Synthesis and Bioactivity of Novel Trisubstituted Triazole Nucleosides

Article abstract of DOI:10.1080/15257770.2015.1115523

A series of novel trisubstituted 1,2,3-triazole purine nucleosides were efficiently synthesized via Huisgen 1,3-dipolar cycloaddition in good yields. Bioactivity against cytomegalovirus (CMV) and varicella-zoster virus (VZV) in human embryonic lung cell cultures was evaluated and all compounds show low antiviral activity.

Full text of DOI:10.1080/15257770.2015.1115523

Nucleosides, Nucleotides and Nucleic Acids
ISSN: 1525-7770 (Print) 1532-2335 (Online) Journal homepage: http://www.tandfonline.com/loi/lncn20
Synthesis and Bioactivity of Novel Trisubstituted
Triazole Nucleosides
Yi-Ning Wen, Zhi-Feng Zhang, Ning-Ning Liu, Yu-Hong Xiang, Zhuo-Yong
Zhang, Graciela Andrei, Robert Snoeck, Dominique Schols, Qing-Shan Zhang
& Qin-Pei Wu
To cite this article: Yi-Ning Wen, Zhi-Feng Zhang, Ning-Ning Liu, Yu-Hong Xiang, Zhuo-Yong
Zhang, Graciela Andrei, Robert Snoeck, Dominique Schols, Qing-Shan Zhang & Qin-Pei Wu
(2016): Synthesis and Bioactivity of Novel Trisubstituted Triazole Nucleosides, Nucleosides,
Nucleotides and Nucleic Acids, DOI: 10.1080/15257770.2015.1115523
To link to this article: http://dx.doi.org/10.1080/15257770.2015.1115523
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Date: 09 February 2016, At: 18:51

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
http://dx.doi.org/./..
Synthesis and Bioactivity of Novel Trisubstituted Triazole
Nucleosides
Yi-ning Wena, Zhi-feng Zhanga, Ning-ning Liua, Yu-hong Xiangb,
Zhuo-yong Zhangb, Graciela Andreic, Robert Snoeckc, Dominique Scholsc,
Qing-shan Zhanga, and Qin-pei Wua
aDepartment of Applied Chemistry and Pharmaceutics, Beijing Institute of Technology, Beijing , China;
bDepartment of Chemistry, Capital Normal University, Beijing , China; cRega Institute for Medical
Research, KU Leuven, Minderbroedersstraat , Leuven, Belgium
ABSTRACT
ARTICLE HISTORY
Received  October 
Accepted  October 
A series of novel trisubstituted 1,2,3-triazole purine nucleosides
were efficiently synthesized via Huisgen 1,3-dipolar cycloaddition
in good yields. Bioactivity against cytomegalovirus (CMV) and
varicella-zoster virus (VZV) in human embryonic lung cell cultures
was evaluated and all compounds show low antiviral activity.
KEYWORDS
triazole; nucleosides;
Huisgen ,-dipolar
cycloaddition; antiviral
Introduction
More than half of the clinic drugs for treating viral disease are nucleoside ana-
logues.[1] Certain acyclic nucleosides, in which the ribose sugar is replaced with
a chain structure, have outstanding biological activity,[2] an example is acyclovir,
the first acyclic nucleoside drug approved for treating HSV-1, HSV-2 and VZV.[1,3]
Other acyclic nucleoside drugs include ganciclovir-treating cytomegalovirus
(CMV),[4] penciclovir-treating varicella-zoster virus (VZV),[4] adefovir-treating
herpesviruses, retroviruses and HBV,[5] tenofovir used as an anti-HIV and
anti-HBV agent,[6] cidofovir-treating herpesviruses (CMV), and adenoviruses
(Figure 1).[7]
Ribavirin, the first example of atriazole-containing nucleoside drug, presents
a broad spectrum of antiviral activity against many DNA and RNA viruses.[8]
Among various structural modifications of nucleosides, 1,2,3-triazole-nucleoside
analogues have been extensively studied and exhibit broad bioactivity,[9] such as
antibacterial[10], antifungal[10b,10c,11], anticancer[12], and antiviral[13].These com-
pounds include the replacement of sugar[9b,14] or nucleobases[15] with a 1,2,3-
triazole moiety as well as an additional linker of 1,2,3-triazoles between a phospho-
noalkyl unit and a nucleobase.[16]
CONTACT Qin-peiWu
qpwu@bit.edu.cn
of Technology, Beijing , China.
DepartmentofAppliedChemistryandPharmaceutics, BeijingInstitute
©  Taylor & Francis Group, LLC

