Synthesis of novel 1,2,3-triazolyl nucleoside analogues bearing uracil, 6-methyluracil, 3,6-dimethyluracil, thymine, and quinazoline-2,4-dione moieties

Article abstract of DOI:10.1016/j.tetlet.2019.151276

A series of novel 1,2,3-triazolyl nucleoside analogues was synthesized via the CuAAC reaction of N1-alkynyl uracil, 6-methyluracil, 3,6-dimethyl uracil, thymine and quinazolin-2,4-dione with protected azido β-D-ribofuranose. The obtained compounds differ in both the nature of the pyrimidine-2,4-dione fragment and the length of the polymethylene linker connecting it with the β-D-ribofuranosyl-1,2,3-triazol-4-yl moiety. The 1,2,3-triazolyl nucleoside analogues were evaluated for their cytotoxicity in vitro.

Full text of DOI:10.1016/j.tetlet.2019.151276

Journal Pre-proofs
Synthesis of novel 1,2,3-triazolyl nucleoside analogues bearing uracil, 6-meth-
yluracil, 3,6-dimethyluracil, thymine, and quinazoline-2,4-dione moieties
Olga V. Andreeva, Maya G. Belenok, Liliya F. Saifina, Marina M. Shulaeva,
Alexey B. Dobrynin, Radmila R. Sharipova, Alexandra D. Voloshina, Alina F.
Saifina, Aidar T. Gubaidullin, Bulat I. Khairutdinov, Yuriy F. Zuev, Vyacheslav
E. Semenov, Vladimir E. Kataev
PII:
S0040-4039(19)31056-1
DOI:
https://doi.org/10.1016/j.tetlet.2019.151276
TETL 151276
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 September 2019
8 October 2019
10 October 2019
Please cite this article as: Andreeva, O.V., Belenok, M.G., Saifina, L.F., Shulaeva, M.M., Dobrynin, A.B., Sharipova,
R.R., Voloshina, A.D., Saifina, A.F., Gubaidullin, A.T., Khairutdinov, B.I., Zuev, Y.F., Semenov, V.E., Kataev,
V.E., Synthesis of novel 1,2,3-triazolyl nucleoside analogues bearing uracil, 6-methyluracil, 3,6-dimethyluracil,
thymine, and quinazoline-2,4-dione moieties, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2019.151276
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Graphical Abstract
Synthesis of novel 1,2,3-triazolyl nucleoside
analogues bearing uracil, 6-methyluracil,
3,6-dimethyluracil, thymine, and
Leave this area blank for abstract info.
quinazoline-2,4-dione moieties
O.V. Andreeva, M.G. Belenok, L.F. Saifina, M.M. Shulaeva, A.B. Dobrynin, R.R. Sharipova, A.D. Voloshina,
A.F. Saifina, A.T. Gubaidullin, B.I. Khairutdinov, Y.F. Zuev, V.E. Semenov, and V.E. Kataev

