Syntheses of 1,2,3-triazole-bridged pyranose sugars with purine and pyrimidine nucleobases and evaluation of their anticancer potential

Article abstract of DOI:10.1080/15257770.2017.1346258

With the aim to create a library of compounds with potential bioactivities by combining special characteristics of two important groups such as nucleobases and carbohydrates, twenty 1,4-disubstituted-triazole nucleosides were synthesized in good yields (80-94%) using the copper catalyzed ‘Click’ reaction between azido-modified pento- or hexopyranoses and alkyne-bearing pyrimidine or purine nucleobases. Structural elucidation was made with the assistance of spectroscopic techniques such as FTIR, 1D-, 2D-NMR, and ESI-TOFMS. All the synthesized triazole nucleosides were evaluated for their cytotoxic activity against three human cancer cell lines (MDA-MB-231, Hep3B, PC-3) by using the MTT assay. Particularly, compounds 3a and 1b were identified as potential hits against Hep3B cell.

Full text of DOI:10.1080/15257770.2017.1346258

Nucleosides, Nucleotides and Nucleic Acids
ISSN: 1525-7770 (Print) 1532-2335 (Online) Journal homepage: http://www.tandfonline.com/loi/lncn20
Syntheses of 1,2,3-triazole-bridged pyranose
sugars with purine and pyrimidine nucleobases
and evaluation of their anticancer potential
Erkan Halay, Emriye Ay, Emine Şalva, Kadir Ay & Tamer Karayıldırım
To cite this article: Erkan Halay, Emriye Ay, Emine Şalva, Kadir Ay & Tamer Karayıldırım (2017)
Syntheses of 1,2,3-triazole-bridged pyranose sugars with purine and pyrimidine nucleobases and
evaluation of their anticancer potential, Nucleosides, Nucleotides and Nucleic Acids, 36:9, 598-619
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Date: 31 October 2017, At: 14:28

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
, VOL. , NO. , –
https://doi.org/./..
Syntheses of ,,-triazole-bridged pyranose sugars with
purine and pyrimidine nucleobases and evaluation of their
anticancer potential
e
Erkan Halaya, Emriye Ayb, Emine S¸alvac, Kadir Ay d, and Tamer Karayıldırım
aScientific Analysis Technological Application and Research Center, Us¸ak University, Us¸ak, Turkey;
bDepartment of Food Technology, S¸ebinkarahisar School of Applied Sciences, Giresun University, Giresun,
c
˙
Turkey; Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Inönü University, Malatya,
Turkey; dDepartment of Chemistry, Faculty of Arts and Sciences, Manisa Celal Bayar University, Manisa,
e
˙
Turkey; Department of Chemistry, Faculty of Science, Ege University, Izmir, Turkey
ABSTRACT
ARTICLE HISTORY
Received  March 
Accepted  June 
With the aim to create a library of compounds with potential
bioactivities by combining special characteristics of two impor-
tant groups such as nucleobases and carbohydrates, twenty
1,4-disubstituted-triazole nucleosides were synthesized in good
yields (80-94%) using the copper catalyzed ‘Click’ reaction
between azido-modified pento- or hexopyranoses and alkyne-
bearing pyrimidine or purine nucleobases. Structural elucidation
was made with the assistance of spectroscopic techniques such
as FTIR, 1D-, 2D-NMR, and ESI-TOFMS. All the synthesized triazole
nucleosides were evaluated for their cytotoxic activity against
three human cancer cell lines (MDA-MB-231, Hep3B, PC-3) by using
the MTT assay. Particularly, compounds 3a and 1b were identified
as potential hits against Hep3B cell.
KEYWORDS
Click chemistry;
,,-Triazoles; azido sugars;
nucleobases; nucleosides;
anticancer activity
Introduction
Click chemistry was developed to be a basic tool in organic and/or bioorganic
chemistry for the preparation of different macromolecules.[1] To reach this aim,
many techniques have been developed including reaction types and methods with
various catalysts and solvent systems.[1,2] The results obtained by any of these meth-
ods are generally excellent and they can be improved with a simple fine-tuning.
Among these methods; CuAAC (Cu(I)-catalyzed azide-alkyne cycloaddition),
the modified form of Huisgen reaction and on the contrary, copper-free type
SPAAC (strain-promoted azide-alkyne cycloaddition) reactions have been the most
common approaches which have been applied for the coupling of azido-modified
CONTACT Kadir Ay
kadir.ay@cbu.edu.tr
Bayar University,  Manisa, Turkey.
Chemistry Department, Faculty of Science and Letters, Manisa Celal
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lncn.
Dedication
We dedicated this work to Prof. Dr. Levent YÜCEER on account of his th birthday and his endless help during
the doctorate research of Kadir AY.
Supplemental data for this article can be accessed on the publisher’s website.
©  Taylor & Francis Group, LLC

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
599
sugars and alkyne containing molecules to produce 1,2,3-triazole derivatives with
improved properties for drug discovery, bioconjugation, fluorescent probing,
proteomic profiling and cellular target identification.[3–6]
Both carbohydrates and nucleobases have an important role in diverse funda-
mental biological processes and have hence been in the centre of attention for
chemists and biologists. According to chemists, azide derivatives of carbohydrates
are an important group of compounds that serves as building blocks for complex
synthetic operations. The anomeric position is usually preferred for linking azide
functionality, though the rest of the sugar ring positions (especially C-3 and free
methylene carbon) have also been used for this aim.[7–9]
Nucleobases are nitrogen-containing heterocyclic compounds with single ring
(pyrimidine) or fused bicyclic (purine) structures serving as basic units of
nucleotides which form DNA and RNA. Nucleobases have at least as much impor-
tance as the carbohydrates, that making modified nucleosides desirable targets.[10]
Of course the compounds within this scope have also been tested for their various
biological activities.[11] As an example, in a similar to ours, a series of novel nucle-
oside compounds were synthesized via the CuAAC reaction of azido sugars with
propynylated pyrimidines, and resulting triazole compounds were evaluated for the
inhibition of α-glucosidase.[12]
From this point, 1,2,3-triazole nucleosides and their attractive analogues with
assorted biological activities such as anticancer,[13–16] antifungal,[17–19] antibacte-
rial,[20–22] antiviral,[23–28] antitubercular,[29–31] antiproliferative,[32–34] are poten-
tially pharmaceutically important molecules.[35] Among the drugs based on 1,2,3-
triazoles, carboxyamidotriazole and cefatrizine with anticancer activity, tazobactam
(β-lactamase inhibitory), tert-butyldimethylsilylspiroamino oxathioledioxide with
anti-HIV activity are currently in clinical trials and have potential to be used as a
pharmacophore in the coming years.[36,37]
The facts mentioned above prompted us to continue our exploration of triazole
analogues for better understanding the relationship between structural changes and
the activities. As an application of the most powerful click reaction to date, CuAAC
was used for designing series of nucleosides containing a 1,2,3-triazole ring. All syn-
thesized compounds were evaluated for their anticancer potential.
Results and discussion
Chemistry
1,4-Disubstituted-1,2,3-triazole bridged nucleosides (1a-5a, 1b-5b, 1c-5c, 1d-5d)
were synthesized in good yield (80-94%) via the CuAAC reaction in the presence
of CuSO4/Na ascorbate from monopropynylated uracil, thymine, 5-fluorouracil
(5-FU), adenine (a-d) nucleobases with azidosugars obtained according to the
literature[38–43], which have a pyranose ring with D-galacto-,[38,39] D-fructo-,[40,41]
D-gluco-,[42] D-xylo,[39,43] configurations (Figure 1). Propargyl derived nucleobases
(a-d) were obtained in moderate yields due to the formation of dipropargylated

600
E. HALAY ET AL.
Figure . Synthesis of ,,-triazole-bridged purine and pyrimidine nucleosides.
by-products and spectral data for their structural elucidation are consistent with the
literature.[44] The coupling patterns for the alkynyl group for a-d were observed as a
triplet for ࣕCH at δ 3.35–3.40 ppm (J = 1.2–2.4 Hz) whereas they were observed as
1
a doublet for CH2Cࣕ, at δ 4.43–5.01 ppm in H NMR spectra. 13C NMR spectra
–
were also confirmed the structure of monoalkynated nucleobases with the evidence
–
–
of signals at about δ 79.0 ( CH2Cࣕ), 76.0 (ࣕCH) and 33.0 ( CH2Cࣕ) ppm, which
are in agreement with literature.[44]
The occurrence of the click reaction was proved by the disappearance of termi-
nal alkyne proton signals (δ 3.35–3.40 ppm) and the presence of triazole olefinic
1
-CH- peaks at δ 7.85–8.39 ppm in H NMR spectra. The appearance of a sharp
singlet for H-5ꢀat about δ 7.85–8.39 ppm was also confirmed the completion of
click reaction for all nucleoside products (1a-5a, 1b-5b, 1c-5c, 1d-5d). (see Sup-
plementary material, Table S1, S3, S5, S8). The diastereotopic geminal methylene
–
protons (N CH2-) between triazole ring and nucleobases appear as AB quartet,
JAB = 15.2 Hz, at about δ 4.84–5.08 ppm for all products except ade-
nine derivatives. For the adenine derivatives (1d-5d) that methylene pro-
tons were established as a singlet at about δ 5.42–5.44 ppm (see Supplemen-
tary material, Table S8). The signal of those methylene carbons resonated
at δ 38.2–43.0 ppm in 13C NMR spectra. Furthermore, 13C NMR spectra
exhibit characteristic signals for C-4ꢀand C-5ꢀof the triazole ring at δ 141.6–
143.7 and 122.8–126.6 ppm, respectively (see Supplementary material, Table S2,
S4, S6, S9). The large difference of chemical shifts between C4ꢀ and C5ꢀ
(about δ 20 ppm) indicated the formation of 1,4-regioisomers.
With regard to 5-FU derivatives (1c-5c), the signals at between δ −169.0–−169.3
ppm corresponding to fluorine atom were determined in the 19F NMR. More-
over, adjacent F-H (JH6,F = ∼6.8–7.2 H z) and F-C (JC4,F = ∼33.0, JC5,F = ∼229.0,
1
13
–
–
JC6,F = ∼26.0 H z) coupling interactions were observed in H and C NMR spec-
tra respectively (see Supplementary material, Table S5, S6, S7).

