Synthesis and biological activities of novel s-triazine bridged dinucleoside analogs

Article abstract of DOI:10.1002/cjoc.201190224

A series of novel dinucleosides linked by s-triazine were synthesized via the nucleophilic substitution reaction of amino nucleoside and cyanuric chloride in THF/H₂O. The biological activities of these novel dinucleoside analogs against HIV-RT, HeLa and A-549 cell lines in vitro were evaluated. Copyright

Full text of DOI:10.1002/cjoc.201190224

FULL PAPER
Synthesis and Biological Activities of Novel s-Triazine Bridged
Dinucleoside Analogs
Shen, Fengjuana,b(申凤娟)
Li, Xiaoliu*,a(李小六)
Yin, Qingmeia(殷庆梅)
Zhang, Jinchaoa(张金超)
Zhang, Xiaoyuana(张晓媛)
Qin, Zhanbina(秦占斌)
Chen, Huaa(陈华)
a Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei
University, Baoding, Hebei 071002, China
b College of Science, Hebei University of Science & Technology, Shijiazhuang, Hebei 050018, China
A series of novel dinucleosides linked by s-triazine were synthesized via the nucleophilic substitution reaction
of amino nucleoside and cyanuric chloride in THF/H2O. The biological activities of these novel dinucleoside ana-
logs against HIV-RT, HeLa and A-549 cell lines in vitro were evaluated.
Keywords dinucleoside, s-triazine, HIV-RT inhibition, cyanuric chloride
Introduction
cleoside analogs containing an s-triazine moiety, such as
Decitabine (aza-dCyd) (A) and Vidaza (aza-Cyd) (B)
(Figure 1), have been approved by FDA to be used in
clinic as anticancer agents.
The synthesis of nucleoside analogs has been the hot
topic in the past decades due to their potential applica-
tion as anticancer and antiviral therapeutic agents.1 To
meet the ever-growing requirements in the discovery of
new drugs, various modifications on the heterocyclic
bases and/or the sugar moiety have been approached,2
such as heterocyclic-sugar nucleosides,3 spirocyclic nu-
cleosides,4 two-headed nucleosides,5 dinucleosides,6 etc.
Among them, the chemically modified dinucleoside
analogs have attracted great attentions because of their
promising biological activities and potential applica-
tions as a building block for preparing backbone-modi-
fied oligonucleotides for DNA repair or mutation in
functional genomics.7 Furthermore, the most modifica-
tion of dinucleotides focused on the replacement of the
phosphate linkage in order to improve the affinity, sta-
bility, resistance, and membrane permeability or cellular
uptake,8 and the dinucleoside analogs linked by thio-
acetamido,9 guanidinium,10 carbonate11 and butadiynyl
group12 have been reported. Recently, a new type of
dinucleoside analogs linked by heterocycle13 have also
been synthesized. These dinucleoside analogs could be
regarded as a special “triple headed” dinucleoside shar-
ing one base, and would exhibit selective affinity to
DNA by simultaneous and synergitic interaction and
recognition with three complementary bases.14
Figure 1 Structure of nucleoside analogs having s-triazine ana-
logs.
From the above points of view, we envisaged to
connect two nucleoside moieties with an s-triazine ring
because such “triple headed” dinucleoside sharing
s-triazine would be beneficial to simultaneously build-
ing and recognizing three complementary bases via base
pairing rules.17,5 In this paper, a series of novel “triple
headed” dinucleoside analogs (1) have been conven-
iently synthesized by stepwise nucleophilic substitutions
of amino nucleosides with cyanuric chloride as shown
in Scheme 1. Their biological activities against HIV-RT,
and HeLa and A-549 cell lines were also preliminarily
evaluated.
s-Triazine derivatives are of broad range of biologi-
cal activity15 and the triazine scaffold provides a basis
for the design of biologically relevant molecule.16 Nu-
*
E-mail: lixl@hbu.edu.cn; Tel. & Fax: 0086-0312-5971116
Received October 5, 2010; revised January 26, 2011; accepted February 25, 2011.
Projected supported by the National Basic Research 973 Pre-research Program of China (No. 2010CB534913), the National Natural Science Foundations of
China (NSFC) (Nos. 20672027 and 20972039), the Natural Science Foundations of Hebei Province (No. B2008000588) and the program of Science and
Technology (S & T) of Hebei Province (No. 09276418D-13).