1
Tetrahedron Letters
Synthesis of novel 1,2,3-triazolyl nucleoside analogues bearing uracil, 6-methyluracil,
3,6-dimethyluracil, thymine, and quinazoline-2,4-dione moieties
a
a
a
a
a
Olga V. Andreeva , Maya G. Belenok , Liliya F. Saifina , Marina M. Shulaeva , Alexey B. Dobrynin ,
a
a
a
a
Radmila R. Sharipova , Alexandra D. Voloshina , Alina F. Saifina , Aidar T. Gubaidullin , Bulat I.
Khairutdinov b, Yuriy F. Zuev b, Vyacheslav E. Semenov a, Vladimir E. Kataev a
a
Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Arbuzov str., 8, Kazan, 420088, Russian
Federation
b
Kazan Institute of Biochemistry and Biophysics, FRC Kazan Scientific Center, Russian Academy of Sciences, Lobachevsky Str., 2/31, Kazan, 420111, Russian
Federation
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of novel 1,2,3-triazolyl nucleoside analogues was synthesized via the CuAAC reaction
of N1-alkynyl uracil, 6-methyluracil, 3,6-dimethyl uracil, thymine and quinazolin-2,4-dione with
protected azido β-D-ribofuranose. The obtained compounds differ in both the nature of the
pyrimidine-2,4-dione fragment and the length of the polymethylene linker connecting it with the
β-D-ribofuranosyl-1,2,3-triazol-4-yl moiety. The 1,2,3-triazolyl nucleoside analogues were
evaluated for their cytotoxicity in vitro.
Available online
Keywords:
2019 Elsevier Ltd. All rights reserved.
Nucleoside analogues
1,2,3-Triazole
Uracil
Click chemistry
The hundred-year study of nucleic acids and, as an apotheosis,
the discovery of their structure in the 1950s, finally made it
possible to understand their fundamental importance for cell
viability in vivo [1]. Almost immediately, the idea appeared that
the nucleoside components of DNA or some of their derivatives
or analogues can affect the biochemical processes in the cells of
bacteria and viruses. In the early 1960s, the first nucleoside
analogues azidothymidine and didanosine which suppressed HIV
DNA replication in monocytes and macrophages in vitro were
synthesized. Over the next 50 years, numerous nucleoside
analogues have been created and used to treat human
immunodeficiency viruses, hepatitis B and C viruses, herpes
simplex virus and cytomegalovirus as well as for the treatment of
various types of cancer [2]. Recently, 1,2,3-triazolyl nucleoside
analogues have been synthesized [3]. In these compounds the
1,2,3-triazole ring plays not only the role of a passive linker
between the nucleic base and the sugar residue; the 1,2,3-triazole
moiety readily associate with biological targets due to the
formation of hydrogen bonds and dipole interactions [4].
[5a]. Moreover, since the 1,2,3-triazole units are not present in
natural products, they are remarkably stable to metabolic
transformations and are therefore utilised in various drugs [5b,c].
The first reported synthesis of 1,2,3-triazole nucleoside
derivatives [6] using Cu alkyne-azide cycloaddition (CuAAC)
was followed by analogous syntheses of modified pyrimidine
nucleosides in which the 1,2,3-triazole ring was attached either
directly to the C5 position of 2'-deoxyuridine [7a,b] or via a
methylene unit [7c,d]. Generation of the 1,2,3-triazole moiety at
the C5’ position of uridine [8a,b] and at the C3’ position of
several nucleosides [8c,d] via CuAAC has been also reported.
The synthesized 1,2,3-triazolyl nucleoside analogues showed
anticancer [7a,8b,8c], antiviral [7b], antitubercular [7c,d] and
antimicrobial [8a,b] activities. In 2012
a series of 1,4-
disubstituted-1,2,3-triazolonucleosides was synthesized for the
first time via CuAAC between 1-deoxy-1-azido-2,3,5-tri-O-
benzoyl-D-ribofuranose and various N1-propargyl pyrimidines
[9a-c]. None of the new compounds were found to inhibit HCV
replication in vitro [9a], but 1,2,3-triazolyl analogs 2a-e (Fig. 1)
appeared to be potent competitive inhibitors of RNase A with
low M inhibition constant values [9c]. Recently, evaluation of
the bioactivity of 5-substituted uridines 1a-e and their
corresponding 1,2,3-triazolyl analogs 2a-e (Fig. 1) revealed their
ability to inhibit the angiogenic activity of hAng in vivo [9d],
The introduction of click chemistry reactions in medicinal
chemistry have drawn attention to 1,2,3-triazole as an attractive
bridge group (linker or spacer), which could connect two
pharmacophores to produce novel bifunctional molecules and at
the same time is resistant to hydrolysis, oxidation or reduction
———
 Corresponding author
E-mail address: kataev57@yandex.ru