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
601
Figure . Significant HMBC Correlations of Some Uracil, Thymine and Adenine Nucleosides.
HSQC and HMBC NMR techniques were also used for the detailed structural
assignments of all 5-FU derivatives (1c-5c) (see Supplementary material).
For all synthesized nucleosides, there are two different methylene groups one of
which is in nucleobase-triazole bridges and the others is in the sugar moieties, and
determination of those related methylene carbons and protons was made with the
assistance of HSQC correlations. In this regard, the diastereotopic geminal methy-
lene protons (δ = 4.84–5.08 ppm) were correlated with methylene carbon (δ =
H
C
38.2–43.2 ppm) and these correlations confirmed identification of methylenes. Sim-
ilarly, the location of all carbon and hydrogen atoms for remaining nucleosides were
verified on the basis of the 1H/13C correlations in HSQC spectra.
Significant HMBC correlations of uracil (3a), thymine (1b), adenine (2d) and
5-FU (1c-5c) nucleosides are given in Figure 2 and 3. C-5ꢀ of the triazole ring shows
long-range couplings (3JC,H) with the H1ꢀꢀ or H6ꢀꢀ protons as well as with the bridge
methylene group. Concordantly, C-4ꢀ did not show any correlations with H1ꢀꢀ/H6ꢀꢀ
while this olefinic carbon had long-range correlation with bridged methylene pro-
tons both confirming the formation of the 4-substituted-1,2,3-triazole part. Those
long-range HMBC correlations that gived 2J and 3JCH coupling constants allowed
–
the assignment of the bridged N CH2- protons correlated with both nucleobase ring
carbons and triazole-C-4ꢀ.
1
13
–
–
In addition to all these, the characteristic H and C NMR peaks of sugar
skeleton were also observed as expected. The 1H-NMR spectra of target nucleosides
exhibited doublets with coupling constants between vicinal H-1ꢀꢀ and H-2ꢀꢀ protons.

602
E. HALAY ET AL.
Figure . Significant HMBC Correlations of -Fluorouracil Nucleosides.
These corresponding large couplings (J = over 6.0 Hz) in the sugar moiety for
compounds 3a-d, 4a-d and 5a-d referred to 1,2-trans relationship and β-anomeric
configuration.
Finally, the predicted structures of all triazole nucleosides given in Figure 1 were
confirmed by molecular ion peaks such as [M + H]+ or [M + Na]+ observed in
positive ion mode TOF-MS (ESI) spectra (see Supplementary material).
Biological activity
The synthesized twenty compounds (1a-5a, 1b-5b, 1c-5c, 1d-5d) as well as alky-
nated nucleobase intermediates (a-d) were screened for their in vitro cytotoxic

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
603
activities against human breast (MDA-MB-231), human hepatoma (Hep3B) and
human prostate (PC-3) cancer cell lines by employing the 3-[4,5-dimethylthiazol-
2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay at 200, 100, 50, 25, and
10 µM concentrations. The concentrations that cause 50% inhibition of cancer cell
growth are expressed as IC50 values and these resulting values of compounds are
summarized in Table 1.
Firstly, because of the importance of selective killing of cancer cells, all com-
pounds were also tested for their possible cytotoxicities towards the L929 control
cell line. The growth of cell lines was not affected by any of the compounds and this
means that none of the compounds exhibited a cytotoxic effect.
From the IC50 results shown in Table 1, we concluded the following;
(1) Based on the detailed IC50 analysis, among nucleobase alkynes, propargyl
substitute 5-FU (c) was the most potent, especially with potential hits against
Hep3B and PC-3 cells. On the other hand, adenine alkyne displayed much
more cytotoxic potency against MDA-MB-231 cells than other alkynated
nucleobases.
(2) Compounds 3a, 1b, 2b, 5b, 5c, 3d, and 5d possessed the strongest inhibitory
activity among all the investigated cancer cells with IC50 value range of 59.3-
82.6 µM. Specifically, compound 3a exhibited more potent inhibitory activity
(59.3 µM) against Hep3B, compound 1c exhibited more potency (112.6 µM)
against MDA-MB-231 cells and compound 1a along with 4d were more
active (106.6 and 107.0 µM, respectively) than other pyranonucleosides.
(3) In the light of the results, Hep3B was defined as the most liable to be influ-
enced by the synthesized pyranonucleosides. The highest activity in this all
Table . IC Values of synthesized compounds (µM).
MDA-MB-
HEPB
PC-
L
a
>
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
>
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
a
a
a
a
a
b
b
b
b
b
b
c
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
>
.
.
>
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
>
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
c
c
c
c
c
d
d
d
d
d
d
.
>
.
.
.
.
.
.
Data presented the mean standard deviation (S.D.) of each compound from three independent experiments.
ND: not detected.

604
E. HALAY ET AL.
line was displayed by the uracil derived, acetyl substituted pyranonucleoside
3a (59.3 µM), with a threefold greater potency than the intermediate uracil
alkyne compound a (177.9 µM). Moreover, compounds 1b, 2b, 5b, 5c, 3d,
and 5d exhibited more potent cytotoxic effects (65.4–82.6 µM) than other
compounds. Contrary to this, higher concentrations of the candidate com-
pounds were essential for the inhibition of other two cancer cells, MDA-MB-
231 and PC-3.
Based on these findings, although integration of sugar and nucleobase scaffolds to
form 1,2,3-triazole skeleton have demonstrated their usefulness by playing specific
roles in the exhibition of cytotoxicity, no considerable potency has been detected
in MDA-MB-231 and PC-3 cells (IC50 ranging from 103.4 to ˃ 200 µM). But, it is
worth noting that the cytotoxicity data obtained from this study indicate that dif-
ferent carbohydrate and/or nucleobase scaffolds, position of linkage and so steric
hindrance markedly influence the activity potential of compounds. In this context,
we recognize that anomeric glycosidic linkage to the triazole ring is important for
keeping the cytotoxic efficacy of compounds and as mentioned above, compound 3a
is the most potent molecule with IC50 value of 59.3 µM. Besides, galactose derived
nucleosides with the glycosidic linkage to the C-6ꢀꢀ position displayed less activity
(65.4 ˃ IC50 > 200) than anomeric glycoside derived nucleosides while fructose
derived nucleosides linking to the triazole at C-2ꢀꢀ position were defined to be the
least potent (77.1 ˃ IC50 > 200) among all synthesized pyranonucleosides.
Conclusion
In conclusion, we have presented fourteen new triazole-bridged purine and pyrim-
idine nucleosides (2a, 5a, 2b, 5b, 1c-5c, 1d-5d) were synthesized along with six
known compounds (1a, 3a, 4a, 1b, 3b, 4b) via the highly efficient CuAAC reaction
of pyrano-sugar azides and terminal alkynated nucleobases. The structures of all
these products were confirmed by FTIR, 1H, 13C, 19F, HSQC, HMBC spectroscopy
and MS data. All 1,4-disubstituted triazole compounds were tested for their biolog-
ical efficacy against human cancer cell lines (MDA-MB-231, Hep3B and PC-3). It
was determined that nucleoside 3a had the best potency against Hep3B cells with
IC50 value of 59.3 µM and Hep3B was the most convenient cell line. Based on these
in vitro assays, it has been aimed to start creating a nucleoside library to see activity-
structure relationship and provide other scientists an opportunity for accession to
these structures throwing light on the future works.
Experimental
General methods
Melting points were determined using a Gallenkamp Electrothermal melting point
apparatus and are uncorrected. IR spectroscopy was performed on a Perkin Elmer
Spectrum 100 FTIR spectrophotometer equipped with ATR apparatus. Optical
rotations were measured on a Rudolph Research Analytical Autopol II automatic

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
605
polarimeter. All 1D- and 2D-NMR spectra (1H, 13C, 19F, HSQC and HMBC) were
recorded on a Varian AS 400 MHz spectrometer in CDCl3 or DMSO-d6 using
TMS as internal standard. High resolution mass spectra (HRMS) analyses were per-
formed on an Agilent 6230 TOF-MS equipped with Jet Stream ESI source operated
in positive ion mode. All reactions were monitored by thin layer chromatography
using precoated silica gel G-60 F254 (Merck 5554) aluminum plates with detection
under UV light (254 and 366 nm) and sprayed with 20% H2SO4 solution in water
followed by heating at 120°C or basic aqueously KMnO4 solution. While 70 × 230
mesh silica gel (Merck 7734) was used for open column chromatographic studies,
flash chromatography was performed using 230 × 400 mesh silica gel (Merck 9385)
with the indicated solvent mixture. All starting materials, solvents and other chem-
icals were purchased from Merck, Fluka, Carlo Erba, Alfa Aesar or Sigma-Aldrich
and were used without purification.
Synthesis
General procedure for the syntheses of propargylated nucleobases
To a stirred suspension of nucleobase (uracil, thymine, 5-fluorouracil and adenine,
1.0 eq.) in anhydrous DMF, K2CO3 (1.0 eq.) was added and stirred for 30 min. Then
propargyl bromide (1.1 eq.) was added to this mixture and allowed to stir at 50°C
for 8–12 hours with the assistance of TLC (CH2Cl2:MeOH, 9:0.4) control. After the
removal of the solvent by evaporating under reduced pressure, the residue was puri-
fied by silica gel column chromatography and afforded the pure monopropynylated
products (a-d).[44]
N--Propargyl uracil (a)
Following the general procedure with uracil (5.0 g, 44.6 mmol) and propargyl bro-
mide (5.5 mL, 61.7 mmol) in DMF, the residue was then subjected to column chro-
matography using CH2Cl2:MeOH (100:0→100:1.5) solvent system and white solid
−1
–
(a) was obtained. Yield: 50%; mp 168–169°C; FTIR (ATR, cm ): 3243 ( NH),
=
–
=
3114 (C CH), 2923 and 2851 ( CH), 2120 (CࣕC), 1715 and 1688 (C O), 1620
1
=
(C C); H NMR (400 MHz, DMSO-d6): δ 11.31 (s, 1H, NH), 7.66 (d, 1H, J5,6
=
–
–
8.0 Hz, H-6), 5.60 (d, 1H, H-5), 4.49 (d, 2H, JCH2,CࣕCH = 2.4 Hz, CH2 CࣕCH),
3.35 (t, 1H, CH2 CࣕCH); 13C NMR (100 MHz, DMSO-d6): δ164.2 (C-4), 151.0
–
–
–
–
–
–
(C-2), 145.1 (C-6), 102.3 (C-5), 79.0 ( CH2 CࣕCH), 76.4 ( CH2 CࣕCH), 37.3
–
–
( CH2 CࣕCH).
N--Propargyl thymine (b)
Following the general procedure with thymine (5.0 g, 39.6 mmol) and propargyl bro-
mide (4.8 mL, 53.8 mmol) in DMF, the residue was then subjected to column chro-
matography using CH2Cl2:MeOH (100:0→100:2) solvent system and white solid
−1
–
(b) was obtained. Yield: 65%; mp 158–160°C; FTIR (ATR, cm ): 3254 ( NH), 3160
1
=
–
=
(C CH), 2932, 2893, 2833 ( CH), 2124 (CࣕC), 1704 and 1680 (C O); H NMR

