Yun-Zheng Li , Zi-Ming Zhou
*
a School of Chemical Engineering & Environment, Beijing Institute of Technology, Beijing 100081, China
b Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100080, China
a r t i c l e i n f o
a b s t r a c t
A series of novel 20,30-dideoxy-20,30-diethanethioribonucleosides and those modified with a triazole ring
were prepared in excellent yields and their antitumor activity was evaluated. Nucleosides with a triazole
ring, 16a–16c, showed significantly improved activity towards a broad range of tumor cell lines.
Ó 2009 Elsevier Ltd. All rights reserved.
Article history:
Received 14 August 2009
Revised 30 September 2009
Accepted 28 October 2009
Available online 4 November 2009
Keywords:
Antitumor
Nucleoside
Triazole
Thiol
Canceris one ofthe leading causesof death in the world. Nucleoside
analogues are rationally designed anticancer drugs used in clinical
therapy for both solid tumors and hematological malignancies. These
include capecitabine (50-deoxy-5-N-[(pentoxy)carbonyl]-cytidine),1
dine and 20-methylene-20-deoxy-uridine,10 20-O-allyl-
anosylcytosine11 as well as 30-C-methyladenosine.12
D-arabifur-
It is worthwhile to note that replacement of the 20,30-hydroxy
groups by a mercapto group which can then react with the active
cladribine (2-chloro-20-deoxyadenosine),2 fludarabine (9-b-
D
-arabi-
nofuranosyl-2-fluoroadenosine),3 clofarabine (2-chloro-9-(20-deoxy-
20-fluoro-b- -arabinofuranosyl)adenine, Fig. 1),4 a next generation
site of RDPR was found to be a potent inhibitor of RDPR
in vitro13 and some 20,30-dideoxy-30-thionucleosides have shown
good anti-HIV activity.14 Furthermore, many nucleosides have pro-
ven to be inhibitors of multienzymes.15 Cladribine 50-triphos-
phate,16 clofarabine17 and gemcitabine 50-diphosphate18 inhibit
both DNA polymerase and ribonucleotide reductase. This work
summarizes a number of novel nucleosides with ethanethio groups
which are potent inhibitors of multienzyme targets.
D
nucleoside analogue which is under clinical investigation as well as
gemcitabine (20,20-difluorodeoxycytidine)5 used for treating broad
kinds of tumors such as pancreatic, metastatic bladder, lung, breast,
ovarian, head and neck cancers.
With an improved understanding of the genes and pathways
responsible for cancer initiation and progression, cancer drug devel-
opment has undergone a paradigm change in recent years, from pre-
dominantly cytotoxic agent-based therapy to therapy aimed at
molecular and genetic targets. Nucleoside transporters are impor-
tant for the cellular uptake of anticancer nucleoside mimetic
drugs.6,15 Some nucleoside mimetics, such as NBMPR (Fig. 1), which
act as potent nucleoside transporter inhibitors, have been reported
for use in cancer therapy.7 Ribonucleotide reductase (RDPR), which
isresponsibleforDNAsynthesisviafreeradicalintermediates, isalso
an attractive target for antitumor chemotherapy.8 A number of
20-position modification nucleoside analogues have been shown to
be effective mechanism-based inhibitors of this enzyme and may
be potential anticancer agents9 such as 20-methylene-20-deoxy-cyti-
1,2:3,5-Di-O-isopropylidene-a-D-xylose 1 prepared from D-xy-
lose was effectively transformed into the corresponding diacetate
2 in a large scale via a one-pot procedure as previously reported.19
Treatment of 2 with ethanethiol in the presence of ZnBr2 generated
the key intermediate 3 in good yield. Compound 3 contains two
ethanethiol groups at C-2 and C-3 with inversed configuration at
C-3.20 Removal of the acetyl groups in 3 was performed with
S
NH2
N
NO2
N
N
N
N
HO
N
N
HO
N
Cl
O
F
O
OH OH
OH
NBMPR
Clofarabine
* Corresponding author. Tel.: +86 10 68918511; fax: +86 10 68912917.
E-mail address: qpwu@bit.edu.cn (Q.-P. Wu).
Figure 1. Clofarabine and NBMPR.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.10.127

J.-L. Yu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 240–243
241
methylamine to give 4 in 94% isolated yield, which was subse-
quently cyclized in the presence of NBS to afford the expected ribo-
furanose derivative 5 in 83% isolated yield without selectively
protecting the primary alcohol as previously described by Miljko-
vic and co-workers.21 Protecting the primary hydroxyl group with
an acetyl group afforded the anticipated intermediator 6 in 56%
overall yield for 5 steps (steps from a to e, Scheme 1).