Chin. J. Chem. 2011, 29, 1205— 1210
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Scheme 1
Reagents and conditions: (i) DIPEA, THF/H2O, 0 ℃; (ii) DIPEA, THF/ H2O, 55 ℃.
Experimental
EtOH/H2O followed by heating. Column chromatogra-
phy was performed using SiO2 (Qingdao 200—300
mesh or 300—400 mesh). Solvents were distilled and
dried immediately prior to use.
General procedure for the synthesis of compounds
3a— 3c
Materials and instruments
Melting points were measured on a SGW@X-4 micro
melting point apparatus and uncorrected. Optical rota-
tions were determined on a SGW@-1 automatic po-
1
larimeter. H NMR and 13C NMR spectra were meas-
To a solution of 2c (1.2 g, 5.0 mmol) and cyanuric
chloride (1.8 g, 10.0 mmol) in THF (30 mL) was added
N,N-diisopropylethlamine (DIPEA) (1.0 mL, 6.0 mmol)
under nitrogen atmosphere at 0 ℃. The reaction was
monitored by TLC [V(CH2Cl2)∶V(CH3OH)＝4∶1].
After the reaction is completed, the solvent was evapo-
rated and the residue was applied on column chroma-
tography with the eluent of CH2Cl2 and CH3OH (V∶V
＝20∶1) to get compound 3c (330 mg, 85%). Similarly,
nucleoside analogs 3a and 3b were synthesized from
nucleosides 2a and 2b in yields of 64% and 35%, re-
spectively.
ured on an RT-NMR Bruker AVANCE 400 (400 MHz)
and an RT-NMR Bruker AVANCE 600 (600 MHz)
NMR spectrometer using tetramethylsilane (Me4Si) as
an internal standard. Mass spectra (MS) and high reso-
lution mass spectra (HRMS) were carried out on an
FTICR-MS (Ionspec 7.0T) mass spectrometer with
electrospray ionization (ESI). The optical densities for
examining the activity of HIV-RT inhibition was meas-
ured on a BioRad Model 3550 microplate spectropho-
tometer. Anticancer activity was evaluated using MTT
assay. Thin-layer chromatography (TLC) was per-
formed on precoated plates (Qingdao GF254) with de-
tection by UV light or with phosphomolybdic acid in
1
3a: White solid, 64%; m.p. 174—176 ℃; H NMR
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Chin. J. Chem. 2011, 29, 1205—1210

Synthesis and Biological Activities of Novel s-Triazine Bridged Dinucleoside Analogs
(DMSO-d6, 400 MHz) δ: 1.73 (s, 3H, CH3), 3.44—3.59
(m, 2H, CH2-5'), 3.82—3.88 (m, 2H, CH-2', CH-3'),
4.06 (s, 1H, H-4'), 5.16 (s, 1H, OH), 5.35 (s, 1H, OH),
5.66 (d, J＝5.88 Hz, 1H, CH-1'), 7.41 (s, 1H, CH-6),
9.24—9.27 (m, 1H, NH), 11.30 (s, 1H, NH); 13C NMR
(DMSO-d6, 100 MHz) δ: 12.83, 43.93, 71.65, 72.88,
82.14, 89.24, 110.59, 137.47, 151.62, 164.50, 166.56,
169.50, 170.364; HRMS calcd for C13H14Cl2N6O5
404.0402, found 404.0398.
5.79—5.81 (m, 2H, CH-1', CH-5), 7.48—7.52 (m, 1H,
CH-6), 7.69—7.79 (m, 1H, CH-6), 8.07—8.16 (m, 2H,
NH), 11.4 (s, 2H, NH); 13C NMR (DMSO-d6, 100 MHz)
δ: 11.93, 42.31, 48.56, 70.62, 70.82, 71.88, 72.10, 81.91,
82.07, 87.55, 87.91, 101.93, 109.68, 136.41, 141.16,
150.74, 150.81, 162.97, 163.65, 165.56, 167.84, 168.25;
HRMS calcd for C22H26ClN9O10 611.1490, found
611.1452.