606
E. HALAY ET AL.
(400 MHz, DMSO-d6): δ 11.30 (s, 1H, NH), 7.52 (t, 1H, J6,CH3 = 1.2 Hz, H-6), 4.45
–
–
–
–
(dd, 2H, JCH2,CࣕCH = 1.2 Hz, CH2 CࣕCH), 3.29 (d, 1H, CH2 CࣕCH), 1.74 (d,
3H, CH3); 13C NMR (100 MHz, DMSO-d6): δ 164.8 (C-4), 151.0 (C-2), 140.7 (C-6),
–
–
–
–
–
–
110.1 (C-5), 79.3 ( CH2 CࣕCH), 76.2 ( CH2 CࣕCH), 36.9 ( CH2 CࣕCH), 12.5
(CH3).
N--Propargyl -fluorouracil (c)
Following the general procedure with 5-fluorouracil (5.0 g, 38.4 mmol) and propar-
gyl bromide (4.7 mL, 52.7 mmol) in DMF, the residue was then subjected to column
chromatography using CH2Cl2:MeOH (100:0→100:1) solvent system and white
−1
–
solid (c) was obtained. Yield: 40%; mp 147–148°C; FTIR (ATR, cm ): 3225 ( NH),
1
=
–
=
=
3030 (C CH), 2825 ( CH), 2132 (CࣕC), 1705 (C O), 1651 (C C); H NMR
(400 MHz, DMSO-d6): δ 11.86 (bs, 1H, NH), 8.08 (d, 1H, J = 6.4 Hz, H-6), 4.43
13
–
–
–
–
(d, 2H, JCH2,CࣕCH = 2.0 Hz, CH2 CࣕCH), 3.36 (t, 1H, CH2 CࣕCH); C NMR
(100 MHz, DMSO-d6): δ 158.1, 157.9 (C-4), 149.7 (C-2), 141.6, 139.3 (C-5), 129.6,
–
–
–
–
–
–
129.4 (C-6), 78.7 ( CH2 CࣕCH), 76.7 ( CH2 CࣕCH), 37.6 ( CH2 CࣕCH).
N--Propargyl adenine (d)
Following the general procedure with adenine (5.0 g, 37.0 mmol) and propargyl
bromide (4.5 mL, 50.5 mmol) in DMF, the residue was then subjected to column
chromatography using CH2Cl2:MeOH (100:0→100:3.5) solvent system and white
solid (d) was obtained. Yield: 69%; mp 214-215°C; FTIR (ATR, cm−1): 3372 and
1
–
=
–
=
3245 ( NH2), 3139 (C CH), 2910 and 2863 ( CH), 2110 (CࣕC), 1686 (C N); H
NMR (400 MHz, DMSO-d6): δ 8.17 (d, 1H, J2,8 = 0.8 Hz, H-2), 8.15 (d, 1H, H-8),
–
–
7.24 (bs, 2H, NH2), 5.01 (d, 2H, JCH2,CࣕCH = 2.0 Hz, CH2 CࣕCH), 3.40 (t, 1H,
13
–
–
CH2 CࣕCH); C NMR (100 MHz, DMSO-d6): δ 156.6 (C-6), 153.4 (C-2), 149.7
–
–
–
–
(C-4), 140.8 (C-8), 119.1 (C-5), 78.9 ( CH2 CࣕCH), 76.4 ( CH2 CࣕCH), 32.9
–
–
( CH2 CࣕCH).
General procedure for the CuAAC reactions
To a well stirred solution of azido-sugar (1-5) (1.1 eq) and propargylated nucleobase
(a-d) (1.0 eq) in THF:t-BuOH:H2O (3:1:1) solvent system, CuSO4.5H2O (0.11 eq)
and sodium ascorbate (0.55 eq) was added.[45] The mixture was then allowed to stir
at 50°C for 3-6 hours along with TLC monitoring. After completion, the reaction
mixture was diluted with water and extracted with CHCl3 (3 × 30 mL). The com-
bined organic fractions were dried over anhydrous Na2SO4 and solvent evaporated
under reduced pressure to afford crude residue. After all, the residue was subjected
to silica gel flash column chromatography using CH2Cl2:MeOH system and afforded
the pure products (1a-5a, 1b-5b, 1c-5c, 1d-5d).
-[{ꢀ-(ꢀꢀ-Deoxy-ꢀꢀ,ꢀꢀ:ꢀꢀ,ꢀꢀ-di-O-isopropylidene-α-D-galactopyranos-ꢀꢀ-yl)-ꢀH-
ꢀ,ꢀ,ꢀ-triazol-ꢀ-yl}methyl]uracil (1a)
According to the general CuAAC procedure, compound 1a[12] (678 mg, 82%) was
obtained from the reaction of azido sugar 1 (600 mg, 2.1 mmol) with propargyl

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
607
uracil a (287 mg, 1.9 mmol) and purified via flash chromatography (CH2Cl2:MeOH,
100:0→100:1.5 ν/ν). White foam; lit mp 177–179°C, mp 189–191°C; [α]2D0-32 (c
−1
–
=
0.25, CHCl3); FTIR (ATR, cm ): 3138 ( NH-), 3051 (C CH), 2987, 2937 and 2835
1
–
=
=
–
–
( CH), 1697 (C O), 1620 (C C), 1385 (C N), 1065 (C-O C); H NMR (400 MHz,
CDCl3): δ 9.86 (bs, 1H, NH), 7.87 (s, 1H, H-5ꢀ), 7.51 (d, 1H, J5,6 = 7.6 Hz, H-6), 5.69
ꢀꢀ
ꢀꢀ ꢀꢀ
(d, 1H, H-5), 5.50 (d, 1H, J1 ,2 = 4.8 Hz, H-1 ), 5.07, 4.96 (q, AB-system, 2H, J =
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
15.2 Hz, CH2), 4.65 (dd, 1H, J2 ,3 = 2.8 Hz, J3 ,4 = 8.0 Hz, H-3 ), 4.61 (dd, 1H,
J5 ,6 a = 3.6 Hz, J6 a,6 b = 14.0 Hz, H-6ꢀꢀa), 4.46 (dd, 1H, J5 ,6 b = 8.8 Hz H-6ꢀꢀb),
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
4.33 (dd, 1H, H-2ꢀꢀ), 4.21 (dd, 1H, J4 ,5 = 8.0 Hz H-4 ), 4.19-4.17 (m, 1H, H-5 ),
1.48, 1.37, 1.36 and 1.28 (s, 12H, 4 × CH3); 13C NMR (100 MHz, CDCl3): δ 164.1
(C-4), 151.1 (C-2), 144.4 (C-6), 141.6 (C-4ꢀ), 125.1 (C-5ꢀ), 110.1 and 109.2 (2 ×
(CH3)2C), 102.7 (C-5), 96.3 (C-1ꢀꢀ), 71.3 (C-4ꢀꢀ), 70.9 (C-3ꢀꢀ), 70.4 (C-2ꢀꢀ), 67.3 (C-
ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
–
5 ), 50.8 (C-6 ), 43.1 (CH2 N), 26.1, 26.0, 25.0 and 24.6 (4 × CH3); TOF-ESIMS
calcd for C19H26N5O7 [M + H]+: 436.1832; found: 436.1912.
-[{ꢀ-(ꢀꢀꢀ-Deoxy-ꢀꢀ,ꢀꢀ:ꢀꢀ,ꢀꢀ-di-O-isopropylidene-β-D-fructopyranos-ꢀꢀ-yl)-ꢀH-ꢀ,
ꢀ,ꢀ-triazol-ꢀ-yl}methyl]uracil (2a)
According to the general CuAAC procedure, 2a (703 mg, 85%) was obtained from
the reaction of azido sugar 2 (600 mg, 2.1 mmol) with propargyl uracil a (287 mg,
1.9 mmol) and purified via flash chromatography (CH2Cl2:MeOH, 100:0→100:1.5
ν/ν). White foam; mp 150–152°C; [α]2D0-56 (c 0.25, CHCl3); FTIR (ATR, cm−1):
–
=
–
=
–
3208 ( NH), 3060 (C CH), 2990, 2940 ( CH), 1683 (C O), 1382 (C N), 1068
1
ꢀ
– –
(C O C); H NMR (400 MHz, CDCl3): δ 9.73 (bs, 1H, NH), 7.89 (s, 1H, H-5 ),
7.53 (d, 1H, J5,6 = 8.0 Hz, H-6), 5.69 (d, 1H, H-5), 5.06, 4.96 (q, AB-system, 2H, J =
15.2 Hz, CH2), 4.73 (d, 1H, J1 a,1 b = 14.0 Hz, H-1ꢀꢀa), 4.65 (dd, 1H, J4 ,5 = 8.0 Hz,
ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
J3 ,4 = 2.8 Hz, H-4 ), 4.56 (d, 1H, H-1 b), 4.43 (d, 1H, H-3 ), 4.25 (dd, 1H, J5 ,6 a
= 1.2 Hz, H-5ꢀꢀ), 3.91 (dd, 1H, J6 a,6 b = 13.2 Hz, H-6ꢀꢀa), 3.79 (d, 1H, H-6ꢀꢀb), 1.50,
1.45, 1.36 and 0.74 (s, 12H, 4 × CH3); 13C NMR (100 MHz, CDCl3): δ 164.0 (C-4),
151.1 (C-2), 144.4 (C-6), 141.7 (C-4ꢀ), 126.6 (C-5ꢀ), 109.7 and 109.5 (2 × (CH3)2C),
ꢀꢀ
ꢀꢀ
102.8 (C-5), 100.8 (C-2ꢀꢀ), 70.9 (C-3ꢀꢀ), 70.7 (C-5ꢀꢀ), 70.2 (C-4ꢀꢀ), 62.0 (C-6ꢀꢀ), 55.3
ꢀꢀ
–
(C-1 ), 43.0 (CH2 N), 26.5, 26.1, 24.3 and 24.2 (4 × CH3); TOF-ESIMS calcd for
C19H26N5O7 [M + H]+: 436.1832; found: 436.1929.
-[{ꢀ-(ꢀꢀ,ꢀꢀ,ꢀꢀ,ꢀꢀ-Tetra-O-acetyl-β-D-glucopyranosyl)-ꢀH-ꢀ,ꢀ,ꢀ-triazol-ꢀ-yl}
methyl]uracil (3a)
According to the general CuAAC procedure, 3a[12] (659 mg, 90%) was obtained
from the reaction of azido sugar 3 (600 mg, 1.6 mmol) with propargyl uracil
a (219 mg, 1.4 mmol) and purified via flash chromatography (CH2Cl2:MeOH,
100:0→100:1.5 ν/ν). White foam; mp 228–229°C; [α]2D0 + 21 (c 0.25, CHCl3); FTIR
−1
1
=
=
=
–
(ATR, cm ): 3055 (C CH), 1753, 1688 (C O), 1630 (C C), 1371 (C N), 1043
ꢀ
–
(C-O C); H NMR (400 MHz, CDCl3): δ 9.79 (bs, 1H, NH), 8.10 (s, 1H, H-5 ),
7.48 (d, 1H, J5,6 = 8.0 Hz, H-6), 5.91 (m, 1H, H-1ꢀꢀ), 5.73 (d, 1H, H-5), 5.48-
5.42 (m, 1H, H-2ꢀꢀ), 5.45 (dd, 1H, J2 ,3 = 6.6 Hz, J3 ,4 = 2.4 Hz, H-3 ), 5.31 (dd,
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
1H, J4 ,5 = 9.8 Hz, H-4 ), 5.06, 5.00 (q, AB-system, 2H, J = 15.2 Hz, CH2), 4.31