2
YI-NING WEN ET AL.
Figure . Antiviral acyclic nucleoside drugs.
In view of the fact that moderate activity is shown by compounds PTriaT, PTriaU,
and PtriaA[16h] against HCV and by compound PTriaP towards HSV-1 and HSV-
2 (Figure 2),[16j] we assumed that 4,5-double substituted 1,2,3-triazole-nucleoside
analogues might be biologically active.
Results and Discussion
Chemistry
Azidation of ethyl bromoacetate 1 with NaN3 gave ethyl 2-azidoacetate 2, which
was directly used to be cyclized with 1,4-butynediol at 110°C without any catalysts
and the corresponding 4,5-bis(hydroxymethyl)-1,2,3-triazole 3 was formed in 51%
yields.[17] Then selectively protecting one hydroxyl group in 3 was successfully per-
formed in 73% yield via treatment with triphenylmethyl chloride. 4 was mesylated
with methanesulfonyl chloride and then treated with nucleobases in DMF at room
temperature to give the expected product 5 in good yields.[18] Removal of the trityl
group was smoothly carried out in the presence of trifluoroacetic acid (TFA) to give
the product 6a and 6b (Scheme 1).
The structures of target compounds 6a and 6b were proven on the basis of 1H
NMR and 13C NMR spectroscopic analysis. The 1H NMR spectrum of 6a showed
singlets at δ 8.80 and 8.67 ppm for CH of the 6-chloropurine group, with signals
Figure . Structures of PTriaT, PTriaU, PtriaA, and PtriaP.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
3
Scheme . Synthesis of ,,-triazole-nucleosides.
at δ 3.79 and 1.03 ppm as quartet and triplet for CH2 and CH3 of the ethoxycar-
bonyl group, in addition to singlets at δ 5.78, 5.57 and 4.74 ppm for three other
CH2, respectively. Its 13C NMR spectra showed the characteristic signals at δ 166.82,
61.56 and 13.63 ppm corresponding to C=O, CH2CH3 and CH2CH3 of the ethoxy-
carbonyl group, signals at δ 151.72, 151.67, 149.12, 147.13, 146.87, 130.58, and
130.01 ppm for the 6-chloropurine group and triazole ring, in addition with signals

4
YI-NING WEN ET AL.
at δ 54.63, 49.20 and 34.54 ppm for three methylene groups, respectively. The spec-
troscopic analysis for 6b was similar with that of 6a and the data was in agreement
with the structure.
After treatment of 6a or 6b with aqueous ammonia, the ester group was con-
verted into the corresponding amides and the 6-chloropurine group was trans-
formed into adenine, e.g. 6a converted to 7d. The 6-chloro atom in 6b, however,
is intact under this condition. In aqueous TFA solution (V(TFA)/V(H2O) = 3:1),
compounds 6b and 7b were converted to the corresponding guanine nucleosides
6c and 7c, respectively.[19] The 1H NMR spectrum of 6c showed the characteristic
signal at δ 10.67 ppm as a singlet, which could prove this conversation.
Treatment of ester 4 with methylamine at room temperature formed the amidic
compound 8, which converted to nucleoside 9 in a good yield under similar condi-
tion for compound 5. The 1H NMR spectrum of 8 showed the characteristic signals
at δ 8.28 and 2.66 ppm corresponding to the presence of the CH3NH group. After
deprotecting the trityl group of 9a and 9b in TFA-CH2Cl2 solution, 10a and 10b
were obtained, respectively. The conversion of 6-chloroguanine 10b to guanine 10c
was smoothly performed in TFA aqueous solution at room temperature.
Selective substitution of the chlorine atom in 5b by amine was efficiently con-
ducted via treatment with cyclopropylamine at 0°C to form 11(Scheme 2). At 60°C,
however, both the chlorine atom and the ester group were transformed to give 12.
The 1H NMR spectrum of 11 showed signals at δ 3.19–3.17, 0.68–0.62, and 0.61–
0.54 ppm as multiplets for the CH and CH2 of the cyclopropyl group, with signals
at δ 3.01 ppm as singlet for the NH of cyclopropylamino group, respectively. Its 13
C
Scheme . Synthesis of N-cyclopropyl-H-purine-,-diamine,,-triazole-nucleosides.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
5
NMR spectrum showed the characteristic signals at δ 24.17 and 6.80 ppm corre-
sponding to CH and CH2 of the cyclopropyl group, respectively. 1H and 13C NMR
spectra of 12 showed the characteristic signals corresponding to the presence of two
cyclopropylamino groups.
The final product 14 was obtained after treating 12 with TFA to remove the trityl
group. Under similar deprotecting conditions, 13 was formed. Treatment of 13 with
aqueous ammonia gave the target compound 15.
Antiviral activity evaluation
All the synthesized compounds 6a–c, 7b-d, 10a-c, and 13–15 were evaluated for
antiviral activities against herpes viruses, using human embryonic lung (HEL) cell-
based assays, cytomegalovirus (AD-169 strain and Davis strain), varicella-zoster
virus (TK+ VZVstrain and TK− VZV strain). Ganciclovir, cidofovir, acyclovir, and
brivudin were used as the reference compounds. The antiviral activity was expressed
as the EC50: the compound concentration required to reduce virus plaque forma-
tion by 50%. Unfortunately, none of these compounds demonstrated activity against
these tested viruses as shown by the EC50 values (>20 μM, Table 1).The cytotox-
icity of the tested compounds toward the uninfected host cells was defined as the
minimum cytotoxic concentration (MCC) that causes a microscopically detectable
alteration of normal cell morphology.
Table . Anti-CMV and anti-VZV activities of the synthesized compounds.
CMV
VZV
Cytotoxicity
Cytotoxicity
EC (µM)a
(µM)
EC (µM)a
(µM)
Cell
Cell
morphology
morphology
Compound
AD-
Davis
(MCC)b
TK+ VZV
TK−VZV
(MCC)b
6a
>
>
>
>
>
>
ND
>
>
>
>
>
.
>