1
1c: White solid, 34%; m.p. 192—194 ℃; H NMR
3b: White solid, 35%; m.p. 132—134 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 3.57 (s, 2H, CH2-5'), 3.89—
3.92 (m, 2H, CH-2', CH-3'), 4.12 (s, 1H, CH-4'), 5.29 (s,
1H, OH), 5.47 (s, 1H, OH), 5.63 (d, J＝8.04 Hz, 1H,
CH-5), 5.72 (d, J＝5.56 Hz, 1H, CH-1'), 7.69 (d, J＝
8.04 Hz, 1H, CH-6), 9.32 (s, 1H, NH), 11.38 (s, 1H,
NH); 13C NMR (CD3OD, 100 MHz) δ: 43.24, 71.51,
73.69, 82.33, 91.88, 102.01, 142.12, 150.50, 151.26,
165.01, 166.80, 169.91, 170.59; HRMS calcd for
C12H12Cl2N6O5 390.0746, found 390.0713.
(DMSO-d6, 400 MHz) δ: 3.47—3.53 (m, 4H, CH2-5'),
3.90—3.93 (m, 4H, CH-3', CH-4'), 4.08 (s, 2H, CH-2'),
5.15 (s, 1H, OH), 5.19 (s, 1H, OH), 5.40 (s, 2H, OH),
5.59—5.63 (m, 2H, CH-5), 5.72—5.74 (m, 2H, CH-1'),
7.92—7.98 (m, 2H, CH-6), 8.02—8.05 (m, 2H, NH),
11.33 (s, 2H, NH); 13C NMR (DMSO-d6, 100 MHz) δ:
43.30, 71.61, 73.14, 73.40, 82.97, 89.23, 102.81, 142.03,
151.59, 163.83, 166.54, 169.20, 169.81; HRMS calcd
for C21H24ClN9O10 597.1334, found 597.1364.
1
1d: White solid, 53%; m.p. 188—190 ℃; H NMR
1
(DMSO-d6, 400 MHz) δ: 1.76—1.79 (m, 6H, CH3), 2.19
—2.31 (m, 2H, CH2-2'), 3.54—3.67 (m, 5H, CH2-5',
CH-2'), 3.88—3.96 (m, 2H, CH-3'), 4.05 (q, J＝5.60,
11.60 Hz, 1H, CH-4'), 4.46—4.49 (m, 1H, CH-4'), 5.74
(d, J＝6.00 Hz, 1H, CH-1'), 6.22—6.25 (m, 1H, CH-1'),
7.37—7.46 (m, 1H, H-6), 7.73—7.83 (m, 1H, H-6),
11.28 (d, J＝8.00 Hz, 1H, NH), 11.34 (s, 1H, NH); 13C
NMR (DMSO-d6, 100 MHz) δ: 11.93, 12.18, 36.50,
41.96, 51.05, 61.56, 70.54, 71.88, 81.90, 83.48, 84.64,
87.31, 109.32, 109.68, 136.18, 136.40, 150.34, 150.80,
163.68, 163.74, 164.95, 165.57, 167.83; HRMS calcd
for C23H28ClN9O9 609.1698, found 609.1673.
3c: White solid, 85%; m.p. 233—235 ℃; H NMR
(DMSO-d6, 600 MHz) δ: 1.79 (s, 3H, CH3), 2.21—2.36
(m, 2H, CH2-2'), 3.62—3.69 (m, 2H, CH2-5'), 3.94—
3.96 (q, J＝5.40, 11.40 Hz, 1H, CH-3'), 4.49—4.55 (m,
1H, CH-4'), 6.20 (t, J＝10.20, 21.00 Hz, 1H, CH-1'),
7.78 (s, 1H, CH-6), 9.54 (d, J＝10.8 Hz, 1H, NH),
11.31 (s, 1H, NH-3); 13C NMR (DMSO-d6, 125 MHz) δ:
12.23, 36.56, 51.47, 61.37, 83.58, 84.05, 109.48, 136.13,
150.35, 163.71, 164.96, 168.54, 169.32; HRMS calcd
for C13H14Cl2N6O4 388.0453, found 388.0428.
General procedure for the synthesis of compounds
(1a— 1f)
1
1e: White solid, 44%; m.p. 182—184 ℃; H NMR
To a solution of 3c (300 mg, 0.8 mmol) in THF (30
mL) was added DIPEA and amino nucleoside derivative
2a (297 mg, 1.2 mmol). The mixture was stirred at 55
℃ for 2 h, and water (1 mL) was added. The reaction
progress was monitored by TLC [V(CH2Cl2) ∶
V(CH3OH)＝20∶1]. After the solvent was evaporated
under reduced pressure, the residue was submitted to
column chromatography [V(CH2Cl2) ∶ V(CH3OH) ＝
20∶1] to afford the dinucleoside derivative 1d (250 mg,
53%). Following the same procedure, the dinucleoside
derivatives 1a—1c and 1f were prepared.