608
E. HALAY ET AL.
(dd, 1H, J5 ,6 a = 4.8 Hz, J6 a,6 b = 12.6 Hz, H-6ꢀꢀa), 4.18 (dd, 1H, J5 ,6 b = 1.6 Hz
H-6ꢀꢀb), 4.05 (ddd, 1H, H-5ꢀꢀ), 2.07, 2.07, 2.01 and 1.82 (s, 12H, 4 × CH3); 13C NMR
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
–
(100 MHz, CDCl3): δ 170.7, 170.1, 169.6, 168.9 (4 × Acetyl C = O), 163.9 (C-4),
151.3 (C-2), 144.ꢀ2ꢀ (C-6), 142.7 (C-4ꢀ), 123.0 (C-5ꢀ), 103.0 (C-5), 86.0 (C-1ꢀꢀ), 75.3
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
–
(C-5 ), 72.6 (C-3 ), 70.7 (C-2 ), 67.9 (C-4 ), 61.8 (C-6 ), 43.2 (CH2 N), 20.8, 20.7,
20.6 and 20.2 (4 × CH3); TOF-ESIMS calcd for C21H26N5O11 [M + H]+: 524.1628;
found: 524.1714.
-[{ꢀ-(ꢀꢀ,ꢀꢀ,ꢀꢀ,ꢀꢀ-Tetra-O-acetyl-β-D-galactopyranosyl)-ꢀH-ꢀ,ꢀ,ꢀ-triazol-ꢀ-yl}
methyl]uracil (4a)
According to the general CuAAC procedure, 4a[12] (674 mg, 92%) was obtained
from the reaction of azido sugar 4 (600 mg, 1.6 mmol) with propargyl uracil
a (219 mg, 1.4 mmol) and purified via flash chromatography (CH2Cl2:MeOH,
100:0→100:1.5 ν/ν). White foam; mp 165–167°C; [α]2D0 + 32 (c 0.25, CHCl3); FTIR
−1
=
–
=
=
(ATR, cm ): 3180 (C CH), 2970 ( CH), 1746 and 1687 (C O), 1630 (C C), 1374
1
–
–
(C N), 1042 (C-O C); H NMR (400 MHz, CDCl3): δ 9.76 (bs, 1H, NH), ꢀ7ꢀ .99 (s,
1H, H-5ꢀ), 7.45 (d, 1H, J5,6 = 8.0 Hz, H-6), 5.83 (d, 1H, J1 ,2 = 9.2 Hz, H-1 ), 5.69
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
(d, 1H, H-5), 5.52 (d, 1H, J3 ,4 = 3.2 Hz, J4 ,5 = 0.0 Hz, H-4 ), 5.46 (dd, 1H, J2 ,3
=
10.0 Hz, H-2ꢀꢀ), 5.25 (dd, 1H, H-3ꢀꢀ), 5.08, 4.90 (q, AB-system, 2H, J = 15.2 Hz, CH2),
4.25–4.16 (m, 2H, H-5ꢀꢀ and H-6ꢀꢀa), 4.11 (dd, 1H, J5 ,6 b =6.4 Hz, J6 a,6 b =11.2 Hz,
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
H-6ꢀꢀb), 2.20, 2.00, 1.97 and 1.82 (s, 12H, 4 × CH3); 13C NMR (100 MHz, CDCl3):
–
δ 170.3, 170.0, 169.8 and 168.9 (4 × Acetyl C = O), 163.8 (C-4), 150.8 (C-2), 144.1
(C-6), 142.4 (C-4ꢀ), 122.5 (C-5ꢀ), 102.6 (C-5), 86.3 (C-1ꢀꢀ), 74.1 (C-5ꢀꢀ), 70.5 (C-3ꢀꢀ),
ꢀꢀ
ꢀꢀ
ꢀꢀ
–
68.1 (C-2 ), 66.7 (C-4 ), 61.2 (C-6 ), 42.7 (CH2 N), 20.6, 20.6, 20.4 and 20.1 (4 ×
CH3); TOF-ESIMS calcd for C21H26N5O11 [M + H]+: 524.1628; found: 524.1609.
-[{ꢀ-(ꢀꢀ,ꢀꢀ,ꢀꢀ-Tri-O-acetyl-β-D-xylopyranosyl)-ꢀH-ꢀ,ꢀ,ꢀ-triazol-ꢀ-yl}methyl]
uracil (5a)
According to the general CuAAC procedure, 5a (666 mg, 82%) was obtained from
the reaction of azido sugar 5 (600 mg, 2 mmol) with propargyl uracil a (271 mg,
1.8 mmol) and purified via flash chromatography (CH2Cl2:MeOH, 100:0→100:1.5
ν/ν). White foam; mp 110–112°C; [α]2D0 + 29 (c 0.25, CHCl3); FTIR (ATR, cm−1):
–
=
–
–
2956, 2937, 2899 and 2867 ( CH), 1596 (C C), 1372 (C N), 1037 (C-O C);
1H NMR (400 MHz, CDCl3): δ 9.66 (bs, 1H, NH), 8.04 (s, 1H, H-5ꢀ), 7.43 (d, 1H,
ꢀꢀ
ꢀꢀ ꢀꢀ
J5,6 = 7.6 Hz, H-6), 5.77 (dd, 1H, J1 ,2 = 8.0 Hz, H-1 ), 5.70 (d, 1H, H-5), 5.43-
5.38 (m, 1H, H-3ꢀꢀ), 5.39 (d, 1H, H-2ꢀꢀ), 5.21–5.16 (m, 1H, H-4ꢀꢀ), 5.05, 4.92 (q, AB-
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
system, 2H, J = 15.2 Hz, CH2), 4.27 (dd, 1H, J4 ,5 a = 6.0 Hz, J5 a,5 b = 11.2 Hz,
H-5ꢀꢀa), 3.58 (dd, 1H, J4 ,5 b = 11.2 Hz, H-5ꢀꢀb), 2.05, 2.02 and 1.82 (s, 9H, 3 ×
ꢀꢀ ꢀꢀ
13
–
CH3); C NMR (100 MHz, CDCl3): δ 169.9, 169.7, 168.8 (3 × Acetyl C = O), 163.6
(C-4), 151.0 (C-2), 144ꢀ.ꢀ0 (C-6), 142.ꢀ4ꢀ (C-4ꢀ), 122.8 (C-5ꢀ), 102.8 (C-5), 86.3 (C-1ꢀꢀ),
ꢀꢀ
ꢀꢀ
–
71.9 (C-3 ), 70.5 (C-2 ), 68.2 (C-4 ), 65.5 (C-5 ), 43.1 (CH2 N), 20.6, 20.5 and
20.1 (3 × CH3); TOF-ESIMS calcd for C18H21N5O9Na[M + Na]+: 474.1237; found:
474.1192.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
609
-[{ꢀ-(ꢀꢀ-Deoxy-ꢀꢀ,ꢀꢀ:ꢀꢀꢀ,ꢀꢀ-di-O-isopropylidene-α-D-galactopyranos-ꢀꢀ-yl)-ꢀH-ꢀ,
ꢀ,ꢀ-triazol-ꢀ-yl}methyl]thymine (1b)
According to the general CuAAC procedure, 1b[12] (785 mg, 92%) was obtained
from the reaction of azido sugar 1 (600 mg, 2.1 mmol) with propargyl thymine
b (313 mg, 1.9 mmol) and purified via flash chromatography (CH2Cl2:MeOH,
100:0→100:2.0 ν/ν). White foam; mp 238–240°C; [α]2D0-24 (c 0.25, CHCl3); FTIR
−1
=
–
=
=
(ATR, cm ): 3129 (C CH), 2995, 2933 and 2828 ( CH), 1680 (C O), 1651 (C C)
1
–
–
1368 (C N), 1050 (C-O C); H NMR (400 MHz, CDCl3): δ 9.30 (bs, 1H, NH), 7.85
(s, 1H, H-5ꢀ), 7.32 (d, 1H, J6,thymine-CH3 = 0.8 Hz, H-6), 5.49 (d, 1H, J1 ,2 = 4.8 Hz,
ꢀꢀ ꢀꢀ
H-1ꢀꢀ), 5.04, 4.91 (q, AB-system, 2H, J = 15.2 Hz, CH2), 4.64 (dd, 1H, J2 ,3 = 2.4 Hz,
ꢀꢀ ꢀꢀ
J3 ,4 = 7.8 Hz, H-3 ), 4.60 (dd, 1H, J5 ,6 a = 4.0 Hz, J6 a,6 b = 10.8 Hz, H-6ꢀꢀa), 4.45
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
(dd, 1H, J5 ,6 b = 8.4 Hz, H-6ꢀꢀb), 4.33 (dd, 1H, H-2ꢀꢀ), 4.20 (dd, 1H, J4 ,5 = 2.0 Hz,
H-4ꢀꢀ), 4.18 (ddd, 1H, H-5ꢀꢀ), 1.89 (d, 3H, thymine-CH3),1.48, 1.37, 1.35 and 1.28 (s,
12H, 4 × CH3); 13C NMR (400 MHz, CDCl3): δ 164.4 (C-4), 151.1 (C-2), 141.9 (C-
4ꢀ), 140.3 (C-6), 125.0 (C-5ꢀ), 111.2 (C-5), 110.1 and 109.2 (2 × (CH3)2C), 96.4 (C-
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
–
1 ), 71.3 (C-4 ), 70.9 (C-3 ), 70.5 (C-2 ), 67.3 (C-5 ), 50.8 (C-6 ), 42.9 (CH2 N),
–
26.0, 26.0, 25.0 and 24.6 (4 × CH3), 12.4 (thymine CH3); TOF-ESIMS calcd for
C20H28N5O7 [M + H]+: 450.1988; found: 450.2091.
-[{ꢀ-(ꢀꢀ-Deoxy-ꢀꢀ,ꢀꢀ:ꢀꢀ,ꢀꢀ-di-O-isopropylidene-β-D-fructopyranos-ꢀꢀ-yl)-ꢀH-ꢀ,ꢀ,
ꢀ-triazol-ꢀ-yl}methyl]thymine (2b)
According to the general CuAAC procedure, 2b (785 mg, 92%) was obtained from
the reaction of azido sugar 2 (600 mg, 2.1 mmol) with propargyl thymine b (313 mg,
1.9 mmol) and purified via flash chromatography (CH2Cl2:MeOH, 100:0→100:2.0
ν/ν). White foam; mp 105–107°C; [α]2D0-24 (c 0.25, CHCl3); FTIR (ATR, cm−1):
1
=
–
=
–
–
3147 (C CH), 2988, 2916 ( CH), 1674 (C O), 1372 (C N), 1067 (C-O C); H
NMR (400 MHz, CDCl3): δ9.80 (bs, 1H, NH), 7.90 (s, 1H, H-5ꢀ), 7.35 (d, 1H, J6,CH3
ꢀꢀ
ꢀꢀ
= 1.2 Hz, H-6), 5.04, 4.93 (q, AB-system, 2H, J = 15.2 Hz, CH2), 4.73 (d, 1H, J1 a,1 b
= 14.4 Hz, H-1ꢀꢀa), 4.65 (dd, 1H, J3 ,4 = 2.8 Hz, J4 ,5 = 7.8 Hz, H-4 ), 4.64 (d, 1H,
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
H-1ꢀꢀb), 4.45 (d, 1H, H-3ꢀꢀ), 4.25 (dd, 1H, J5 ,6 a = 1.6 Hz, J5 ,6 b = 0.0 Hz, H-5ꢀꢀ),
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
3.91 (dd, 1H, J6 a,6 b = 12.8 Hz, H-6ꢀꢀa), 3.79 (d, 2H, H-6ꢀꢀb), 1.88 (s, 3H, thymine-
CH3), 1.50, 1.45, 1.36 and 0.72 (s, 12H, 4 × CH3); 13C NMR (100 MHz, CDCl3): δ
164.6 (C-4), 151.2 (C-2), 142.2 (C-4ꢀ), 140.3 (C-6), 126.6 (C-5ꢀ), 111.3 (C-5), 109.7
and 109.5 (2 × (CH3)2C), 100.8 (C-2ꢀꢀ), 70.8 (C-3ꢀꢀ), 70.7 (C-5ꢀꢀ), 70.2 (C-4ꢀꢀ), 62.0
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
–
(C-6 ), 55.2 (C-1 ), 42.7 (CH2 N), 26.5, 26.1, 24.3 and 24.2 (4 × CH3), 12.3
+
–
(thymine CH3); TOF-ESIMS calcd for C20H28N5O7 [M + H] : 450.1988; found:
450.1987.
-[{ꢀ-(ꢀꢀ,ꢀꢀ,ꢀꢀ,ꢀꢀꢀ-Tetra-O-acetyl-β-D-glucopyranosyl)-ꢀH-ꢀ,ꢀ,ꢀ-triazol-ꢀ-yl}
methyl]thymine (3b)
According to the general CuAAC procedure, 3b[12] (654 mg, 87%) was obtained
from the reaction of azido sugar 3 (600 mg, 1.6 mmol) with propargyl thymine
b (239 mg, 1.4 mmol) and purified via flash chromatography (CH2Cl2:MeOH,
100:0→100:2.0 ν/ν). White foam; mp 242–244°C; [α]2D0 + 27 (c 0.25, CHCl3); FTIR