2
Tetrahedron Letters
with pyrimidine nucleosides possessing a 1,2,3-triazolyl linker
chromatography. The N-alkylation of uracil and thymine with 3-
halogenoprop-1-ynes in DMF in the presence of K2CO3 also
proceeds non-selectively [11]. To achieve selectivity in the
alkylation, uracil or thymine were first converted to their bis
being more potent than the ones without. The strongest inhibitor
2a in the series of compounds 2a-e completely inhibited the
angiogenic activity of hAng, blocking both the entrance of hAng
into the cell and its ribonucleolytic activity [9d]. Analysis of the
obtained data [9d] revealed that introduction of the 1,2,3-triazole
bridge group between the pyrimidine and ribose moieties
substantially enhances the ability of uridine 1a and its 5-
substituted derivatives 1b-e to inhibit the angiogenic activity of
hAng.
(trimethylsilyl) ethers by treatment with
a
mixture of
hexamethyldisilazane (HMDS) and chlorotrimethylsilane
(TMSCl) [12a,b]. Next, the bis (trimethylsilyl) derivatives were
alkylated by treatment with an appropriate alkyl halide in DMF
or 1,2-dichloroethane [12a,b]. The reactions proceeded
selectively with the formation of exclusively N1 substituted
pyrimidines [12a, b]. We then used this approach to synthesize
N-1-ω-alkyne uracil derivatives 3a,b; 4b,c; 5a,b. However, the
reactions of bis silylated derivatives 7 of the starting pyrimidine-
2,4-diones 3-5 with propargyl bromide, 5-chloro-1-pentyne, and
6-chloro-1-hexyne afforded the target compounds 3a,b; 4b,c;
5a,b in low yields (5-10%). Moreover, the silylation reaction of
quinazolin-2,4-dione 6 under conventional conditions [12a,b]
(quinazolin-2,4-dione 6, HMDS, TMSCl, reflux, 20 h) did not
lead to the corresponding bis silylated derivative. Therefore, N-1-
ω-alkyne derivatives of uracil 3a,b; 4b,c; 5a,b and quinazolin-
2,4-dione 6a,b were synthesized according to the previously
described procedure [13]. Firstly, starting compounds 3–6 were
reacted with an excess of HMDS in toluene in the presence of
H2SO4 at reflux for 8 hours to afford the required bis silylated
derivatives 7 which were then engaged in the alkylation without
purification (Scheme 1). For the alkylation of bis silylated uracil
derivatives 7, we used the ω-iodo-α-alkynes prepared from
commercially available ω-chloro-α-alkynes via the Finkelstein
reaction. Alkyne derivatives of uracil 3a,b; 4b,c; 5a,b and
quinazolin-2,4-dione 6a,b were obtained in 33-71% yield. It
should be noted that this procedure was not suitable for the
synthesis of propargyl derivative of 6-methyluracil 4a. The
reactions led to mixtures of the regioisomeric products N1-(prop-
2-yn-1-yl)- and N-3-(prop-2-yn-1-yl)-6-methyluracils which
could not be separated. Therefore, for the selective N1
propargylation of 6-methyluracil 4, firstly, its monopotassium
salt was prepared by reaction of 4 with KOH in water, followed
by alkylation with propargyl bromide in toluene at reflux, which
afforded the required N1 monopropargylated 6-methyluracil 4a in
34% yield (Scheme 1). Since the preparation of N1 alkyne
derivatives of 3,6-dimethyluracil 8 did not require any selectivity,
the conventional approach [10] was used (Scheme 1). First, the
monosodium salt of uracil derivative 8 was obtained by the
reaction with sodium hydride in DMF, followed by alkylation
with ω-bromo-α-alkynes to afford alkyne derivatives 8a-c in
good yields (72-94%).
Taking into account these findings we decided to study the
effect of the distance between the pyrimidine and D-
ribofuranosyl-1,2,3-triazol-4-yl moieties on the ability to inhibit
the angiogenic activity of hAng. Moreover it would be of interest
to determine the effect of replacing uracil and thymine in 1,2,3-
triazolyl nucleoside analogues 2a,b with 6-methyluracil, 3,6-
dimethyluracil and quinazoline-2,4-dione on the inhibitory
ability. Herein, we report the syntheses of novel 1,2,3-triazolyl
nucleoside analogues in which the above mentioned uracil
derivatives are bonded with the D-ribofuranosyl-1,2,3-triazol-4-
yl moiety by a polymethylene linker of variable length.
Figure. 1. 5-Substituted uridines 1a-e and their 1,2,3-triazolyl
analogues 2a-e which inhibited the angiogenic acivity of hAng in
vivo [9d].
The carbohydrate route focused on the synthesis of 2,3,5-tri-
O-acetyl-β-D-ribofuranosyl azide 9c (Scheme 1). Firstly,
commercially available D-ribose 9 was converted into methyl D-
α/β-ribofuranoside [14] which was immediately acetylated [15]
to afford a mixture of α- and β-anomers of methyl 2,3,5-tri-O-
acetyl-D-ribofuranoside 9a which were separated by silica gel
flash chromatography. Next, the methoxy group of the β-anomer
of sugar 9a was substituted for an acetoxy group by the treatment
of 9a with glacial AcOH and Ac2O in the presence of H2SO4
[14]. The obtained β-D-ribofuranose 1,2,3,5-tetraacetate 9b was
reacted with trimethylsilyl azide (TMSN3) in the presence of tin
tetrachloride [16] to afford the protected azido ribofuranose 9с in
95% yield.
To obtain the target 1,2,3-triazolyl nucleoside analogues, we
used a convergent approach consisting of pyrimidine and
carbohydrate routes (Scheme 1). The first route focused on the
synthesis of uracil derivatives 3a,b; 4a-c; 5a,b; 6a,b bearing ω-
alkyne substituents at the N1 atom. The conventional method for
the alkylation of uracil and its 3-, 5-, 6-methyl derivatives is
conversion to a monosodium salt using sodium hydride in DMF,
followed by the reaction with alkyl halides [10]. The reaction
proceeds non-selectively and affords a mixture of mono- and di-
N-alkylated products which can be separated by column