(DMSO-d6, 400 MHz) δ: 1.78 (s, 3H, CH3), 2.20—2.27
(m, 2H, CH2-2' (AZT)), 3.46—3.65 (m, 4H, CH2-5'),
4.07 (s, 1H, CH-4'), 4.41—4.48 (m, 1H, CH-4'), 5.09—
5.15 (m, 2H, CH-3'), 5.41 (d, J＝5.80 Hz, 1H, CH-2'),
5.61 (m, 1H, CH-5), 5.72 (d, J＝5.92 Hz, 1H, CH-1'),
6.14 (m, 1H, CH-1'), 7.61—7.82 (m, 2H, CH-6), 11.26
(d, J＝7.36 Hz, 1H, NH), 11.34 (s, 1H, NH); 13C NMR
(DMSO-d6, 100 MHz) δ: 168.35, 166.02, 165.49,
164.24, 163.59, 151.20, 150.92, 141.63, 136.70, 110.05,
102.40, 88.50, 85.08, 84.04, 82.43, 72.64, 71.17, 61.95,
51.33, 42.69, 37.04, 12.63; HRMS calcd for
C22H26ClN9O9 595.1541, found 595.1535.
1a: White solid, 30%; m.p. 230 ℃ ; 1H NMR
(DMSO-d6, 400 MHz) δ: 1.76 (s, 6H, CH3), 3.45—3.52
(m, 4H, CH-5'), 3.89—3.94 (m, 4H, CH-2', CH-3'), 4.07
(s, 2H, CH-4'), 5.13 (s, 1H, OH), 5.18 (s, 1H, OH), 5.37
(s, 2H, OH), 5.72 (s, 1H, CH-1'), 5.74 (s, 1H, CH-1'),
7.40—7.45 (m, 2H, H-6), 8.00—8.10 (m, 2H, NH),
11.31 (s, 2H, NH); 13C NMR (DMSO-d6, 100 MHz) δ:
12.74, 43.13, 71.68, 72.92, 82.60, 82.9, 88.86, 110.55,
137.34, 151.66, 164.49, 166.60, 169.24, 169.80; HRMS
calcd for C23H28ClN9O10 625.1649, found 625.1614.
1f: White solid, 51%; m.p. 250 ℃ ; 1H NMR
(DMSO-d6, 400 MHz) δ: 1.72 (s, 3H, CH3), 2.19 (s, 2H,
CH2-2'), 3.59 (s, 2H, CH2-5'), 3.83 (s, 1H, H-4'), 4.42 (s,
1H, H-3'), 5.02 (d, J＝7.74, 1H, OH), 6.15 (s, 1H, H-1'),
7.66 (s, 1H, H-6), 8.31 (d, J＝5.84 Hz, 1H, NH), 11.25
(s, 1H, NH); 13C NMR (DMSO-d6, 100 MHz) δ: 13.03,
37.73, 51.72, 62.37, 84.90, 85.61, 110.38, 137.02,
151.27, 164.54, 165.77, 168.75, 169.07; HRMS calcd
for C23H28ClN9O8 593.1749, found 593.1723.
1
1b: White solid, 33%; m.p. 214—216 ℃; H NMR
(DMSO-d6, 400 MHz) δ: 1.84 (s, 3H, CH3), 3.59—3.60
(m, 4H, CH2-5'), 3.99—4.00 (m, 4H, CH-2', CH-3'),
4.15—4.18 (m, 2H, CH-4'), 5.19—5.29 (m, 2H, OH),
5.43—5.50 (m, 2H, OH), 5.67—5.70 (m, 1H, CH-1'),
Biological activity assay
Antitumor activity18
The cytotoxicity of the compounds was evaluated
Chin. J. Chem. 2011, 29, 1205—1210
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using HeLa (human cervical cancer cell line) and A-549
(human lung adenocarcinoma epithelial cell line) cell
lines by the modified Mosmann’s protocol as follows:
Briefly, cells (104 cells per well) were plated in 96-well
culture plates and cultured overnight at 37 ℃ in a 5%
CO2 humidified incubator. Compounds were added to
the wells at final concentrations of 1, 10, and 100
µmol/L. Control wells were prepared by the addition of
DMEM. Wells containing DMEM without cells were
used as blanks. The plates were incubated at 37 ℃ in a
5% CO2 incubator for 48 h. Upon completion of the
incubation, stock MTT dye solution (10 µL, 5 mg/mL)
was added to each well. After 4 h incubation, the su-
pernatant was removed and DMSO (100 mL) was added
to solubilize the MTT. The optical density of each well
was measured on a microplate spectrophotometer at a
wavelength of 570 nm. The inhibition rate was calcu-
Scheme 2
lated according to the formula: (ODcontrol
－
ODtreated)/ODcontrol×100%.