610
E. HALAY ET AL.
−1
=
–
=
(ATR, cm ): 3043 (C CH), 2815 ( CH), 1749, 1739, 1696 and 1678 (C O), 1369
1
–
–
(C N), 1038 (C-O C); H NMR (400 MHz, CDCl3): δ 9.76 (bs, 1H, NH), 8.04 (s, 1H,
H-5ꢀ), 7.24 (s, 1H, H-6), 5.87 (dd, 1H, J1 ,2 = 8.4 Hz, H-1 ), 5.45–5.37 (m, 2H, H-2
ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
and H-3ꢀꢀ), 5.23 (dd, 1H, J3 ,4 = J4 ,5 =9.6 Hz, H-4 ), 4.99, 4.89 (q, AB-system, 2H,
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
J = 15.2 Hz, CH2), 4.25 (dd, 1H, J5 ,6 a = 4.8 Hz, J6 a,6 b = 12.4 Hz, H-6ꢀꢀa), 4.12 (d,
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
1H, J5 ,6 b = 0.0 Hz, H-6ꢀꢀb), 4.05 (dd, 1H, H-5ꢀꢀ), 2.01, 2.01, 1.96 and 1.77 (s, 12H,
ꢀꢀ ꢀꢀ
4 × CH3), 1.84 (s, 3H, thymine-CH3); 13C NMR (100 MHz, CDCl3): δ 170.7, 170.1,
ꢀ
–
169.5, 168.9 (4 × Acetyl C = O), 164.4 (C-4), 151.3 (C-2), 143.0 (C-4 ), 140.1 (C-
6), 123.0 (C-5ꢀ), 111.5 (C-5), 85.9 (C-1ꢀꢀ), 75.3 (C-5ꢀꢀ), 72.7 (C-3ꢀꢀ), 70.7 (C-2ꢀꢀ), 67.9
ꢀꢀ
ꢀꢀ
–
(C-4 ), 61.8 (C-6 ), 42.8 (CH2 N), 20.8, 20.6, 20.6 and 20.2 (4 × CH3), 12.3
(thymine CH3); TOF-ESIMS calcd for C22H28N5O11 [M + H]+: 538.1785; found:
–
538.1896.
-[{ꢀ-(ꢀꢀ,ꢀꢀ:ꢀꢀ,ꢀꢀ-Tetra-O-acetyl-β-D-galactopyranosyl)-ꢀH-ꢀ,ꢀ,ꢀ-triazol-ꢀ-yl}
methyl]thymine (4b)
According to the general CuAAC procedure, 4b[12] (677 mg, 90%) was obtained
from the reaction of azido sugar 4 (600 mg, 1.6 mmol) with propargyl thymine
b (239 mg, 1.4 mmol) and purified via flash chromatography (CH2Cl2:MeOH,
100:0→100:2.0 ν/ν). White foam; mp 211–213°C; [α]2D0 + 16 (c 0.25, CHCl3); FTIR
−1
=
–
=
(ATR, cm ): 3034 (C CH), 2836 ( CH), 1747, 1732, 1708 and 1682 (C O), 1367
1
–
–
(C N), 1044 (C-O C); H NMR (400 MHz, CDCl3): δ 9.87 (s, 1H, NH), 7.98 (s,
1H, H-5ꢀ), 7.25 (s, 1H, H-6), 5.82 (d, 1H, J1 ,2 = 9.2 Hz, H-1 ), 5.49 (d, 1H, J3 ,4
=
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
3.2 Hz, H-4ꢀꢀ), 5.44 (t, 1H, J2 ,3 = 10.0 Hz, H-2 ), 5.24 (dd, 1H, H-3 ), 5.05, 4.84
ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
(q, AB-system, 2H, J = 15.2 Hz, CH2), 4.23 (t, 1H, J5 ,6 b = 6.8 Hz, H-5ꢀꢀ), 4.15 (dd,
ꢀꢀ ꢀꢀ
1H, J5 ,6 a = 6.0 Hz, H-6ꢀꢀa), 4.08 (dd, 1H, J6 a,6 b = 11.2 Hz, H-6ꢀꢀb), 2.18, 1.98,
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
1.95 and 1.80 (s, 12H, 4 × CH3), 1.84 (s, 3H, thymine-CH3); 13C NMR (100 MHz,
–
CDCl3): δ 170.3, 170.0, 169.8 and 168.9 (4 × Acetyl C = O), 164.5 (C-4), 151.0
(C-2), 142.6 (C-4ꢀ), 140.0 (C-6), 122.5 (C-5ꢀ), 111.1 (C-5), 86.2 (C-1ꢀꢀ), 74.0 (C-5ꢀꢀ),
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
–
70.5 (C-3 ), 68.1 (C-2 ), 66.8 (C-4 ), 61.2 (C-6 ), 42.5 (CH2 N), 20.6, 20.5, 20.4
–
and 20.1 (4 × CH3), 12.2 (thymine CH3); TOF-ESIMS calcd for C22H28N5O11 [M
+ H]+: 538.1785; found: 538.1888.
-[{ꢀ-(ꢀꢀ,ꢀꢀ,ꢀꢀ-Tri-O-acetyl-β-D-xylopyranosyl)-ꢀH-ꢀ,ꢀ,ꢀ-triazol-ꢀ-yl}methyl]
thymine (5b)
According to the general CuAAC procedure, 5b (703 mg, 84%) was obtained from
the reaction of azido sugar 5 (600 mg, 2 mmol) with propargyl thymine b (297 mg,
1.8 mmol) and purified via flash chromatography (CH2Cl2:MeOH, 100:0→100:2.0
ν/ν). White foam; mp 122–124°C; [α]2D0 + 38 (c 0.25, DMSO); FTIR (ATR, cm−1):
1
=
=
–
–
3154, 3045 (C CH), 1744, 1683 (C O), 1215 (C N), 1038 (C-O C); H NMR
(400 MHz, DMSO-d6): δ 8.35 (s, 1H, H-5ꢀ), 7.50 (s, 1H, H-6), 6.17 (d, 1H, J1 ,2
=
ꢀꢀ ꢀꢀ
9.2 Hz, H-1ꢀꢀ), 5.57 (t, 1H, J2 ,3 = 9.6 Hz, H-3 ), 5.45 (t, 1H, H-2 ), 5.09 (td, 1H,
ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
J4 ,5 a = 5.6 Hz, H-4ꢀꢀ), 4.91, 4.86 (q, AB-system, 2H, J = 15.2 Hz, CH2), 4.06 (dd,
ꢀꢀ ꢀꢀ
1H, J5 a,5 b = 11.2 Hz, H-5ꢀꢀa), 3.80 (t, 1H, H-5ꢀꢀb), 1.99, 1.96 and 1.75 (s, 9H, 3 ×
ꢀꢀ
ꢀꢀ

