Synthesis and cytotoxic profile of glycosyl-triazole linked to 1,2,4-oxadiazole moiety at C-5 through a straight-chain carbon and oxygen atoms

Article abstract of DOI:10.1016/j.ejmech.2009.03.002

The convergent synthesis of an unusual (but simple) class of compounds 5a-g has been achieved by the copper-catalyzed [3 + 2] cycloaddition reaction of 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl azide 4 with propynyl 3-[3-(aryl)-1,2,4-oxadiazol-5-yl] propi

Full text of DOI:10.1016/j.ejmech.2009.03.002

European Journal of Medicinal Chemistry 44 (2009) 3571–3576
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and cytotoxic profile of glycosyl–triazole linked to 1,2,4-oxadiazole
moiety at C-5 through a straight-chain carbon and oxygen atoms
a
,
,
*
Janaına V. dos Anjos b, Ricardo A.W. Neves Filho a, Silene C. do Nascimento c, Rajendra M. Srivastava a
,
´
Sebastia˜o J. de Melo c, Denis Sinou b
a
´
Departamento de Qu´ımica Fundamental, Universidade Federal de Pernambuco, Cidade Universitaria, Avenida Professor Luis Freire, 50740-540 Recife, PE, Brazil
b Laboratoire de Synthe`se Asyme´trique, UMR 5246-ICBMS, CPE Lyon, Universite´ de Lyon, 43 boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
c
´
ˆ
Departamento de Antibio´ticos, Universidade Federal de Pernambuco, Cidade Universitaria, Avenida Professor Mozart Rego, 50670-901 Recife, PE, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The convergent synthesis of an unusual (but simple) class of compounds 5a–g has been achieved by the
copper-catalyzed [3 þ 2] cycloaddition reaction of 2,3,4,6-tetra-O-acetyl- -glucopyranosyl azide 4 with
Received 15 September 2008
Received in revised form
27 February 2009
Accepted 6 March 2009
Available online 19 March 2009
b-D
propynyl 3-[3-(aryl)-1,2,4-oxadiazol-5-yl] propionates 3a–g. The formerly known azide 4 has been
prepared according to the literature procedure; however, the synthesis of esters 3a–g is being reported
for the first time. The infrared as well as 1H NMR spectra of all new products are in agreement with their
proposed structures. By carrying out the nOe experiment of one of the final compounds 5a, we have been
able to establish that only the 1,4-regioisomers have been formed in the cycloaddition reaction. All final
products presented weak cytotoxic activity, but 5e and 5g had somewhat better behaviour showing 22–
25% cell growth inhibition against two cell strains: NCI-H292 (lung carcinoma) and HEp-2 (larynx
carcinoma).
Keywords:
1,2,4-Oxadiazoles
1,2,3-Triazoles
Neoglycoconjugates
Click chemistry
Cytotoxic activity
Ó 2009 Elsevier Masson SAS. All rights reserved.
1. Introduction
peptide chemistry and in the development of peptidomimetics [18–
21]. Some compounds containing this ring in their structures have
The great cancer incidence worldwide increases the search for
new, safer and efficient anticancer agents, aiming the prevention or
the cure of this illness. In spite of all the efforts to combat cancer,
the success of the treatment of certain types of tumors has shown
little progress due their aggressiveness and to the mechanisms of
malignant cell metastasis. In addition, anticancer agents show
toxicity not only to cancer cells, but also to the non-neoplastic cells,
showing no selectivity to the target and thus limiting the treatment
[1]. Therefore, it would be interesting to discover more potent
anticancer drugs for treating such a horrible disease.
Since our group has been involved in synthesizing and testing
the biological activities of 1,2,4-oxadiazoles for a long time [2–9]
and the recent findings that compounds carrying this heterocyclic
ring possess antineoplastic properties [10,11] led us to conceptu-
alize the incorporation of this heterocycle to a triazole nucleus
displayed, for example, anti-inflammatory [22], antimicrobial [23],
antiviral [24], diuretic [25], anti-helmintic [26,27] and cytotoxic
[11] activities.
1,2,3-Triazoles are also known to have antitumor properties
[28]. Besides, they also possess other activities like anti-HIV [29,30],
cytostatic [31] and anti-bactericidal [32] and can also act as GABA
[33] and glycosidase inhibitors [34]. This heterocycle has been
compared to amide bonds and may serve as bioisosters of peptide
bonds due its electronic features [35,36].