>
>
>
>
ND
>
>
>
>
>
.
ࣙ
ࣙ
ࣙ
ࣙ
ࣙ
ࣙ
ND
ࣙ
ࣙ
ࣙ
ࣙ
>
>
>
ND
>
>
>
>
>
>
ND
>
>
>
>
>
ND
>
>
>
>

>
ND
>
>
>
>
>
ND
>
>
>
>
>
>
ND
>
>
>
>
>
ND
6b
6c
7b
7c
7d
10a
10b
10c
13
14
15
Ganciclovir
Cidofovir
Acyclovir
Brivudin
.
ND
ND
.
ND
ND
ND
.
.
ND
.

ND
>
>
ND
aEffective concentration required to reduce virus plaque formation by %. Virus input was  plaque forming units
(PFU) for HCMV. Virus input was  plaque forming units (PFU).
bMinimum cytotoxic concentration that causes a microscopically detectable alteration of cell morphology.
cNot determined.

6
YI-NING WEN ET AL.
Conclusion
In conclusion, a number of1,4,5-trisubstituted 1H-1,2,3-triazole purines were effec-
tively synthesized. Antiviral activity against CMV and VZV in human embryonic
lung (HEL) cell cultures was evaluated and none show significant activity towards
these selected virus.
Experimental
1H NMR, 13C NMR spectra were recorded on a Bruker AM-400 nuclear magnetic
resonance spectrometer. Chemical shifts (δ) are reported in ppm relative to the
TMS peak. Melting points are uncorrected and were determined on a XT4A type
melting point apparatus. High-resolution mass spectra were acquired with an
Agilent Accurate-Mass-Q-TOF MS 6520 system equipped with an electrospray
ionization (ESI) source. Thin-layer chromatography (TLC) was carried out on
silica gel precoated plates purchased from Yantai Institute of Chemical Industry.
Column chromatography separation was carried out on silica gel (40∼50 μm,
Yantai Institute of Chemical Industry). All the chemical reagents were analytical or
chemical pure reagents.
Ethyl 2-(4,5-bis(hydroxymethyl)-1H-1,2,3-triazol-1-yl)acetate(3)
A solution of ethyl 2-bromoacetate 1 (11.40 mL, 100 mmol) and NaN3 (8.60 g,
100 mmol) in acetone / H2O (50 mL, V/V = 3:2) was heated at 60°C overnight.
The residue was dissolved in EtOAc and washed with brine, the organic layer was
dried over MgSO4, filtered, and evaporated under reduced pressure to afford ethyl
2-azidoacetate 2 (9.67 g, 75%) as an colorless oil, which was used in the next step
without being further purified.
A solution of2 (9.67 g, 75 mmol) and 1,4-butynediol (5.86 g, 68 mmol) was stirred
at 110°C overnight. The reaction was monitored by TLC (stained with iodine).
When the reaction was completed, the mixture was cooled to room temperature and
diluted in EtOAc. The organic layer was evaporated under reduced pressure. The
residue was purified by silica gel column chromatography using petroleum ether—
ethyl acetate (3:7, v/v) as an eluent to afford compound 3 (7.20 g, 51%) as a white
solid, m.p.105°C ∼ 107°C.1H NMR (400 MHz, DMSO-d6) δ 5.38 (t, J = 5.5 Hz,
1 H), 5.12 (t, J = 5.5 Hz, 1 H), 4.58 (d, J = 5.3 Hz, 2 H), 4.51 (d, J = 5.4 Hz, 2 H),
4.17 (q, J = 7.0 Hz, 2 H), 1.21 (t, J= 7.2 Hz, 3 H).13C NMR (400 MHz, DMSO-
d6) δ 167.16, 144.36, 134.71, 61.38, 54.12, 51.19, 49.24, 13.96. HRMS calculated for
[C8H14N3O4+H]+: 216.0984, Found: 216.0987.
Ethyl 2-(5-(hydroxymethyl)-4-((trityloxy)methyl)-1H-1,2,3-triazol-1-yl)acetate (4)
To a solution of 3 (4.30 g, 20 mmol) in CH2Cl2 (25 mL) was added TEA (2.90 mL,
22 mmol) and triphenylmethyl chloride (6.05 g, 22 mmol) at 0°C. The mixture was