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
611
CH3), 1.73 (s, 3H, thymine-CH3); 13C NMR (100 MHz, DMSO-d6): δ 169.9, 169.9
ꢀ
–
and 168.9 (3 × Acetyl C = O), 164.6 (C-4), 151.1 (C-2), 143.7 (C-4 ), 141.2 (C-6),
123.0 (C-5ꢀ), 109.4 (C-5), 85.1 (C-1ꢀꢀ), 72.2 (C-3ꢀꢀ), 70.7 (C-2ꢀꢀ), 68.3 (C-4ꢀꢀ), 64.5
ꢀꢀ
–
–
(C-5 ), 42.4 (CH2 N), 20.8, 20.7 and 20.3 (3 × CH3), 12.3 (thymine CH3); TOF-
ESIMS calcd for C19H23N5O9Na [M + Na]+: 488.1393; found: 488.1411.
-[{ꢀ-(ꢀꢀ-Deoxy-ꢀꢀ,ꢀꢀ:ꢀꢀ,ꢀꢀ-di-O-isopropylidene-α-D-galactopyranos-ꢀꢀ-yl)-ꢀH-ꢀ,
ꢀ,ꢀ-triazol-ꢀ-yl}methyl]-fluorouracil (1c)
According to the general CuAAC procedure, 1c (809 mg, 94%) was obtained from
the reaction of azido sugar 1 (600 mg, 2.1 mmol) with propargyl 5-fluorouracil
c (321 mg, 1.9 mmol) and purified via flash chromatography (CH2Cl2:MeOH,
100:0→100:1.0 ν/ν). White foam; mp 213–215°C; [α]2D0-32 (c 0.25, DMSO); FTIR
−1
=
–
=
=
(ATR, cm ): 3168 (C CH), 2981, 2828 ( CH), 1718, 1693 (C O), 1659 (C C),
1
–
–
–
1382 (C N), 1223 ( NH), 1052 (C-O C); H NMR (400 MHz, DMSO-d6): δ 11.81
(bs, 1H, NH), 8.11 (d, 1H, J6,F = 6.4 Hz, H-6), 8.06 (s, 1H, H-5ꢀ), 5.38 (d, 1H, J1 ,2
=
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
–
4.8 Hz, H-1 ), 4.89 (s, 2H, CH2 N), 4.64 (dd, 1H, J2 ,3 = 2.4 Hz, J3 ,4 = 8.0 Hz,
H-3ꢀꢀ), 4.54 (dd, 1H, J5 ,6 a = 2.8 Hz, J6 a,6 b = 14.0 Hz, H-6ꢀꢀa), 4.36 (dd, 1H, J5 ,6 b
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
= 9.6 Hz, H-6ꢀꢀb), 4.34 (dd, 1H, H-2ꢀꢀ), 4.29 (dd, 1H, J4 ,5 = 8.0 Hz, H-4 ), 4.15
ꢀꢀ
ꢀꢀ ꢀꢀ
(bd, 1H, H-5ꢀꢀ), 1.38, 1.30, 1.32 and 1.21 (s, 12H, 4 × CH3); 13C NMR (100 MHz,
DMSO-d6): δ157.9 and 157.7 (C-4, J = 25.6 Hz), 149.7 (C-2), 142.3 (C-4ꢀ), 141.2 and
138.9 (C-5, J = 228.6 Hz), 130.3 and 129.9 (C-6, J = 33.3 Hz), 124.4 (C-5ꢀ), 109.2
and 108.5 (2 × (CH3)2C), 95.9 (C-1ꢀꢀ), 71.0 (C-4ꢀꢀ), 70.6 (C-3ꢀꢀ), 70.1 (C-2ꢀꢀ), 67.2
(C-5 ), 50.6 (C-6 ), 43.0 (CH2 N), 26.3, 26.0, 25.2 and 24.7 (4 × CH3); 19F NMR
ꢀꢀ
ꢀꢀ
–
–
(376 MHz, DMSO-d6): δ−169.1 (d, 1F, JF,H6 = 6.8 Hz, CF = CH N); TOF-ESIMS
calcd for C19H25FN5O7 [M + H]+: 454.1738; found: 454.1802.
-[{ꢀ-(ꢀꢀ-Deoxy-ꢀꢀ,ꢀꢀ:ꢀꢀ,ꢀꢀ-di-O-isopropylidene-β-D-fructopyranos-ꢀꢀ-yl)-ꢀH-ꢀ,
ꢀ,ꢀ-triazol-ꢀ-yl}methyl]-fluorouracil (2c)
According to the general CuAAC procedure, 2c (800 mg, 93%) was obtained from
the reaction of azido sugar 2 (600 mg, 2.1 mmol) with propargyl 5-fluorouracil
c (321 mg, 1.9 mmol) and purified via flash chromatography (CH2Cl2:MeOH,
100:0→100:1.0 ν/ν). White foam; mp 129–131°C; [α]2D0-24 (c 0.25, DMSO); FTIR
−1
=
–
=
=
(ATR, cm ): 3120 (C CH), 2987, 2948, 2834 ( CH), 1691 (C O), 1644 (C C),
1
–
–
–
1373 (C N), 1211 ( NH), 1065 (C-O C); H NMR (400 MHz, DMSO-d6): δ 11.79
(bs, 1H, NH), 8.14 (d, 1H, J6,F = 6.8 Hz, H-6), 8.04 (s, 1H, H-5ꢀ), 4.90, 4.86 (q, AB-
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
system, 2H, J = 15.2 Hz, CH2), 4.62 (dd, 1H, J3 ,4 = 2.8 Hz, J4 ,5 = 8.0 Hz, H-4 ),
4.58 (s, 2H, H-1ꢀꢀ), 4.38 (d, 1H, H-3ꢀꢀ), 4.23 (bd, 1H, J5 ,6 a = 1.2 Hz, H-5ꢀꢀ), 3.73
ꢀꢀ ꢀꢀ
(dd, 1H, J6 a,6 b = 12.8 Hz, H-6ꢀꢀa), 3.60 (d, 1H, H-6ꢀꢀb), 1.37, 1.37, 1.28 and 0.73 (s,
12H, 4 × CH3); 13C NMR (100 MHz, DMSO-d6): δ 157.9 and 157.6 (C-4, J = 26.6
Hz), 149.8 (C-2), 142.2 (C-4ꢀ), 141.1 and 138.9 (C-5, J = 228.6 Hz), 130.4 and 130.1
(C-6, J = 33.4 Hz), 126.5 (C-5ꢀ), 109.0 and 108.7 (2 × (CH3)2C), 100.9 (C-2ꢀꢀ), 70.6
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
–
(C-3 ), 70.2 (C-5 ), 69.7 (C-4 ), 61.4 (C-6 ), 55.0 (C-1 ), 42.9 (CH2 N), 26.5, 26.2,
24.4 and 24.3 (4 × CH3); 19F NMR (376 MHz, DMSO-d6): δ−169.3 (d, 1F, JF,H6
=