Finally, the purpose of the glycosyl residue is that glycosides are
relatively more water-soluble than their aglycones, and attaching
this moiety into the molecule enhances its hydrophilicity, which in
turn influences pharmacokinetic behaviour. The increased hydro-
philicity of the molecule helps the membrane transport. Certain
substances enter the cell because of the solubility within the
membranal framework [37].
which in turn contains a b-glucopyranosyl function at N-1. In fact,
the 1,2,4-oxadiazole nucleus is present in many biologically active
compounds [12–16], and is considered bioisoster of amide and
ester functions [17]. Further, this heterocycle has found use in
Considering the advantages of three heterocyclic rings con-
tained in one molecule, we decided to synthesize seven such
compounds 5a–g in a convergent fashion. First, we prepared the
prop-2-ynyl esters of 3-[3-(aryl)-1,2,4-oxadiazol-5-yl]propionic
acids 2a–g starting from arylamidoximes 1a–g and succinic anhy-
dride followed by the esterification of the acid using propargyl
* Corresponding author. Tel.: þ55 81 2126 8440; fax: þ55 81 2126 8442.
E-mail address: rms@ufpe.br (R.M. Srivastava).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.03.002

3572
J.V. dos Anjos et al. / European Journal of Medicinal Chemistry 44 (2009) 3571–3576
N
N
O
O
N
OH
ii
i
O
OH
N
N
R
R
R
NH2
O
O
1a-g
2a-g
3a-g
a: R = H
e: R = p-Br
f: R = p-Cl
g: R = p-NO2
b: R = o-CH3
c:R = m-CH3
d:R = p-CH3
Scheme 1. Synthesis of 3-(1,2,4-oxadiazol-5-yl)propionic acids prop-2-ynyl esters 3a–g. Reagents and conditions: (i) Succinic anhydride, 120–130 ꢀC, neat, 3 h; (ii) Propargyl
alcohol, H2SO4, 60 ꢀC, 12 h.
alcohol to furnish 3a–g (Scheme 1). Second, tetra-O-acetyl gluco-
sylazide was prepared. Cycloaddition of azide to the acetylenic
linkage easily afforded 5a–g. These triheterocyclic compounds have
not been found in the literature, and their complete synthesis is
described in this paper. Further, they presented interesting cyto-
toxic activity.
above-mentioned protons. With this experiment, we feel that all
compounds were obtained as 1,4-regiomers.
In order to get more insight about the stable conformation of 5a,
we decided to carry out the ab initio molecular orbital calculations
of this compound employing HF/6-31G(d) method [45]. Examining
the geometry optimization of different possible conformations of
5a, we found that the lowest energy for conformer A is close to the
one shown in Fig. 1. The torsion angle between H-1 of the pyranosyl
ring and H-5 of the triazole moiety was 24.70 degrees and the
distance between these two protons in question was 2.53 Å, suit-
able for the spatial interaction between them. These data corrob-
orate with our nOe experiment. The dihedral angle cited above may
vary a little bit in the NMR experiment due to the solvent used for
obtaining the spectrum, but the arrangement of the protons under
consideration have reasonably the correct conformational
arrangement for the nuclear Overhauser effect.
1.1. Chemistry
The first step was the preparation of the 1,2,4-oxadiazoles
containing a terminal acetylenic function, which involved the
condensation of benzamidoximes 1a–g [38] with succinic anhy-
dride at 120–130 ꢀC, under solvent-free conditions, to afford 3-[3-
(aryl)-1,2,4-oxadiazol-5-yl]propionic acids 2a–g in excellent yields
[39]. Then, these acids were esterified with propargyl alcohol to
furnish the unknown esters 3a–g in 74–95% yields (Scheme 1).
Compounds 3a–g were then submitted to the copper-catalyzed
1.2. Biology
[3 þ 2] cycloaddition with the 2,3,4,6-tetra-O-acetyl-
b-D-glucopyr-
anosyl azide 4 [40] using Cu(OAc)2 and sodium ascorbate as catalyst
in 1:1 dichloromethane:water [41,42] to give the products 5a–g in
good yields (Scheme 2 and Table 1).