3
Scheme 1. Convergent synthesis of 1,2,3-triazolyl nucleoside analogues containing uracil, thymine, 6-methyluracil, 3,6-dimethyluracil, and
quinazolin-2,4-dione.

4
Tetrahedron
Finally, CuAAC was utilized to complete the convergent
synthesis and couple the protected azido ribofuranose 9c with
N1-alkynylated uracil derivatives 3a,b; 4a-c; 5a,b; 6a,b, and 8a-c
(Scheme 1). The CuAAC reactions were performed in t-BuOH /
H2O (1:1) using equimolar amounts of the reactants,
CuSO45H2O (10 mol%), and sodium ascorbate (20 mol%).
These conditions were found to be optimum in terms of the
solvent and the amount of catalyst [5a, 6, 7, 8]. 1,2,3-Triazolyl
nucleoside analogues with protected OH groups 3c,d; 4d-f; 5c,d;
6c,d; 8d-f were obtained in good yields (84-94%). The formation
1
of the 1,2,3-triazole ring was indicated by the presence in the H
NMR spectra of 3c,d; 4d-f; 5c,d; 6c,d; 8d-f of the signal for the
triazolyl proton C5”-H within the range 7.50-7.97 ppm. Triazolyl
carbons C4” in the 13C NMR spectra resonated within the range
142.9-147.7 ppm and the signals of triazolyl carbons C5” were
observed within the range 120.1-123.5 ppm. These facts were in
A
6c
1
full accordance with the characteristic features of the H and 13C
NMR spectra of 1,2,3-triazoles previously described in the
literature [7-9, 17]. It is worth noting that all performed CuAAC
reactions provided 1,2,3-triazolyl nucleoside analogues 3c,d; 4d-
f; 5c,d; 6c,d; 8d-f as β-glycosides. Their 1H NMR spectra
displayed the anomeric protons of the acetylated D-ribofuranose
moieties as doublets within the range 5.98-6.13 ppm with vicinal
coupling constants within the range 3.5-4.2 Hz. This strongly
suggested a β-orientation of the glycosidic bond in compounds
3c,d; 4d-f; 5c,d; 6c,d; 8d-f in full accordance with the literature
data [16]. Finally, removal of the O-acetyl protective groups of
3c,d; 4d-f; 5c,d; 6c,d; 8d-f with 0.1N MeONa/MeOH solution
furnished the target 1,2,3-triazolyl nucleoside analogues 3e,f; 4g-
i; 5e,f; 6e,f; 8g-i bearing unprotected OH groups in good yields
(89-98%).
All synthesized 1,2,3-triazolyl nucleoside analogues were
characterized by NMR spectroscopy, mass spectrometry and
elemental analysis (see ESI). Moreover, the structures of 1-
alkynyluracils 8a and 8b, as well as one of the nucleoside
analogues 6c, were confirmed by single crystal X-ray diffraction
analysis. Their structures are shown in Figure 2 and Figure 3.
Figure 3 clearly shows that compound 6c has a β-orientation of
the glycosidic bond. The structures of the independent molecules
A and B differ significantly. In molecule A the quinazoline ring
has a syn-orientation relative to the CH2OC(O)CH3 group at the
C4’ atom, while in the molecule B the quinazoline ring is
oriented in the opposite direction (anti-orientation).
B
Figure 3. X-ray crystal structure of independent molecules A and B
of 1,2,3-triazolyl nucleoside analogue 6c. Hydrogen atoms are not
shown for clarity.
The reason for this is the conformational flexibility of
compound 6c with increasing length of the polymethylene linker
between the nucleobase and the 1,2,3-triazolyl ring. Unlike native
nucleosides, in 1,2,3-triazolyl analogues 3c-f; 4d-i; 5c-f; 6c-f;
8d-i due to the increase in the distance between the nucleobase
and the sugar residue, steric and electronic interactions between
them are completely eliminated. Such changes in structure may
lead to changes in the biological activities. This short
communication begins a series of articles devoted to the
synthesis and study of the biological activity of 1,2,3-triazolyl
nucleoside analogues with a variable linker length between a
pyrimidine-2,4-dione and 1,2,3-triazole moieties.
Novel 1,2,3-triazolyl nucleoside analogues 3c-f, 4d-i, 5c-f, 6c-
f, 8d-i were subjected to in vitro evaluation for cytotoxicity
toward a normal human cell line (Chang liver) and a diploid
human cell strain (WI-38) composed of fibroblasts. All tested
compounds were non-cytotoxic in relation to the normal human
cell lines used in these experiments. The obtained IC50 values
were more than 100 µM. Thus, nucleoside analogs 3c-f, 4d-i, 5c-
f, 6c-f, 8d-i can be considered as a promising scaffold for the
creation of new therapeutic agents.
The study of the ability of nucleoside analogues 3c-f, 4d-i, 5c-
f, 6c-f, 8d-i to inhibit the angiogenic activity of hAng is currently
in progress and will be reported in due course.
In summary, a series of novel 1,2,3-triazolyl nucleoside
analogues was synthesized via the CuAAC reaction of N1-
alkynyl uracil, 6-methyluracil, 3,6-dimethyl uracil, thymine and
quinazolin-2,4-dione with protected azido β-D- ribofuranose. The
compounds obtained differ in both the nature of the pyrimidine-
2,4-dione fragment and the length of the polymethylene linker
connecting it to the β-D-ribofuranosyl-1,2,3-triazol-4-yl moiety.
All novel 1,2,3-triazolyl nucleoside analogues were non-
cytotoxic in relation to a normal human cell line (Chang liver)
and a diploid human cell strain (WI-38).
8a
8b
Figure 2. X-ray crystal structures of N1-alkynylated uracil
derivatives 8a and 8b.
Conflict of interests:
The authors declare they have no conflict of interests.