612
E. HALAY ET AL.
+
–
7.2 Hz, CF = CH N); TOF-ESIMS calcd for C19H25FN5O7 [M + H] : 454.1738;
found: 454.1763.
-[{ꢀ-(ꢀꢀ,ꢀꢀ,ꢀꢀ,ꢀꢀ-Tetra-O-acetyl-β-D-glucopyranosyl)-ꢀH-ꢀ,ꢀ,ꢀ-triazol-ꢀ-yl}
methyl]-fluorouracil (3c)
According to the general CuAAC procedure, 3c (682 mg, 90%) was obtained from
the reaction of azido sugar 3 (600 mg, 1.6 mmol) with propargyl 5-fluorouracil
c (245 mg, 1.4 mmol) and purified via flash chromatography (CH2Cl2:MeOH,
100:0→100:1.0 ν/ν). White foam; mp 229–230°C; [α]2D0 + 8 (c 0.25, DMSO);
−1
=
=
=
FTIR (ATR, cm ): 3150, 3075 (C CH), 1740, 1689 (C O), 1668 (C C), 1370
1
–
–
–
(C N), 1226 ( NH), 1042 (C-O C); H NMR (400 MHz, DMSO-d6): δ11.81
(bs, 1H, NH), 8.39 (s, 1H, H-5ꢀ), 8.09 (d, 1H, J6,F = 6.4 Hz, H-6), 6.30 (d,
ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
1H, J1 ,2 = 9.2 Hz, H-1 ), 5.59 (t, 1H, J2 ,3 = 9.2 Hz, H-2 ), 5.52 (t, 1H,
ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
–
J3 ,4 = 9.6 Hz, H-3 ), 5.15 (t, 1H, J4 ,5 = 9.6 Hz, H-4 ), 4.90 (s, 2H, CH2 N),
4.34 (m, 1H, H-5ꢀꢀ), 4.14–4.04 (m, 2H, J5 ,6 a = 4.8 Hz, J6 a,6 b = 14.8 Hz,
H-6ꢀꢀa and H-6ꢀꢀb), 2.01, 1.98, 1.94 and 1.76 (s, 12H, 4 × ꢀꢀCH3); 13C NMR
ꢀꢀ ꢀꢀ
ꢀꢀ
–
(100 MHz, DMSO-d6): δ 170.4, 169.9, 169.7, 168.8 (4 × Acetyl C = O), 157.9
and 157.7 (C-4, J = 25.6 Hz), 149.7 (C-2), 143.4 (C-4ꢀ), 141.3 and 139.0 (C-5,
J = 228.6 Hz), 130.3 and 129.9 (C-6, J = 33.3 Hz), 123.1 (C-5ꢀ), 84.3 (C-1ꢀꢀ), 73.7 (C-
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
–
5 ), 72.5 (C-3 ), 70.6 (C-2 ), 67.9 (C-4 ), 62.2 (C-6 ), 43.0 (CH2 N), 20.9, 20.7, 20.6
and 20.2 (4 × CH3); 19F NMR (376 MHz, DMSO-d6): δ−169.1 (d, 1F, JF,H6 = 7.2 Hz,
+
–
CF = CH N); TOF-ESIMS calcd for C21H24FN5O11Na [M + Na] : 564.1354;
found: 564.1371.
-[{ꢀ-(ꢀꢀ,ꢀꢀ,ꢀꢀ,ꢀꢀ-Tetra-O-acetyl-β-D-galactopyranosyl)-ꢀH-ꢀ,ꢀ,ꢀ-triazol-ꢀ-yl}
methyl]-fluorouracil (4c)
According to the general CuAAC procedure, 4c (644 mg, 85%) was obtained from
the reaction of azido sugar 4 (600 mg, 1.6 mmol) with propargyl 5-fluorouracil
c (245 mg, 1.4 mmol) and purified via flash chromatography (CH2Cl2:MeOH,
100:0→100:1.0 ν/ν). White foam; mp 109–111°C; [α]2D0 + 11 (c 0.25, DMSO); FTIR
−1
=
–
=
–
(ATR, cm ): 3088 (C CH), 2840 ( CH), 1746, 1697 (C O), 1367 (C N), 1211
1
–
–
( NH), 1043 (C-O C); H NMR (400 MHz, DMSO-d6): δ11.82 (bs, 1H, NH), 8.34
(s, 1H, H-5ꢀ), 8.11 (d, 1H, J6,F = 6.8 Hz, H-6), 6.23 (d, 1H, J1 ,2 = 9.2 Hz, H-1 ),
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
5.54 (t, 1H, J2 ,3 = 10.0 Hz, H-2 ), 5.43 (dd, 1H, J3 ,4 = 3.6 Hz, H-4 ), 5.41 (t, 1H,
H-3ꢀꢀ), 4.93, 4.89 (q, AB-system, 2H, J = 15.6 Hz, CH2), 4.56 (t, 1H, J5 ,6 b = 6.4 Hz,
ꢀꢀ ꢀꢀ
H-5ꢀꢀ), 4.12 (dd, 1H, J5 ,6 a = 5.2 Hz, J6 a,6 b = 11.6 Hz, H-6ꢀꢀa), 4.01 (dd, 1H, H-
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
6ꢀꢀb), 2.16, 1.96, 1.92 and 1.78 (s, 12H, 4 × CH3); 13C NMR (100 MHz, DMSO-d6):
–
δ170.4, 170.3, 169.9, 168.9 (4 × Acetyl C = O), 158.0 and 157.7 (C-4, J = 25.6 Hz),
149.8 (C-2), 143.2 (C-4ꢀ), 141.3 and 139.0 (C-5, J = 228.6 Hz), 130.3 and 130.0 (C-6,
J = 33.3 Hz), 123.5 (C-5ꢀ), 84.7 (C-1ꢀꢀ), 73.4 (C-5ꢀꢀ), 70.7 (C-3ꢀꢀ), 68.2 (C-2ꢀꢀ), 67.7
(C-4 ), 61.9 (C-6 ), 42.9 (CH2 N), 20.8, 20.8, 20.7 and 20.3 (4 × CH3); 19F NMR
ꢀꢀ
ꢀꢀ
–
–
(376 MHz, DMSO-d6): δ−169.1 (d, 1F, JF,H6 = 7.2 Hz, CF = CH N); TOF-ESIMS
calcd for C21H24FN5O11Na [M + Na]+: 564.1354; found: 564.1367.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
613
-[{ꢀ-(ꢀꢀ,ꢀꢀ,ꢀꢀꢀ-Tri-O-acetyl-β-D-xylopyranosyl)-ꢀH-ꢀ,ꢀ,ꢀ-triazol-ꢀ-yl}methyl]
-fluorouracil (5c)
According to the general CuAAC procedure, 5c (675 mg, 80%) was obtained from
the reaction of azido sugar 5 (600 mg, 2 mmol) with propargyl 5-fluorouracil
c (304 mg, 1.8 mmol) and purified via flash chromatography (CH2Cl2:MeOH,
100:0→100:1.0 ν/ν). White foam; mp 137–139°C; [α]2D0 + 29 (c 0.25, DMSO);
−1
1
=
=
–
–
FTIR (ATR, cm ): 3066 (C CH), 1747, 1688 (C O), 1367 (C N), 1212 ( NH),
ꢀ
–
1043 (C-O C); H NMR (400 MHz, DMSO-d6): δ 8.38 (s, 1H, H-5 ), 8.07 (d,
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
1H, J6,F = 6.8 Hz, H-6), 6.18 (d, 1H, J1 ,2 = 8.8 Hz, H-1 ), 5.55 (t, 1H, J2 ,3
=
9.6 Hz, H-2ꢀꢀ), 5.45 (t, 1H, H-3ꢀꢀ), 5.08 (td, 1H, J4 ,5 a = 5.6 Hz, H-4ꢀꢀ), 4.89 (s,
ꢀꢀ ꢀꢀ
2H, CH2 N), 4.06 (dd, 1H, H-5 a), 3.81 (t, 1H, J5 a,5 b = 10.8 Hz, H-5ꢀꢀb); 13C
ꢀꢀ
ꢀꢀ
ꢀꢀ
–
–
NMR (100 MHz, DMSO-d6): δ 169.9, 169.9 and 168.9 (3 × Acetyl C = O), 158.2
and 157.9 (C-4, J = 25.2 Hz), 149.9 (C-2), 143.4 (C-4ꢀ), 141.3 and 139.0 (C-5, J
= 228.7 Hz), 130.1 and 129.8 (C-6, J = 33.6 Hz), 123.1 (C-5ꢀ), 86.1 (C-1ꢀꢀ), 72.2
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
–
(C-3 ), 70.7 (C-2 ), 68.4 (C-4 ), 64.5 (C-5 ), 43.0 (CH2 N), 20.8, 20.7 and 20.3
(3 × CH3); 19F NMR (376 MHz, DMSO-d6): δ−169.0 (d, 1F, JF,H6 = 7.2 Hz, CF
+
–
= CH N); TOF-ESIMS calcd for C18H20FN5O9Na [M + Na] : 492.1142; found:
492.1152.
-[{ꢀ-(ꢀꢀ-Deoxy-ꢀꢀ,ꢀꢀ:ꢀꢀ,ꢀꢀ-di-O-isopropylidene-α-D-galactopyranos-ꢀꢀꢀ-yl)-ꢀH-ꢀ,
ꢀ,ꢀ-triazol-ꢀ-yl}methyl]adenine (1d)
According to the general CuAAC procedure, 1d (757 mg, 87%) was obtained from
the reaction of azido sugar 1 (600 mg, 2.1 mmol) with propargyl adenine d (331 mg,
1.9 mmol) and purified via flash chromatography (CH2Cl2:MeOH, 100:0→100:4.0
ν/ν). White foam; mp 132–134°C; [α]2D0-36 (c 0.25, DMSO); FTIR (ATR, cm−1):
–
–
=
=
–
3314, 3153 ( NH2), 2990, 2936 ( CH), 1651 (C N), 1600 (C C), 1578 ( NH2),
1
–
–
1212 (C N), 1068 (C-O C); H NMR (400 MHz, DMSO-d6): δ8.16 (s, 2H, H-2
ꢀ
–
and H-8), 8.04 (s, 1H, H-5 ), 7.32 (bs, 2H, NH2), 5.43 (s, 2H, CH2 N),ꢀ5ꢀ .35 (d, 1H,
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
J1 ,2 = 5.2 Hz, H-1 ), 4.62 (dd, 1H, J2 ,3 = 2.4 Hz, J3 ,4 = 8.0 Hz, H-3 ), 4.52 (dd,
1H, J5 ,6 a = 2.8 Hz, J6 a,6 b = 14.4 Hz, H-6ꢀꢀa), 4.35 (dd, 1H, J5 ,6 b = 9.6 Hz, H-
6ꢀꢀb), 4.32 (dd, 1H, H-2ꢀꢀ), 4.26 (dd, 1H, J4 ,5 = 8.0 Hz, H-4ꢀꢀ), 4.12 (bd, 1H, H-
5ꢀꢀ), 1.36, 1.27, 1.24 and 1.19 (s, 12H, 4 ×ꢀꢀCꢀHꢀ 3); 13C NMR (100 MHz, DMSO-
d6): δ156.2 (C-6), 152.7 (C-2), 149.9 (C-4), 143.0 (C-4ꢀ), 141.3 (C-8), 124.6 (C-
5ꢀ), 119.2 (C-5), 109.5 and 108.7 (2 × (CH3)2C), 96.1 (C-1ꢀꢀ), 71.2 (C-4ꢀꢀ), 70.8
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
–
(C-3 ), 70.3 (C-2 ), 67.4 (C-5 ), 50.8 (C-6 ), 38.8 (CH2 N), 26.5, 26.1, 25.4 and
24.9 (4 × CH3); TOF-ESIMS calcd for C20H27N8O5 [M + H]+: 459.2104; found:
459.2098.
-[{ꢀ-(ꢀꢀ-Deoxy-ꢀꢀ,ꢀꢀ:ꢀꢀ,ꢀꢀ-di-O-isopropylidene-β-D-fructopyranos-ꢀꢀ-yl)-ꢀH-ꢀ,
ꢀ,ꢀ-triazol-ꢀ-yl}methyl]adenine (2d)
According to the general CuAAC procedure, 2d (792 mg, 91%) was obtained
from the reaction of azido sugar 2 (600 mg, 2.1 mmol) with propargyl adenine
d (331 mg, 1.9 mmol) and purified via flash chromatography (CH2Cl2:MeOH,
100:0→100:4.0 ν/ν). White foam; mp 128–129°C; [α]2D0-24 (c 0.25, DMSO); FTIR