HIV-RT kit assay
The HIV-RT inhibition assay was performed by us-
ing an RT assay kit (Roche), and the procedure for as-
saying RT inhibition was performed as described in the
kit protocol. Briefly, the reaction mixture consists of
template/primer
complex,
2'-deoxy-nucleotide-5'-
triphosphates (dNTPs) and reverse transcriptase (RT)
enzyme in the lysis buffer with or without inhibitors.
After 1 h incubation at 37 ℃ the reaction mixture was
transferred to streptavidin-coated microtitre plate (MTP).
The biotin labeled dNTPs that are incorporated in the
template due to the activity of RT were bound to strep-
tavidin. The unbound dNTPs were washed using wash
buffer and antidigoxigenin-peroxidase (DIG-POD) was
added in MTP. The DIG-labeled dNTPs incorporated in
the template were bound to anti-DIG-POD antibody.
The unbound anti-DIG-POD was washed and the per-
oxide substrate (ABST) was added to the MTP. A col-
ored reaction product was produced during the cleavage
of the substrate catalyzed by a peroxide enzyme. The
absorbance of the sample was determined at OD 405
Reagents and conditions: (i) acetone, H2SO4, r.t.; (ii) TsCl, pyridine,
r.t.; (iii) NaN3, DMF, 80 ℃; (iv) PPh3, H2O or Pt/C (10%), H2; (v)
TFA/H2O (90%), r.t.
The nucleophilic substitution of cyanuric chloride
was mainly carried out in THF solution.20 At first, the
2,3-propylidene protected nucleoside (9a) was used as
the starting material for approaching the preparation of
the dinucleoside, and the successive two-step substitu-
tions were carried out smoothly and provided the corre-
sponding dinucleoside analog 11a as shown in Scheme
3. However, the following deprotection of 2,3-pro-
pylidene could not proceed well under the conventional
condition, which gave the desired product in a poor
yield less than 10%. Then, we tried to use compound 2a
without protective group as the starting material for the
synthesis of the dinucleosides. After careful examina-
tion on various conditions, the reaction was found to
undergo smoothly in THF solution containing a small
amount of H2O by improving the solubility of com-
pounds 2, and could directly afford the desired dinu-
cleosides 1 as shown in Scheme 1. Thus, the solution of
2a in THF with minimal water was stirred at ice bath for
10 min, then cyanuric chloride and N,N-diisopropyl-
ethylamine (DIPEA) were added and was stirred for
another 30 min to afford the corresponding monosub-
stitution product 3a in 63% yield (Scheme 1). The
disubstituted 1a was obtained in 30% upon treatment of
2a with 3a in presence of DIPEA at 55 ℃. Under the
nmol•L－ using microtiter plate ELISA reader. The re-
1
sulting color intensity is directly proportional to the ac-
tual RT activity. The percentage inhibitory activity of
RT inhibitors was calculated by comparing to a sample
that does not contain an inhibitor. The percentage inhi-
bition was calculated by formula as given below: Inhi-
bition ＝ 100% － [(OD405
with inhibitor/OD405
nm
nm
without inhibitor)×100%].
Results and discussion
The requisite raw materials 2 (amino nucleosides)
were synthesized from commercially available nucleo-
sides 5-methyl uridine (4a) and uridine (4b) according
to the literature procedure,19 and compound 2c was pre-
pared from azidothymidine (4c) via the reduction of
azido, as shown in Scheme 2.
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1205—1210

Synthesis and Biological Activities of Novel s-Triazine Bridged Dinucleoside Analogs
Scheme 3
Reagents and conditions: (i) DIPEA, THF, 0 ℃; (ii) DIPEA, THF, 55 ℃; (iii) TFA/H2O (90%).