5
K.; Kantsadi, A.L.; Skamnaki, V.T.; Zographos, S.E.;
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Acknowledgments
This work was supported by the Russian Science Foundation
(grant no. 19-13-00003). The authors from Arbuzov Institute of
Organic and Physical Chemistry, FRC Kazan Scientific Center,
RAS are grateful to the Assigned Spectral-Analytical Center of
FRC Kazan Scientific Center of RAS for technical assistance in
research.
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Conflict of interest
The authors declare they have no conflict of interests.
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Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
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…
. These data include the description of syntheses,
characterization of compounds, and crystallographic data for the
structures in this article.
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Vasseur, J. J.; Secrist, J. A.; Lazrek, H. B. ARKIVOC. 2012, (viii),
76-89; (b) Amant, A. H. St.; Bean, L. A.; Guthrie, J. P.; Hudson,
R. H. E. Org. Biomol. Chem. 2012, 10, 6521-6525; (c)
Parmenopoulou, V.; Chatzileontiadou, D.S.M.; Manta, M.;
Bougiatioti, S.; Maragozidis, P.; Gkaragkouni, D.-N.; Kaffesaki,

6
Tetrahedron
 A series of novel 1,2,3-triazolyl
pyrimidine nucleoside analogues was
synthesized
 The pyrimidine moiety was
connected to a triazolyl ring by a
linker of variable length
 The obtained compounds differ in the
nature of pyrimidine moiety and the
linker length
 All obtained compounds were non-
cytotoxic in relation to the normal
human cell lines