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
7
stirred at 0°C for 5 h and subsequently quenched with saturated aqueous NaHCO3.
The mixture was extracted with CH2Cl2 (50 mL). The organic layer was dried over
MgSO4, filtered, and concentrated under reduced pressure. The residue was puri-
fied by silica gel column chromatography using the mixture petroleum ether—ethyl
acetate (1:1, v/v) as an eluent to afford compound 4 (6.67 g, 73%) as a white solid,
m.p.107°C ∼ 109°C.1H NMR (400 MHz, DMSO-d6) δ 7.44 –7.26 (m, 15H), 5.42
(t, J= 5.4 Hz, 1 H) 5.38 (s, 2 H), 4.47 (d, J= 5.3 Hz, 2 H), 4.17 (q, 7.0 Hz, 2 H),
4.05 (s, 2 H), 1.21 (t, J= 7.1 Hz, 3 H). 13C NMR (100 MHz, DMSO-d6) δ 167.05,
143.47, 140.76, 135.55, 128.27, 127.99, 127.15, 86.55, 61.41, 56.71, 51.17, 49.38,
13.92. HRMS calculated for [C27H28N3O4+H]+: 458.2080, Found:. 458.2078.
Ethyl 2-(5-((6-chloro-9H-purin-9-yl)methyl)-4-((trityloxy)methyl)-1H-1,2,3-triazol-
1-yl)acetate (5a)
To a solution of 4 (4.57 g, 10 mmol) in CH2Cl2 (25 mL) was added TEA (1.46 mL,
11 mmol) and methanesulfonyl chloride (850 µL, 11 mmol) at 0°C. The mixture
was stirred at 0°C for 10 min and subsequently quenched with saturated aque-
ous NaHCO3. The mixture was extracted with CH2Cl2 (50 mL). The organic layer
was dried over MgSO4, filtered, and concentrated under reduced pressure afforded
crude product 4. A mixture of crude methane sulfate 4 (4.16 g, 8.0 mmol), K2CO3
(1.32 g, 9.60 mmol) and 6-chloropurine (1.47 g, 9.6 mmol) in DMF (20 mL) was
stirred at room temperature for 5 h. The reaction mixture was quenched with dis-
tilled water. The residue was dissolved in CH2Cl2 (100 mL) and washed with H2O
(80 mL). The organic layer was dried over MgSO4, filtered, and concentrated in
vacuo. The crude residue was purified on a silica gel column using petroleum ether
– EtOAc (1:1, v/v) as eluent, giving pure compound 5a (3.32 g, 70%) as a white
1
solid, m.p.110°C ∼ 111°C. H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1 H), 8.46
(s, 1 H), 7.35 – 7.25 (m, 15 H), 5.64 (s, 4 H), 4.23 (s, 2 H), 3.97 – 3.90 (m, 2 H),
1.09 (t, J= 7.1 Hz, 3 H). 13C NMR (100 MHz, DMSO-d6) δ 166.82, 151.63, 151.58,
149.18, 146.60, 143.29, 130.69, 130.60, 128.18, 127.93, 127.12, 86.77, 61.69, 56.96,
49.34, 34.95, 13.66. HRMS calculated for [C32H29ClN7O3+H]+ : 594.2020, Found:
594.2025.
Ethyl 2-(5-((2-amino-6-chloro-9H-purin-9-yl)methyl)-4-((trityloxy)methyl)-1H-
1,2,3-triazol-1-yl)acetate (5b)
Compound 5b was synthesized from 4 by a similar procedure to that described for
5a as a white solid (3.6 g, 69%), m. p. 115°C ∼ 117°C. 1H NMR (400 MHz, DMSO-
d6) δ 7.76 (s, 1 H), 7.34 – 6.90 (m, 15 H), 5.76 (s, 2 H), 5.62 (s, 2 H), 5.33 (s, 2 H),
4.15 (s, 2 H), 3.99 (q, J= 7.1 Hz, 2 H), 1.14 (t, J= 7.1 Hz, 3 H). 13C NMR (100 MHz,
DMSO-d6) δ 166.87, 159.67, 153.69, 149.52, 143.30, 142.89, 141.92, 131.13, 128.20,
127.89, 127.08, 122.99, 86.72, 61.65, 56.73, 49.46, 34.23, 13.67. HRMS calculated for
[C32H30ClN8O3+H]+: 609.2129, Found: 609.2130.

