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Nucleoside analogs have acquired an important role as therapeutic agents in the field of
chemotherapy on account of their extensive biological activities. Introduction of a triazole ring into
nucleosides to improve their bioactivity for antitumor or antiviral applications has become wide spread in
drug design practices.1,2 The 1,2,3-triazole unit may be considered as a surrogate of the amide group
because these moieties have a similar H-bond acceptor capacity, a similar distance between
substituents, and a similar dipolar properties.
Scheme 1. Synthesis of mono- and disubstituted furo[2,3-d]pyrimidine
derivatives with 1,4-disubstituted 1,2,3,- triazoles.
Scheme 3. Hybrids of purines, pseudopurines and 1,2,3-triazoles.
Fig.1. a) Molecular structure of compound 3a; b) Part of the crystal structure of the
compound 3a, which shows a one-dimensional chain created two CH ••• O and one CH
••• N hydrogen bond; c) crystal packing of 3a , shown along the crystallographic axis b,
which shows the two-dimensional ribbon formed by hydrogen bonds and hydrophobic
layers between them.
a)
b)
c)
The target regioselective 1,4-disubstituted 1,2,3-triazole
derivatives were prepared by the microwave assisted Cu-
catalyzed alkyne-azide cycloaddition (CuAAC). Linear alkyl
chain, substituted aromatic moiety and cyclopropyl ring
were introduced as alkynyl substituents at C-5 and C-6 of
furo[2,3-d]pyrimidine core using modified palladium
catalyzed cross-coupling Sonogashira reaction.
Compd. X3 X7 Y R4 Yield (%) ClogPa
6 N NH - - 15 0.97
7 N N - - 50 0.97
8 N C - - 92 1.74
9 N C Br - 70 2.56
10 CH N - - 36 0.83
11 CH NH - - 67 0.83
12 N N - 64 2.68
11 N N - 36 8.68
12 N N - 26 3.44
13 N N - 34 1.68
14 N C - 61 3.84
15 N C - 74 3.44
OO OH
Compd. X3 X7 Y R4 Yield (%) ClogPa
16 N C - 49 3.44
17 N C - 41 4.20
18 N C - 55 1.68
19 N C Br 34 4.27
20 N C Br 35 5.00
21 N C Br 37 3.27
22 CH N - 80 3.29
23 CH N - 74 1.53
24 N N - 38 2.14
25 CH N - 51 2.93
26 CH N - 72 2.53
27 CH N - 80 3.29
28 CH N - 66 1.53
CF3
a Values of n-octanol/water partition coefficients logP were calculated using ChemAxon algorithm (MarvinView Ver. 6.2.2.).
N
X3 N
X7
Cl Y
propargyl bromide
K2CO3, DMF, Ar,
60 oC, 24 h
N
X3 N
N
Cl
N
X3 N
X7
Cl Y
N3R4, Cu (0), 1M CuSO4,
t-BuOH:H2O=1:1, DMF
MW, 300 W, 80OC
N3R4,Cu (0), 1M CuSO4,
t-BuOH:H2O=1:1, DMF
MW, 300 W, 80OC
X3 N
N
Cl
X3 N
X7
Cl Y
N N
N
NN
N
R4'
R4'
4, 9
5-8 10-21
22-28
Synthesis
Scheme 2. Synthesis of N-1 and N-1, N-3-subsituted
pyrimidine derivatives with 1,2,3-triazoles.
1,2,3-TRIAZOLE PHARMACOPHORE-BASED DERIVATIVES OF PURINE
BIOISOSTERES AND PYRIMIDINES
T. Gregorić1, A. Bistrović1, A. Tomljenović Paravić2, M. Sedić2, S. Kraljević Pavelić2, V. Stepanić3, T. Gazivoda-Kraljević1, S. Raić-Malić1
1Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, Marulićev trg 19, 10000 Zagreb, Croatia
2Department of Biotechnology, University of Rijeka, HR-51000 Rijeka, Croatia 3Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia
Financial support from the Croatian Science
Foundation under the project No. 5596.