Under Silyl-Hilbert-Johnson nucleoside synthetic conditions,22
2,3-dideoxy-D-ribofuranose derivative 6 was treated with trimeth-
ylsilylated N4-acetylcytosine in the presence of trimethylsilyl tri-
fluoromethanesulfate (TMSOTf) to give the corresponding
nucleosides as an anomeric mixture (b/a = 2.5:1), which was iso-
lated using a short column to afford the b-isomer 7 in 51% yield
(Scheme 2). After a series of attempts at improving the yield, we
found that displacement of TMSOTf with ethylaluminum dichlo-
ride (EtAlCl2) led to 7 (76% isolated yield) as the sole product with-
out the counterpart
a-isomer. Ethylaluminum dichloride possibly
leads to the formation of the key intermediate A (Fig. 2) directing
nucleophilic base attack from only the top face rather than from
either face of the sugar ring. Whereas oxonium intermediate B
(Fig. 2) generated by the strong Lewis acid, TMSOTf, could be at-
Scheme 2. Reagents: (a) EtAlCl2, MeCN; (b) CH3NH2, C2H5OH.
tacked from both faces to give both a- and b-isomers. Removal of
B(TMS)x
Major
the acetyl protecting group was performed with methylamine in
ethanol to generate the desired nucleoside 10 in nearly quantita-
tive yield. Under similar conditions, the expected nucleosides 11
and 12 were also synthesized in good yields.
The molecular structure of 7 was further confirmed to be the
b-anomer by a NOESY spectrum. In the 1H-1H dimensional NMR
spectrum of compound 7, two cross-peaks are observed between
the H-6 (at d 8.18) and H-30 (at d 3.58) as well as H-20 (at d 3.87),
respectively. Furthermore, it was also observed that the resonance
signal of the anomeric proton (at d 5.99) interacts with the methy-
lene proton of 20-SCH2CH3 (at d 2.79) (Fig. 3). These NOESY spectro-
AcO
EtS
B(TMS)x
minor
AcO
OMe
O
O
AlEtCl2
S
EtS
SEt
Et
A
B
Figure 2. Proposed intermediates.
MeO
NHAc
N
H
scopic dataprovidestrongevidencefor a b-D-ribofuranoassignment.
4
5
6
N
N
1,2,3-Triazoles recently have gained significant interest in vari-
ous fields of drug discovery and bioconjugation.23 Introduction of a
triazole ring into nucleosides to improve bioactivity in antitumor
and/or antivirus agents24 has become widespread in drug design
practices since the first synthetic nucleoside drug, ribavirin,25
showed a broad spectrum of antiviral activity against many RNA
and DNA viruses.
Therefore, we next concentrated on further modifications of the
nucleosides by introducing a triazole group expecting that this
type of aromatic system will provide the triazole nucleoside with
advantageous binding properties to the corresponding biological
target.
H
O
H
N
N
AcO
HO
O
O
H
H
H
4'
EtS
H
H
S
H
H
H
H
H
3'
2'
2'
EtS
S
7
16C
Figure 3. Through space proton–proton interactions indicated by the 1H–1H NOESY
spectra of compound 7 and 16c.
anomeric by the NOESY spectrum of the following nucleoside
products. Huisgen cycloaddition of the triazole group with a series
of alkynes was successfully carried out in the presence of Cu–
CuSO4 at rt without sodium ascorbate23e to give the corresponding
triazole nucleosides in excellent yields (89–95%). Cleavage of the
protecting groups in 15 was performed with methylamine in eth-
anol to afford the final products 16 in approximately 90% yield.
The triazole structure was identified to be an unambiguous 1,4-
disubstituted cycloaddition product according to the 1H–1H NOESY
spectrum data of the deprotected product 16c (Fig. 3).
The molecular structure of 16c was further elucidated to be a b-
isomer by a NOESY spectrum (Fig. 3). In the 1H–1H dimensional
NMR spectrum of compound 16c, two cross-peaks are observed be-
tween the resonance signals of the anomeric proton (at d 6.26) and
the methylene proton of 20-SCH2CH3 (at d 2.59) and 40-H (at d 4.07),
respectively (Fig. 3). Moreover, it was also observed that the proton
in the triazole ring (at d 8.72) couples with H-30 (at d 3.89) as well
as H-20 (at d 4.21). Additionally, these two cross-peaks also indi-
cated that the substitute groups are at the 1,4-positions in the
1,2,3-triazole ring. These NOESY spectroscopic data provide strong
evidence for the b-anomeric configuration assignments and the tri-
azole ring structure.