8
YI-NING WEN ET AL.
Ethyl 2-(5-((6-chloro-9H-purin-9-yl)methyl)-4-(hydroxymethyl)-1H-1,2,3-triazol-1-
yl)acetate (6a)
To a solution of 5a (3.00 g, 5.06 mmol) in CH2Cl2 (15 mL) at 0°C (ice bath) was
added TFA (2.28 mL, 25.30 mmol). After stirred 7 h at 0°C, the mixture was neu-
tralized to pH 7 with saturated aqueous NaHCO3. The residue was concentrated in
vacuo and purified on a silica gel column using petroleum ether – EtOAc (2:3, v/v) as
eluent to afford compound 6a (0.78 g, 74%) as a white solid, m.p.172°C ∼ 173°C. 1H
NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.67 (s, 1 H), 5.78 (s, 2 H), 5.57 (s, 2 H),
4.74 (s, 2 H), 3.79 (q, J = 7.2 Hz, 2 H), 1.03 (t, J= 7.1 Hz, 3 H). 13C NMR (400 MHz,
DMSO-d6) δ 166.82, 151.72, 151.67, 149.12, 147.13, 146.87, 130.58, 130.01, 61.56,
54.63, 49.20, 34.54, 13.63. HRMS calculated for [C13H14ClN7 O3+H]+: 352.0918,
Found:. 352.0919.
Ethyl 2-(5-((2-amino-6-chloro-9H-purin-9-yl)methyl)-4-(hydroxymethyl)-1H-
1,2,3-triazol-1-yl)acetate (6b)
Compound 6b was synthesized from 5b by a similar procedure to that described for
6a as a white solid (0.94 g, 81%), m.p.185°C ∼ 187°C. 1H NMR (400 MHz, DMSO-
d6) δ 7.64 (s, 1 H), 6.52 (s, 2 H), 5.08 (d, J= 15.4 Hz, 2 H), 5.01 (s, 2 H), 4.23 (s, 2 H),
3.39 (q, J= 7.1 Hz, 2 H), 0.62 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, DMSO-
d6) δ 166.80, 159.79, 153.79, 149.47, 146.69, 142.69, 130.42, 122.95, 61.65, 54.62,
49.31, 33.90, 13.67. HRMS calculated for [C13H15ClN8O3+H]+: 367.1028, Found:.
367.1028.
Ethyl 2-(5-((2-amino-6-oxo-9H-purin-9-yl)methyl)-4-(hydroxymethyl)-1H-1,2,3-
triazol-1-yl)acetate (6c)
To a solution of 6b (183 mg, 0.50 mmol) in CH2Cl2 at room temperature was drop-
wise added TFA/H2O = 3:1 (4 mL, v/v) and stirred overnight. The residue was con-
centrated in vacuo and purified on a silica gel column using CH3OH – CH2Cl2 (1:9,
v/v) as eluent to afford compound 6c (78 mg, 45%) as a white solid, m. p. 175°C
∼ 177°C. 1H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1 H), 7.68 (s, 1 H), 6.48 (s,
2 H), 5.53 (s, 2 H), 5.40 (t, J = 5.5 Hz, 1 H), 5.34 (s, 2 H), 4.66 (d, J= 5.5 Hz, 2 H),
3.93 (q, J= 7.1 Hz, 2 H), 1.11 (t, J= 7.1 Hz, 3 H). 13C NMR (100 MHz, DMSO-
d6) δ 166.81, 156.74, 153.63, 150.84, 146.29, 137.08, 130.82, 116.11, 61.62, 54.54,
49.22, 33.56, 13.73. HRMS calculated for [C13 H16 N8 O4+H]+: 349.1367, Found:
349.1369.
2-(5-((6-Chloro-9H-purin-9-yl)methyl)-4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)
acetamide (7d)
A solution of 6a (121mg, 0.35 mmol) and NH3·H2O (10.00 mL) was stirred at room
temperature overnight. The residue was concentrated in vacuo and purified with