Compounds 4a-4d and 5a-5d were
evaluated for their cytostatic activities
against human malignant tumor cell
lines: lung carcinoma (A549),
hepatocellular carcinoma (HepG2),
pancreatic carcinoma (CFPAC-1)
cervical carcinoma (HeLa), colorectal
adenocarcinoma (SW620), pancreatic
carcinoma (MiaPaCa-2) as well as
normal mouse embryonic fibroblast
(3T3) cell lines. Compounds 4c, 5a,
5c and 5d showed marked cytostatic
activities. Cytostatic evaluations for
other synthesized compounds are
currently underway.
IC50: 50% inhibitory concentration or concentration of the compound required to inhibit tumor cell
proliferation by 50%. The cell growth rate was evaluated by performing the MTT assay.
[1] S. Raić-Malić, A. Meščić, Curr. Med. Chem. 2015, 22, 1462
[2] S. Krištafor, A. Bistrović, J. Plavec, D. Makuc, T. Martinović, S. Kraljević Pavelić, S. Raić-Malić,
Tetrahedron Lett. 2015, 56, 1222
References
Acknowledgement
12
Table 1. Antitumor activitie of compounds 4a-4d
and 5a-5d.
Introduction
Fig.3 Comparison of binding energy and binding site between known inhibitor tomudex and compounds
5a and 4c in the active site of the enzyme thymidylate synthase and their antitumor activities.
IC50 (µM)
Cell lines
Cmpd A549 Hep-G2 CFPAC-1 HeLa SW620 3T3
5c 5.33 7.11 4.53 1.64 7.86 0.59
4c 80.68 7.66 5.51 8.42 9.87 1.16
E5a= -10,02 kcal E4c= -8,39 kcal Eref= -11,19 kcal
IC50 (µM)
Cmpd. A549 Hep-G2 CFPAC-1 HeLa SW620 3T3
4a 40.93 19.14 39.54 33.28 >100 6.7
4b 64 68.93 >100 72.9 >100 50.79
4c 80.68 7.66 5.51 8.42 9.87 1.16
4d 70.27 40.75 62.74 56.36 89.58 <0.01
5a 25.49 4.47 6.87 12.58 9.82 0.07
5b 95.79 42,.73 >100 >100 >100 4.3
5c 5.33 7.11 4.53 1.64 7.86 0.59
5d 7.41 3.62 5.92 6.13 5.63 0.37
Molecular docking of compounds 4a-4d and
5a-5d in the active site of thymidilate
synthase was performed and compared with
known inhibitors. It was found that
interactions with dUMP is of great importance
for inhibitory effect of compounds. Naimly,
pyrimidine ring of synthesized compounds is
responsible for the interaction with dUMP.
F
CF3
FOO OH
OO OH
OO OH
CF3
Cl
Cl
CF3
F
FCF3
OO OH
FCF3
OO OH
F
HN
NH
O
O
I
HN
N
I
O
O
HN
N
O
O
N N
N R1
I
N
NO
N N
N R1
N
N
O
N N
N R1
O
R2
NaHDMFrt, 24 hpropargyl bromide
N3R1, Cu(0), 1M CuSO4
DMF, t-BuOH:H2O=1:1
300W, 80 oC, MW
R1=
Cl
F
R2 =
CuI
, (PPH 3
) 4Pd,
R 2
N,N
-DIP
EA, t
olue
ne
80 o C
, 24
hCl
C5H11
Br
C6H13
OR2
R2
1
2
3
a
b
c
d
e
1a-1e2a-2e3a-3e
1'a-1'e2'a-2'e3'a-3'e
HN
NH
O
O
BrN
N
O
O
BrHN
N
O
O
Br
NaH, DMFrt., 24 h
HN
N
O
O
Br
N N
N R1
N
N
O
O
Br
N N
N R2
N
N N
R2
R1, Cu (0), 1M CuSO4
DMF, t-BuOH: H2O=1:1
MW, 300W, 80 oC
N3
N3
N3
N3
F
Cl
Cl
F
Cl
R2 =
O
N3
O
N3
N3
N3
Cl
Cl
F
Cl
R1 =
R2 , DMF
CuSO4
Na-ascorbate
rt
4a-4d 5a-5d
4 5
propargyl bromide
a
b
c
d
a
b
c
dN N
N
N
Cl
N
N
N
CF3
5c
Tomudex
4c