614
E. HALAY ET AL.
−1
–
–
=
=
(ATR, cm ): 3311, 3154 ( NH2), 2987, 2937 ( CH), 1644 (C N), 1597 (C C),
1
–
–
–
1575 ( NH2), 1211 (C N), 1067 (C-O C); H NMR (400 MHz, DMSO-d6): δ8.17
(s, 1H, H-8), 8.13 (s, 1H, H-2), 8.05 (s, 1H, H-5ꢀ), 7.21 (s, 2H, NH2), 5.42 (s, 2ꢀHꢀ ,
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
–
CH2 N), 4.59 (dd, 1H, J3 ,4 = 2.4 Hz, J4 ,5 = 8.0 Hz, H-4 ), 4.57 (s, 1H, H-1 ),
4.35 (d, 1H, H-3ꢀꢀ), 4.21 (d, 1H, H-5ꢀꢀ), 3.70 (d, 1H, J6 a,6 b = 12.8 Hz, H-6ꢀꢀa), 3.59
(d, 1H, H-6ꢀꢀb), 1.34, 1.32, 1.26 and 0.63 (s, 12H, 4 × CH3); 13C NMR (100 MHz,
DMSO-d6): δ156.3 (C-6), 152.9 (C-2), 149.7 (C-4), 142.7 (C-4ꢀ), 141.0 (C-8), 126.4
(C-5ꢀ), 119.0 (C-5), 109.0 and 108.7 (2 × (CH3)2C), 100.8 (C-2ꢀꢀ), 70.6 (C-3ꢀꢀ), 70.2
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
–
(C-5 ), 69.7 (C-4 ), 61.4 (C-6 ), 55.0 (C-1 ), 38.2 (CH2 N), 26.4, 26.1, 24.4 and
24.2 (4 × CH3); TOF-ESIMS calcd for C20H27N8O5 [M + H]+: 459.2104; found:
459.2106.
-[{ꢀ-(ꢀꢀ,ꢀꢀ,ꢀꢀ,ꢀꢀ-Tetra-O-acetyl-β-D-glucopyranosyl)-ꢀH-ꢀ,ꢀ,ꢀ-triazol-ꢀ-yl}
methyl]adenine (3d)
According to the general CuAAC procedure, 3d (711 mg, 93%) was obtained from
the reaction of azido sugar 3 (600 mg, 1.6 mmol) with propargyl adenine d (253 mg,
1.4 mmol) and purified via flash chromatography (CH2Cl2:MeOH, 100:0→100:4.0
ν/ν). White foam; mp 213–215°C; [α]2D0 + 18 (c 0.25, DMSO); FTIR (ATR,
−1
–
=
=
=
cm ): 3403, 3322 ( NH2), 3197 (C CH), 1751, 1708 (C O), 1647 (C N), 1601
1
=
–
–
–
(C C), 1579 ( NH2), 1227 (C N), 1060 (C-O C); H NMR (400 MHz, DMSO-d6):
δ8.37 (s, 1H, H-5ꢀ), 8.12 (s, 2H, H-2, H-8), 7.20 (s, 2H, NH2), 6.30 (d, 1H, J1 ,2
=
ꢀꢀ ꢀꢀ
9.2 Hz, H-1ꢀꢀ), 5.59 (t, 1H, J2 ,3 = 9.2 Hz, H-2 ), 5.50 (t, 1H, J3 ,4 = 9.6 Hz, H-3 ),
ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
5.44 (s, 2H, CH2 N), 5.14 (t, 1H, H-4 ), 4.32 (m, 1H, J5 ,6 a = 2.0 Hz, H-6ꢀꢀa), 4.10
ꢀꢀ
ꢀꢀ ꢀꢀ
–
(dd, 1H, J6 a,6 b = 12.8, H-6ꢀꢀb), 4.05 (td, 1H, J5 ,6 b = 4.8, H-5ꢀꢀ), 1.99, 1.96, 1.93 and
ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
1.72 (s, 12H, 4 × CH3); 13C NMR (100 MHz, DMSO-d6): δ170.6, 170.2, 170.0, 169.1
ꢀ
–
(4 × Acetyl C = O), 156.6 (C-6), 153.3 (C-2), 150.0 (C-4), 143.9 (C-4 ), 141.2 (C-
8), 123.4 (C-5ꢀ), 119.2 (C-5), 84.6 (C-1ꢀꢀ), 74.0 (C-5ꢀꢀ), 72.8 (C-3ꢀꢀ), 70.8 (C-2ꢀꢀ), 68.2
ꢀꢀ
ꢀꢀ
–
(C-4 ), 62.4 (C-6 ), 38.6 (CH2 N), 21.1, 21.0, 20.8 and 20.4 (4 × CH3); TOF-ESIMS
calcd for C22H27N8O9 [M + H]+: 547.1901; found 547.1893.
-[{ꢀ-(ꢀꢀ,ꢀꢀ:ꢀꢀ,ꢀꢀ-Tetra-O-acetyl-β-D-galactopyranosyl)-ꢀH-ꢀ,ꢀ,ꢀ-triazol-ꢀ-yl}
methyl]adenine (4d)
According to the general CuAAC procedure, 4d (681 mg, 89%) was obtained from
the reaction of azido sugar 4 (600 mg, 1.6 mmol) with propargyl adenine d (253 mg,
1.4 mmol) and purified via flash chromatography (CH2Cl2:MeOH, 100:0→100:4.0
ν/ν). White foam; mp 105–108°C; [α]2D0-8 (c 0.25, DMSO); FTIR (ATR, cm−1):
–
=
=
=
=
3399, 3331 ( NH2), 3148 (C CH), 1744 (C O), 1636 (C N), 1596 (C C), 1579
1
–
–
–
( NH2), 1211 (C N), 1046 (C-O C); H NMR (400 MHz, DMSO-d6): δ8.36 (s, 1H,
H-5ꢀ), 8.14 (s, 1H, H-8), 8.12 (s, 1H, H-2), 7.22 (s, 2H, NH2), 6.22 (d, 1H, J1 ,2
=
ꢀꢀ ꢀꢀ
9.2 Hz, H-1ꢀꢀ), 5.54 (t, 1H, J2 ,3 = 9.6 Hz, H-2 ), 5.44 (s, 2H, CH2 N), 5.42 (dd, 1H,
ꢀꢀ
ꢀꢀ ꢀꢀ
–
J3 ,4 = 3.2 Hz, H-3 ), 5.40 (dd, 1H, H-4 ), 4.54 (t, 1H, J5 ,6 a = 5.6 Hz, H-5ꢀꢀ), 4.10
ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
ꢀꢀ ꢀꢀ
(dd, 1H, J6 a,6 b = 11.6 Hz, H-6ꢀꢀa), 3.99 (dd, 1H, J5 ,6 b = 7.2 Hz, H-6ꢀꢀb), 2.16, 1.95,
ꢀꢀ
ꢀꢀ
ꢀꢀ ꢀꢀ
1.92 and 1.74 (s, 12H, 4 × CH3); 13C NMR (100 MHz, DMSO-d6): δ170.4, 170.3,

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
615
–
169.9, 168.9 (4 × Acetyl C = O), 156.4 (C-6), 153.0 (C-2), 149.7 (C-4), 143.5 (C-
4ꢀ), 140.9 (C-8), 123.7 (C-5ꢀ), 119.0 (C-5), 84.7 (C-1ꢀꢀ), 73.4 (C-5ꢀꢀ), 70.7 (C-3ꢀꢀ), 68.2
ꢀꢀ
ꢀꢀ
ꢀꢀ
–
(C-2 ), 67.7 (C-4 ), 61.9 (C-6 ), 38.2 (CH2 N), 20.9, 20.8, 20.7 and 20.3 (4 × CH3);
TOF-ESIMS calcd for C22H27N8O9 [M + H]+: 547.1901; found 547.1897.
-[{ꢀ-(ꢀꢀ,ꢀꢀ,ꢀꢀ-Tri-O-acetyl-β-D-xylopyranosyl)-ꢀH-ꢀ,ꢀ,ꢀ-triazol-ꢀ-yl}methyl]
adenine (5d)
According to the general CuAAC procedure, 5d (682 mg, 80%) was obtained from
the reaction of azido sugar 5 (600 mg, 2 mmol) with propargyl adenine d (313 mg,
1.8 mmol) and purified via flash chromatography (CH2Cl2:MeOH, 100:0→100:4.0
ν/ν). White foam; mp 122–124°C; [α]2D0 + 52 (c 0.25, DMSO); FTIR (ATR, cm−1):
–
=
=
=
=
3360, 3240 ( NH2), 3103 (C CH), 1739 (C O), 1683 (C N), 1608 (C C), 1579
1
–
–
–
( NH2), 1220 (C N), 1041 (C-O C); H NMR (400 MHz, DMSO-d6): δ 8.35 (s,
1H, H-5ꢀ), 8.11 (s, 2H, H-8 and H-2), 7.19 (s, 2H, NH2), 6.16 (d, 1H, J1 ,2
=
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
–
9.2 Hz, H-1 ), 5.54 (t, 1H, H-2 ), 5.44 (t, 1H, H-3 ), 5.43 (s, 2H, CH2 N), 5.08
(td, 1H, J4 ,5 a = 5.6 Hz, H-4ꢀꢀ), 4.04 (dd, 1H, J5 a,5 b = 11.2 Hz, H-5ꢀꢀa), 3.78 (t,
ꢀꢀ ꢀꢀ
ꢀꢀ
ꢀꢀ
1H, J4 ,5 b = 10.8 Hz, H-5ꢀꢀb), 1.99, 1.76 and 1.73 (s, 9H, 3 × CH3); 13C NMR
ꢀꢀ ꢀꢀ
–
(100 MHz, DMSO-d6): 169.9, 169.9, 168.8 (3 × Acetyl C = O), 156.3 (C-6), 153.0
(C-2), 149.7 (C-4), 143ꢀ.ꢀ6 (C-4ꢀ), 140ꢀ.ꢀ9 (C-8), 123.1 (C-5ꢀ), 118.9 (C-5), 85.1 (C-1ꢀꢀ),
ꢀꢀ
ꢀꢀ
–
72.2 (C-3 ), 70.7 (C-2 ), 68.3 (C-4 ), 64.5 (C-5 ), 38.3 (CH2 N), 20.8, 20.7 and
20.2 (3 ×CH3); TOF-ESIMS calcd for C19H22N8O7Na[M + Na]+: 497.1509; found
497.1526.
Cytotoxic Activity Assay
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay (Cell
Proliferation Kit I, Roche Diagnostic, Germany) was performed for the evalua-
tion of cytotoxic properties and in vitro anticancer potentials of the synthesized
compounds.[46]
The cell lines used for testing the in vitro cytotoxicity, and cell viability including
MDA-MB-231 (Human breast cancer, ATCC HTB-26), Hep3B (Human hepatoma
cancer, ATCC HB-8064), PC-3 (Human prostate cancer, ATCC CRL-1435) and
L929 (control cell line, ATCC CRL-6364) were obtained from the American Type
Culture Collection (USA) and maintained in Dulbecco’s Modified Eagles’s Medium
(DMEM) supplemented with 10% (v/v ) of fetal bovine serum (FBS; Gibco, Carls-
bad, CA, USA). Cells were routinely grown in 25 and 75 cm2 flasks in an environ-
ment containing 5% CO2 and passed every 3 days. Cells were seeded in 96 multiwell
plate at a density of 5 × 103 cells/well for 24 h before treating with the compounds
to allow attachment of cells. The compounds were dissolved in dimethyl sulfoxide
(DMSO, Sigma D2650) and the final concentration of DMSO was 0.1%. After 24 h
of growth, the medium was replaced with fresh medium containing compounds at
the different concentrations (10, 25, 50, 100 and 200 µM). Triplicate wells were pre-
pared for each individual concentration. Cells were incubated with the compounds
for 48 h at 37°C, under a 5% CO2 atmosphere. After the incubation period, 10 µL

616
E. HALAY ET AL.
MTT was added to each well and incubated overnight. MTT containing medium
was removed and 100 µL solubilization buffer (10% SDS in 0.01 M HCl) was added
to the formazan crystal formed by live cells. Plates were incubated for overnight
and absorbances were measured at 550 and 600 nm wavelength using a multimode
microplate reader (BioTek, USA).
The percentage cell viability was calculated by expressing the absorbance of
treated cells as a percentage of untreated control cells. Three independent experi-
ments with triplicate data were performed to obtain mean cell viability. The IC50
value is the concentration (μM) of a compound was able to cause 50% cell death
with respect to the control culture. The IC50 values of the compounds were calcu-
lated using GraphPad Prism 7.02 software according to the inhibition ratios.
Acknowledgements
This work was supported by TUBITAK-Research Council of Turkey with the project number
114Z757. Halay also offers his profound thanks to TUBITAK-BIDEB 2211A for scholarship
support.
ORCID
Kadir Ay http://orcid.org/0000-0003-0197-2779
Tamer Karayıldırım http://orcid.org/0000-0001-7451-0810
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