We evaluated the cytotoxic profile of 3a and 5a–g against two
cell strains: NCI-H292 (lung carcinoma) and HEp-2 (larynx carci-
noma). The cytotoxic assays were based on the 3-(4,5-dime-
thylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method
[46–48]. Drugs 3a and 5a–g were tested in the following concen-
In all cases, only 1,4-regioisomers were obtained, which is in
agreement with earlier literature for this kind of copper-catalyzed
dipolar cycloaddition [43,44]. Only one singlet was observed in the
trations: 1.25; 2.5; 5.0; 6.25; 10.0; 12.5; 25.0 and 50.0 mg/mL.
1H NMR spectra for the triazole ring (
d
8.47–8.49 ppm), which can
Compound 3a presented extremely low inhibitory effect. However,
5a–g showed 9–25% cell growth inhibition (Table 2). The
percentage of inhibition is low except in 5e and 5g, but it does
demonstrate that transformation of the triple bond of 3a–g into
a triazole moiety connected to glucosyl group does enhance the
cytotoxic activity. In conclusion, compounds with electron with-
drawing groups in the phenyl ring like bromine atom in 5e and
nitro group in 5g presented the best cell growth inhibition
percentages (more than 20% in both cell strains). Although this
inhibition is still not sufficient, we feel that further research is
needed to improve the inhibitory property. This could be done by
putting one or more electron-attracting group(s) in the phenyl ring.
Compounds containing the 1,2,4-oxadiazole ring have already
been reported as apoptosis inducers in cancer cell strains [11].
These substances act by activating a group of proteases, the caspase
family. Once activated, the proteolytic degradation process occurs,
leading to the programmed cell death [49]. Apoptosis inducers can
be attributed to the proton in the C-5 position of the triazole ring. In
fact, there are two possible regioisomers, which are shown in Fig. 1.
In the first case (A), the triazole ring could adopt various confor-
mations, where one of them might have the arrangement as indi-
cated in A. In this arrangement, the H-5 of triazole and H-1 of the
pyranosyl function are facing each other. In the other regioisomer
(B), no matter how the conformations are arranged, the above-cited
protons cannot acquire face-to-face arrangement. To verify this, the
differential spectrum, using the nOe technique, clearly demon-
strated the spatial effect between the two protons in question as
shown in 5a. This observation strongly supports the existence of
1,4-regioisomer and eliminates 1,5-regioisomer B.
Fig. 2 shows the 1H NMR spectrum including the nOe experi-
ment. As we can see, the nOe differential spectrum of 5a indicates
that the irradiation of the anomeric proton increases the H-5 signal
of triazole by 6.1%, showing the spatial interaction between the
OAc
N
O
Ar
O
N
N
AcO
N
O
N
AcO
3a-g
4
+
OAc
O
5a-g
Scheme 2. Synthesis of O-{[1-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-1H-1,2,3-triazol-4-yl]methyl}-3-[3-aryl-1,2,4-oxadiazol-5-yl] propanoates (5a–g). Reagents and condi-
tions: (i) Copper acetate (5 mol%), Sodium ascorbate (15 mol%), CH2Cl2:H2O, rt, 20 h.

J.V. dos Anjos et al. / European Journal of Medicinal Chemistry 44 (2009) 3571–3576
3573
internal standard at
oxadiazoles 2a–g [39] and 2,3,4,6-tetra-O-acetyl-
d
¼ 77.23 ppm. Benzamidoximes 1a–g [38],
-D-glucopyr-
b
Table 1
anosyl azide (4) [40] were prepared according to known litera-
ture procedures.
Synthesis of O-{[1-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-1H-1,2,3-triazol-4-
yl]methyl}-3-[3-aryl-1,2,4-oxadiazol-5-yl] propanoates (5a–g).
Entry
Product
Aryl
Yield (%)a
3.1.1. Synthesis of 3-[3-(aryl)-1,2,4-oxadiazol-5-yl]propionic acids
prop-2-ynyl esters (3a–g)
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
Phenyl
o-Tolyl
m-Tolyl
p-Tolyl
p-Bromophenyl
p-Chlorophenyl
p-Nitrophenyl
83
77
74
84
73
66
69
An appropriate carboxylic acid 2a–g, (2.3 mmol), propargyl
alcohol (6.9 mmol) and 5 drops of sulphuric acid were taken in
a round-bottom flask and the mixture was allowed to react for 12 h
at 60 ꢀC. The progress of the reaction was verified by TLC. The
contents were allowed to cool to room temperature and then
extracted with ethyl acetate (3 ꢁ 20 mL). The combined organic
phase was washed with a saturated NaHCO3 solution, brine and
water. The organic layer was dried over Na2SO4 and evaporated
under reduced pressure to afford brown oil. The crude product was
purified by column chromatography using 7:3 cyclohexane:ethyl
acetate as eluant. The resulting crystals were recrystallized from
methylene chloride:cyclohexane.