－
1
same conditions, the dinucleoside analogs 1b— 1f were
synthesized. It should be mentioned that the synthesis of
such trinucleoside analog connected with triazine was
also attempted, but no desired product was obtained,
possibly due to the lower reactivity of the chlorine on
triazine in compound 1 and their steric effect.12
of 8.6 and 10.5 µmol•L , respectively. Moreover, the
intermediates 3, which would be regarded as “double
headed” nucleoside analogs, gave a high selectivity
against HeLa cells. However, compounds 1 and 3 dis-
played very weak activity against HIV-RT incompari-
son to the control AZT.
HIV-1 reverse transcriptase (RT) inhibitory and an-
titumor activities of nucleoside analogs 1 and 3 were
evaluated. Their cytotoxicity was examined using HeLa
(human cervical cancer cell) and A-549 (human lung
adenocarcinoma epithelial cell) by the modified Mos-
mann’s protocol18 and the results are summarized in
Table 1. It could be seen from Table 1 that some of the
compounds 1 showed good inhibitory activities against
the HeLa and A-549, for instance, compounds 1c and 1e
exhibited inhibitory activity to HeLa cells with the IC50
Conclusions
In summary, we have synthesized a series of novel
s-triazine linked “triple headed” dinucleoside analogs 1
by stepwise substitutions of unprotected nucleosides
with cyanuric chloride. Some of the compounds, such as
1c and 1e, showed good in vitro inhibitory activity
against human cervical cancer cell (HeLa), but none of
them exhibited anti-HIV-RT activity. The further syn-
thesis and biological study for the similar novel hetero-
cycle-linked dinucleoside analogs are underway in this
laboratory.
Table 1 Anticancer activities of nucleoside analogs 1 and 3
against HeLa and A-549 cells
IC50/(µmol•L－
)
1
Compound
References
A-549
HeLa
1
(a) Parker, W. B. Chem. Rev. 2009, 109, 2880.
(b) Chu, C. K. Antiviral Nucleoside: Chiral Synthesis and
Chemotherapy, Elsevier, B. V., 2003, pp. 1—76.
(a) Robins, R. K. Pharm. Res. 1984, 1, 11.
(b) Jones, R. J.; Bischofberger, N. Antivir. Res. 1995, 27, 1.
Romeo, G.; Chiacchio, U.; Corsaro, A.; Merino, P. Chem.
Rev. 2010, 110, 3337.
Hartung, R.; Paquette, L. A. J. Org. Chem. 2005, 70, 1597.
Kašnar, B.; Škarió, V.; Klaió, B.; Žinić, M. Tetrahedron
Lett. 1993, 34, 4997.
(a) Chen, L. Q.; Petrelli, R.; Olesiak, M.; Wilson, D. J.; La-
bello, N. P.; Pankiewicz, K. W. Bioorg. Med. Chem. 2008,
1a
1b
1c
1d
1e
1f
74.2±1.0
48.2±0.2
＞100
＞100
60.0±1.3
＞100
8.6±0.3
52.7±0.8
10.5±0.2
＞100
2
3
20.8±1.4
＞100
4
5
3a
3b
3c
＞100
32.5±0.9
41.6±0.8
77.9±0.8
＞100
＞100
6
Chin. J. Chem. 2011, 29, 1205—1210
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1209

Shen et al.
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16, 7462.
3570.
(b) Cattaneo-Pangrazzi, R. M. C.; Schott, H.; Schwendener,
R. A. Prostate 2000, 45, 8.
15 Zacharie, B.; Abbott, S. D.; Bienvenu, J. F.; Cameron, A. D.;
Cloutier, J.; Duceppe, J. S.; Ezzitouni, A.; Fortin, D.; Houde,
K.; Lauzon, C.; Moreau, N.; Perron, V.; Wilb, N.; Asselin,
M.; Doucet, A.; Fafard, M. E.; Gaudreau, D.; Grouix, B.;
Sarra-Bournet, F.; St-Amant, N.; Gagnon, L.; Penney, C. L.
J. Med. Chem. 2010, 53, 1138.
7
(a) Hanuš, J.; Barvík, I.; Ruszová-Chmelová, K.; ŠtÆpánek,
J.; Turpin, P.-Y.; Bok, J.; Rosenberg, I.; Petrová-Endová, M.
Nucleic Acids Res. 2001, 29, 5182.
(b) Grajkowski, A.; Pedras-Vasconcelos, J.; Wang, V.;
Ausín, C.; Hess, S.; Verthelyi, D.; Beaucage, S. L. Nucleic
Acids Res. 2005, 33, 3550 and reference 6.