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
9
1
CH3OH to give pure 7d (73 mg, 65%) as a white solid, m.p.189°C ∼ 191°C. H
NMR (400 MHz, DMSO-d6) δ 8.15 (s, 2 H), δ7.78 (s, 1 H), 7.39 (s, 1 H), 7.27 (s,
2 H), 5.58 (s, 2 H), 5.44 (m, 1 H), 5.29 (s, 2 H), 4.62 (s, 2 H). 13C NMR (100 MHz,
DMSO-d6) δ 167.62, 156.44, 152.95, 149.62, 146.50, 141.08, 131.36, 118.84, 54.98,
50.62, 34.61. HRMS calculated for [C11H13N9O2+H]+: 304.1270, Found: 304.1272.
2-(5-((2-Amino-6-chloro-9H-purin-9-yl)methyl)-4-(hydroxymethyl)-1H-1,2,3-
triazol-1-yl)acetamide (7b)
Compound 7b was synthesized from 6b by a similar procedure to that described
1
for 7d as a white solid (75 mg, 67%), m.p. 215°C ∼ 217°C. H NMR (400 MHz,
DMSO-d6) δ 8.11 (s, 1 H), 7.78 (s, 1 H), 7.45 (s, 1 H), 6.98 (s, 2 H), 5.37 (s, 2 H),
5.29 (s, 2 H), 4.60 (s, 2 H). 13C NMR (400 MHz, DMSO-d6) δ 167.34, 159.69, 153.81,
149.41, 146.19, 142.85, 130.44, 123.06, 54.61, 50.38, 34.36. HRMS calculated for
[C11H13N9O3+H]+: 338.08752, Found: 338.08765.
2-(5-((2-Amino-6-oxo-9H-purin-9-yl)methyl)-4-(hydroxymethyl)-1H-1,2,3-triazol-
1-yl)acetamide (7c)
A solution of 7b (188 mg, 0.56 mmol) and TFA/H2O = 3:1 (4 mL, v/v) was heated
to 60°C and stirred overnight. The residue was concentrated in vacuo and purified
with CH3OH to give pure 7c (72 mg, 41%) as a white solid, m.p. 237°C ∼ 239°C.
1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1 H), 7.77 (s, 1 H), 6.48 (s, 2 H), 5.44 (s,
2 H), 5.40 – 5.31 (m, 3 H), 4.62 (s, 2 H). 13C NMR (100 MHz, DMSO-d6) δ 168.32,
156.57, 153.68, 150.81, 146.16, 137.08, 130.49, 115.72, 54.56, 49.40, 33.89. HRMS
calculated for [C11H13N9O3+H]+: 320.1214, Found: 320.1216.
2-(5-(Hydroxymethyl)-4-((trityloxy)methyl)-1H-1,2,3-triazol-1-yl)-N-
methylacetamide (8)
To a solution of 4 (914 mg, 2.0mmol) in CH2Cl2 at 0°C (ice bath) was added methy-
lamine (2 mL) and stirred for 10 min. The residue was concentrated in vacuo and
purified on a silica gel column using petroleum ether – EtOAc (3:7, v/v) as elu-
ent to afford compound 8 (831 mg, 94%) as a white solid, m.p.109°C ∼ 110°C. 1H
NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 4.5 Hz, 1 H), 7.52 – 7.26 (m, 15 H),
5.34 (t, J = 5.4 Hz, 1 H), 5.13 (s, 2 H), 4.48 (d, J = 5.4 Hz, 2 H), 4.07 (s, 2H), 2.66
(d, J = 4.6 Hz, 3 H). 13C NMR (101 MHz, DMSO-d6) δ 166.43, 144.02, 141.43,
136.22, 128.79, 128.46, 127.62, 87.04, 57.29, 51.57, 50.80, 26.13. HRMS calculated
for [C26H27N4O3+H]+: 443.2083, Found: 443.2084.
2-(5-((6-Chloro-9H-purin-9-yl)methyl)-4-((trityloxy)methyl)-1H-1,2,3-triazol-1-yl)-
N-methylacetamide (9a)
Compound 9a was synthesized from 8 by a similar procedure to that described
for 5a as a white solid (464 mg, 68%), m.p. 105°C ∼ 106°C. 1H NMR (400 MHz,