Treatment of D-ribose derivative 5 with benzoyl chloride pro-
vided 13 (Scheme 3), which was subsequently treated with tri-
methylsilyl azide and stannic chloride to form, exclusively, the
desired azidoribofuranoside 14 in 74% isolated yield in 2 steps
(steps a and b, Scheme 3). Compound 14 was identified to be b-
AcO
O
AcO
AcO
OAc
O
a
EtS
O
O
b
c
SEt
O
O
O
O
91%
94%
86%
SEt
EtS
2
1
3
HO
HO
HO
AcO
OMe
SEt
OMe
SEt
EtS
e
d
O
O
SEt
83%
93%
EtS
EtS
EtS SEt
5
6
4
Scheme 1. Reagents and conditions: (a) Ac2O, HClO4–SiO2, CH2Cl2, rt, 91%; (b) EtSH,
ZnBr2, CH2Cl2, rt, 86%; (c) CH3NH2, C2H5OH, 94%; (d) NBS, CH3OH, 83%; (e) Ac2O,
Et3N, CH2Cl2, 93%.

242
J.-L. Yu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 240–243
HO
EtS
BzO
OMe
SEt
BzO
OMe
SEt
N3
O
O
a
O
b
98%
76%
EtS
EtS
SEt
5
13
14
N
N
N
N
N
N
BzO
HO
d
R
O
c
R
O
89-93%
89-95%
EtS
15a-g
SEt
EtS
SEt
16a-g
Compound
15 and 16
a
b
c
d
e
f
g
O
NH2
N
OMe
F
NH
O
HO
MeHN
N
O
N
O
R
Scheme 3. Reagents and conditions: (a) BzCl, Et3N, CH2Cl2, rt, 98%; (b) TMSN3, SnCl4 (5 mol %), CH2Cl2, 76%; (c) alkyne, Cu, CuSO4, THF/BuOH/H2O (2:1:1); (d) CH3NH2,
C2H5OH.
These novel nucleosides were evaluated for their cytotoxicity
in vitro towards the following human cancer cell lines: human
hepatocellular liver carcinoma cell line (HepG2), human lung ade-
nocarcinoma cell line (A549), human pulmonary carcinoma cell
(LAC), 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. Floxuridine was used as the
reference compound and the results are presented in Table 1.
Compounds 10–12 showed moderate activity against the three
tested tumor cells, with EC50 values ranging from 29.47 to
The possible conjugation between the triazole ring and the benzene
ring in nucleosides 16a, 16b and 16c may offer improved binding po-
tential to a biological target, but further studies will be needed to ad-
dress this hypothesis.
In conclusion, a series of novel 20,30-dideoxy-20,30-diethanethio-
ribonucleosides, 10–12, were prepared in 40–44% overall yields in
7 steps (Schemes 1 and 2) and those nucleosides containing a tri-
azole ring, 16a–16g, were obtained in 59–65% overall yields in four
steps (Scheme 3). Their antitumor activity against four human can-
cer cell lines was evaluated in vitro. Nucleosides 10–12 exhibited
only moderate antitumor activity. In contrast, the series of triazole
modified nucleosides 16a–16c showed significantly improved
antitumor activity towards HepG2, A549 and Hela cell lines and
higher cytotoxicity towards HepG2, LAC and Hela cell lines than
the control drug floxuridine. Moreover, compounds 16b and 16c
showed similar antitumor activity towards the four cell lines and
may be potential inhibitory agents towards a broader range of tu-
mor cell lines. However, triazole nucleosides 16d–16g were inac-
tive to all four tested cancer cell lines. These results might
suggest that the conjugation effects of the triazole ring with the
aromatic system is important for bioactivity. Further structure–
activity studies with similar nucleosides are currently underway
in our laboratory.
177.13 lM (Table 1). The thymidine analogue 11 showed the best
activity against Hela cells. Remarkably, the triazole nucleosides
16a, 16b and 16c exhibit activity against HepG2 cells with EC50 rang-
ing from 9.6 to 10.98
and around twofold higher than those for the reference drug floxur-
idine, EC50 = 18.84 M. Towards A549 cells, nucleosides 10–12
lM, about 10-fold better than those for 10–12
l
showed much lower cytotoxicity than 16a, 16b and 16c. Nucleosides
16b and 16c were also found to be more active than the reference
drug and compounds 10–12 against both the LAC and Hela cell lines.
However, nucleosides 16d–16g were found to be inactive against
these 4 types of cancer cell lines (EC50 >100 lM, Table 1). The higher
cytotoxic activity exhibited by nucleosides 16a–16c than nucleo-
sides 10–12 towards all four tested tumor cells might stem from
the triazole ring. On the other hand, nucleosides 16d–16g were inac-
tive against these cancer cell lines perhaps because of the methylene
group between the triazole ring and the nucleobase, which inter-
rupts the conjugation of the triazole ring with the aromatic system.
Acknowledgment
Financial support of this work by the Ministry of Science and
Technology of China (2006AA100216) is appreciated.
Table 1
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EC50
(
lM)
HepG2
A549
86.41
LAC
Hela
10
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