16 (a) Menicagli, R.; Samaritani, S.; Signore, G.; Vaglini, F.;
Via, L. D. J. Med. Chem. 2004, 47, 4649.
8
9
(a) Uhlmann, E.; Peyman, A. Chem. Rev. 1990, 90, 543.
(b) Cook, P. D. Anti-Cancer Drug Des. 1991, 6, 585.
(c) Milligan, J. F.; Matteucci, M. D.; Martin, J. C. J. Med.
Chem. 1993, 36, 1923.
Gogoi, K.; Gunjal, A. D.; Phalgune, U. D.; Kumar, V. A.
Org. Lett. 2007, 9, 2697.
(b) Moon, H.-S.; Jacobson, E. M.; Khersonsky, S. M.; Lu-
zung, M. R.; Walsh, D. P.; Xiong, W.; Lee, J. W.; Parikh, P.
B.; Lam, J. C.; Kang, T. W.; Rosania, G. R.; Schier, A. F.;
Chang, Y. T. J. Am. Chem. Soc. 2002, 124, 11608.
(c) Hodous, B. L.; Geuns-Meyer, S. D.; Hughes, P. E.;
Albrecht, B. K.; Bellon, S.; Bready, J.; Caenepeel, S.; Cee,
V. J.; Chaffee, S. C.; Coxon, A.; Emery, M.; Fretland, J.;
Gallant, P.; Gu, Y.; Hoffman, D.; Johnson, R. E.; Kendall,
R.; Kim, J. L.; Long, A. M.; Morrison, M.; Olivieri, P. R.;
Patel, V. F.; Polverino, A.; Rose, P.; Tempest, P.; Wang, L.;
Whittington, D. A.; Zhao, H. L. J. Med. Chem. 2007, 50,
611.
10 Barawkar, D. A.; Linkletter, B.; Bruice, T. C. Bioorg. Med.
Chem. Lett. 1998, 8, 1517.
11 Taourirte, M.; Mohamed, L. A.; Rochdi, A.; Vasseur, J. J.;
Fernández, S.; Ferrero, M.; Gotor, V.; Pannecouque, C.; De
Clercq, E.; Lazrek, H. B. Nucleosides Nucleotides Nucleic
Acids 2004, 23, 701.
12 Jung, F.; Burger, A.; Biellmann, J. F. Org. Lett. 2003, 5,
383.
(d) Nozaki, S.; Maeda, M.; Truda, H.; Sledze, G. W. Breast
Cancer Res. Tr. 2004, 83, 195.
13 (a) Lucas, R.; Elchinger, P. H.; Faugeras, P. A.; Zerrouki, R.
Nucleosides Nucleotides Nucleic Acids 2010, 29, 168.
(b) Lucas, R.; Zerrouki, R.; Granet, R.; Krausz, P.; Cham-
pavier, Y. Tetrahedron 2008, 64, 5467.
(c) Chittepu, P.; Sirivolu, V. R.; Seela, F. Bioorg. Med.
Chem. 2008, 16, 8427.
14 (a) Shen, T. Y. Angew. Chem., Int. Ed. Engl. 1970, 9, 678.
(b) Zhang, X. Y.; Amer, A.; Fan, X. S.; Balzarini, J.; Neyt,
J.; Clercq, E. D.; Prichard, M.; Kern, E.; Torrence, P. F.
Bioorg. Chem. 2007, 35, 221.
(e) Xiong, Y. Z.; Chen, F. E.; Balzarini, J.; De clercq, E.;
Pannecouque, C. Eur. J. Med. Chem. 2008, 43, 1230, and
references cited therein.
17 Pedersen, S. L.; Nielsen, P. Org. Biomol. Chem. 2005, 3,
3570.
18 Mosmann, T. J. Immunol. Methods 1983, 65, 55.
19 (a) Winans, K. A.; Bertozzi, C. R. Chem. Biol. 2002, 9, 113.
(b) Babič, A.; Gobec, S.; Gravier-Pelletier, C.; Merrer, Y. L.;
Pečar, S. Tetrahedron 2008, 64, 9093.
20 (a) Robins, L. I.; Kurth, M. J. Org. Lett. 2007, 9, 171.
(b) Masala, S.; Taddei, M. Org. Lett. 1999, 1, 1355.
(c) Pedersen, S. L.; Nielsen, P. Org. Biomol. Chem. 2005, 5,
(E1011052 Zhao, C.; Lu, Z)
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