10
YI-NING WEN ET AL.
DMSO-d6) δ 8.65 (s, 1 H), 8.47 (s, 1 H), 8.28 (d, J= 4.6 Hz, 1 H), 7.31 – 7.22 (m,
15 H), 5.59 (s, 2 H), 5.31 (s, 2 H), 4.08 (s, 2 H), 2.54 (d, J= 4.5 Hz, 3 H). 13C NMR
(101 MHz, DMSO-d6) δ 166.05, 152.04, 151.96, 149.52, 147.16, 143.72, 143.29,
131.44, 131.09, 128.59, 128.33, 127.54, 87.14, 57.41, 50.90, 35.75, 26.02. HRMS cal-
culated for [C31H28ClN8O2+H]+ : 579.2024, Found: 579.2023.
2-(5-((2-Amino-6-chloro-9H-purin-9-yl)methyl)-4-((trityloxy)methyl)-1H-1,2,3-
triazol-1-yl)-N-methylacetamide (9b)
Compound 9b was synthesized from 8 by a similar procedure to that described
1
for 5a as a white solid (456 mg, 65%), m.p.112°C ∼ 114°C. H NMR (400 MHz,
DMSO-d6) δ 8.29 (d, J= 4.6 Hz, 1 H), 7.79 (s, 1 H), 7.33 – 7.24 (m, 15 H), 6.86 (s,
2 H), 5.34 (s, 2 H), 5.31 (s, 2 H), 4.01 (s, 2 H), 2.62 (d, J= 4.5 Hz, 3 H). 13C NMR
(101 MHz, DMSO-d6) δ 166.21, 160.16, 154.22, 149.94, 143.76, 142.99, 142.52,
131.75, 128.63, 128.33, 127.51, 123.54, 87.14, 57.27, 51.03, 35.19, 26.11. HRMS cal-
culated for [C31H29ClN9O2+H]+ : 594.2133, Found: 594.2136.
2-(5-((6-Chloro-9H-purin-9-yl)methyl)-4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)-
N-methyl
acetamide (10a)
Compound 10a was synthesized from 9a by a similar procedure to that described
1
for 6a as a white solid (129 mg, 70%), m.p.168°C ∼ 169°C. H NMR (400 MHz,
DMSO-d6) δ 8.76 (s, 1 H), δ 8.63 (s, 1 H), 8.14 (d, J= 4.4 Hz, 1 H), 5.72 (s,
2 H), 5.30 (t, J=5.2 Hz, 1 H), 5.24 (s, 2 H), 4.64 (d, J= 5.2 Hz, 2 H), 2.42 (d, J =
4.4 Hz, 3 H). 13C NMR (400 MHz, DMSO-d6) δ 165.92, 152.26, 151.96, 149.35,
147.63, 146.93, 131.07, 130.60, 55.04, 50.77, 35.33, 25.90. HRMS calculated for
[C12H13ClN8O2+H]+: 337.0923, Found: 337.0922.
2-(5-((2-Amino-6-chloro-9H-purin-9-yl)methyl)-4-(hydroxymethyl)-1H-1,2,3-
triazol-1-yl)-N-methylacetamide (10b)
Compound 10b was synthesized from9b by a similar procedure to that described for
6a as a white solid (148 mg, 65%), m.p.175°C ∼ 177°C. 1H NMR (400 MHz, DMSO-
d6) δ 8.12 (d, J = 4.3 Hz, 1 H), 8.02 (s, 1 H), 6.87 (s, 2 H), 5.35 (s, 2 H), 5.25 (s, 2 H),
5.21 (t, J= 5.4 Hz, 1 H), 4.54 (d, J= 5.2 Hz, 2 H), 2.49 (d, J= 4.4 Hz, 3 H).13C NMR
(100 MHz, DMSO-d6) δ 165.71, 159.67, 153.78, 149.36, 146.24, 142.79, 130.42,
123.03, 54.61, 50.49, 34.27, 25.62. HRMS calculated for [C12H14ClN9O2+H]+
:
352.1037, Found: 352.1033.
2-(5-((2-Amino-6-oxo-9H-purin-9(6H)-yl)methyl)-4-(hydroxymethyl)-1H-1,2,3-
triazol-1-yl)-N-methylacetamide (10c)
Compound 10c was synthesized from 10b by a similar procedure to that described
1
for 6c as a white solid (68 mg, 42%), m.p. 159°C ∼ 161°C. H NMR (400 MHz,

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
11
DMSO-d6) δ 10.78 (s, 1 H), 8.24 (s, 1 H), 7.84 (s, 1 H), 6.56 (s, 2 H), 5.64 – 4.96
(m, 5 H), 4.59 (s, 2 H), 2.61 (s, 3 H). 13C-NMR (100 MHz, DMSO-d6) δ 165.78,
156.42, 153.78, 146.05, 130.67, 115.17, 54.55, 50.46, 34.14, 25.68. HRMS calculated
for [C12H15N9O3+H]+: 334.1371, Found: 334.1373.
Ethyl 2-(5-((2-amino-6-(cyclopropylamino)-9H-purin-9-yl)methyl)-4-((trityloxy)
methyl)-1H-1,2,3-triazol-1-yl)acetate (11)
To a solution of 5b (1.15 g, 1.89 mmol) in DMF (5 mL) was added cyclopropylamine
(654 µL) and K2CO3 (312 mg, 2.23 mmol) at 0°C. The mixture was stirred at 0°C for
7 h and subsequently quenched with saturated aqueous NaHCO3. The mixture was
extracted with CH2Cl2 (50 mL). The organic layer was dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was purified by silica gel col-
umn chromatography using the CH3OH – CH2Cl2 (5:95, v/v) as eluent to afford
compound 11 (816 mg, yield 69%) as a white solid, m.p.123°C ∼ 125°C. 1H NMR
(400 MHz, DMSO-d6) δ 7.44 – 7.22 (m, 16 H), 5.78 (s, 2 H), 5.62 (s, 2 H), 5.19 (s,
2 H), 4.16 (s, 2 H), 3.99 (q, J= 7.1 Hz, 2 H), 3.19 – 3.17 (m, 1 H), 3.01 (s, 1 H), 1.13
(t, J = 7.1 Hz, 3 H), 0.68 – 0.62 (m, 2 H), 0.61 – 0.54 (m, 2 H). 13C NMR (101 MHz,
DMSO-d6) δ 167.29, 160.61, 156.33, 143.86, 143.08, 136.34, 132.35, 128.76, 128.44,
127.60, 113.43, 87.23, 62.07, 57.20, 49.94, 33.87, 24.17, 14.15, 6.80. HRMS calculated
for [C35H36N9O3+H]+ : 630.2941, Found:. 630.2944.
2-(5-((2-Amino-6-(cyclopropylamino)-9H-purin-9-yl)methyl)-4-((trityloxy)
methyl)-1H-1,2,3-triazol-1-yl)-N-cyclopropylacetamide (12)
A solution of 5b (383 mg, 0.63 mmol) and cyclopropylamine (3 mL) was heated at
60°C overnight in a seal tube. The residue was concentrated under reduced pressure
and purified by silica gel column chromatography using the CH3OH – CH2Cl2 (5:95,
v/v) as eluent to afford compound 12 (290 mg, 72%) as a white solid, m.p.167°C ∼
169°C.1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J= 3.9 Hz, 1 H), 7.42 – 7.21 (m,
16 H), 5.84 (s, 2 H), 5.42 (s, 2 H), 5.18 (s, 2 H), 4.06 (s, 2 H), 3.19 – 3.17 (m, 1 H), 3.01
(s, 1 H), 2.68 – 2.61 (m, 1 H), 0.68 – 0.62 (m, 4 H), 0.60 – 0.54 (m, 2 H), 0.49 – 0.44
(m, 2 H). 13C NMR (100 MHz, DMSO-d6) δ 166.96, 160.60, 156.35, 143.84, 142.80,
136.41, 132.47, 128.73, 128.41, 127.56, 113.46, 87.17, 57.21, 51.06, 34.33, 22.84, 6.83,
6.09; HRMS calculated for [C36H37N10O2+H]+ : 641.3101, Found:.641.3108.
Ethyl 2-(5-((2-amino-6-(cyclopropylamino)-9H-purin-9-yl)methyl)-4-(hydroxy
methyl)-1H-1,2,3-triazol-1-yl)acetate (13)
Compound 13 was synthesized from 11 by a similar procedure to that described for
6a as a white solid (67 mg, 35%), m.p.165°C ∼ 167°C. 1H NMR (400 MHz, DMSO-
d6) δ 7.98 (s, 1 H), 7.39 (s, 2 H), 5.55 (s, 2 H), 5.44 (s, 2 H), 4.67 (s, 2 H), 3.95 (q,
J= 7.1 Hz, 2 H), 2.88 (m, 1 H), 1.12 (t, J= 7.1 Hz, 3 H), 0.91 – 0.80 (m, 2 H), 0.77
– 0.67 (m, 2 H). 13C NMR (100 MHz, DMSO-d6) δ 166.82, 158.10, 157.79, 146.26,

12
YI-NING WEN ET AL.
130.98, 118.74, 115.76, 112.78, 61.55, 54.54, 49.25, 33.26, 21.13, 13.69, 6.48. HRMS
calculated for [C16H21N9O3+H]+ : 388.1846, Found: 337.1848.
2-(5-((2-Amino-6-(cyclopropylamino)-9H-purin-9-yl)methyl)-4-(hydroxymethyl)-
1H-1,2,3-triazol-1-yl)-N-cyclopropylacetamide (14)
Compound 14 was synthesized from 12 by a similar procedure to that described
1
for 6a as a white solid (105 mg, 65%), m.p.178°C ∼ 180°C. H NMR (400 MHz,
DMSO-d6) δ 8.43 (d, J =4.0 Hz, 1 H), 7.73 (s, 1 H), 7.37 (s, 2 H), 5.40 (s, 2 H), 5.31
(s, 2 H), 4.61 (d, J =5.3 Hz, 2 H), 3.01 (s, 1 H), 2.60–2.66 (m, 1 H), 0.66 – 0.63 (m,
4 H), 0.58 – 0.57 (m, 2 H), 0.48 – 0.44 (m, 2 H).13C NMR (100 MHz, DMSO-d6)
δ 166.50, 160.09, 155.94, 145.88, 136.81, 131.15, 112.94, 54.60, 50.43, 33.58, 22.34,
6.38, 5.62. HRMS calculated for [C17H22N10O2+H]+: 399.2000, Found: 399.2000.
2-(5-((2-Amino-6-(cyclopropylamino)-9H-purin-9-yl)methyl)-4-(hydroxymethyl)-
1H-1,2,3-triazol-1-yl)acetamide (15)
Compound 15 was synthesized from 13 by a similar procedure to that described for
7d as a white solid (66 mg, 60%), m.p. 202°C ∼ 204°C. 1H NMR (400 MHz, DMSO-
d6) δ 8.46 (s, 1 H), 7.74 (s, 1 H), 7.40 (s, 1 H), 5.95 (s, 2 H), 5.48 (s, 2 H), 5.31 (s, 2 H),
4.62 (s, 2 H), 2.99 (s, 1 H), 2.63 (m, 1 H), 0.65 – 0.61 (m, 2 H), 0.57 – 0.46 (m, 2 H).
13C NMR (100 MHz, DMSO-d6) δ 166.56, 160.13, 155.96, 145.91, 136.82, 131.21,
112.95, 54.62, 50.46, 33.59, 22.38, 6.41. HRMS calculated for [C14H18N10O2+H]+:
359.1690, Found: 359.1687.
Acknowledgments
Financial support of this work by the National Natural Science Foundation of China (Grant No.
21172019) is appreciated.
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