5g
a
Isolated yields.
be selective cancer cell killers, once apoptosis is a consequence of
various precise genetic events [50]. We believe that compounds 5e
and 5g, for example, could also act by inducing the apoptotic
process in the cancer cell strains.
2. Conclusion
3-(3-Phenyl-1,2,4-oxadiazol-5-yl)propionic acid prop-2-ynyl
ester (3a) prepared from 2a (0.5 g); 95% (0.56 g); recrystallized
from methylene chloride:cyclohexane (1:3, v/v); colorless crystals;
m.p.: 66–67 ꢀC; Rf 0.61 (EtOAc/cyclohexane 3:7); IR nmax (KBr):
In brief, we have accomplished the synthesis of seven distinctive
heterocyclic compounds 5a–g containing three such rings,
a glycosyl function, a triazole moiety and an 1,2,4-oxadiazole ring.
The triazole ring has substituents at N-1 and C-4 atoms. The
molecular orbital calculations using ab initio method (HF/6-31G(d))
provided the optimized conformation of 5a, where H-1 of the
carbohydrate portion and H-5 of the triazole ring are facing each
other. All seven compounds 5a–g were tested against two neoplastic
cell strains, among them 5e and 5g presented better inhibitory
properties.
1185, 1328, 1590, 1752, 2920, 3253 cmꢂ1; 1H NMR (CDCl3):
d 2.50 (t,
1H, J 2.5 Hz, C^CH), 3.00 (t, 2H, J 7.3 Hz, CH2), 3.27 (t, 2H, J 7.3 Hz,
CH2), 4.26 (d, 2H, J 2.5 Hz, CH2O), 7.43–7.50 (m, 3H, Harom), 8.04–
8.08 (m, 2H, Harom); 13C NMR (CDCl3):
d 21.8, 30.1, 52.3, 75.1, 77.2,
126.6, 127.3, 128.7, 131.1, 168.1, 170.5, 177.9. Anal. Calcd. for
C14H12N2O3 (C,H,N): C, 65.62%; H, 4.72%; N: 10.93%. Found: C,
65.81%; H, 4.49%; N, 11.33%.
3-[3-(2-Tolyl)-1,2,4-oxadiazol-5-yl]propionic acid prop-2-ynyl
ester (3b). Prepared from 2b (0.53 g); 84% (0.52 g); recrystallized
from methylene chloride:cyclohexane (1:3, v/v); colorless crystals;
m.p.: 50–51 ꢀC; Rf 0.72 (EtOAc/cyclohexane 3:7); IR nmax (KBr): 1161,
3. Experimental protocols
1344, 1590, 1751, 2948, 3262 cmꢂ1; 1H NMR (CDCl3):
d 2.49 (t, 1H, J
3.1. General methods
2.6 Hz, C^CH), 2.61 (s, 3H, CH3), 2.99 (t, 2H, J 7.3 Hz, CH2), 3.28 (t,
2H, J 7.3 Hz, CH2), 4.73 (d, 2H, J 2.6 Hz, CH2O), 7.26–7.40 (m, 3H,
All commercially available reagents were used without any
further purification. All reactions were monitored by TLC anal-
ysis (TLC plates GF254 E. Merck). Melting points were determined
on a Bu¨ chi apparatus and are uncorrected. Column chromatog-
raphy was performed on Silica Gel 60 (70–230 mesh, E. Merck).
Optical rotations were recorded using a JASCO DIP 370 polar-
imeter. NMR spectra were recorded with a Varian Unity Plus
300 MHz spectrometer and referenced as following: 1H
Harom); 7.96 (d, 1H, J 7.5 Hz, Harom); 13C NMR (CDCl3):
d 21.7, 22.0,
30.1, 52.3, 75.1, 77.2, 125.8, 129.9, 130.4, 131.2, 138.1, 168.7, 170.5,
176.9. Anal. Calcd. for C15H14N2O3 (C,H,N): C, 66.66%; H, 5.22%, N,
10.36%. Found: C, 66.74%; H, 5.20%; N, 10.57%.
3-[3-(3-Tolyl)-1,2,4-oxadiazol-5-yl]propionic acid prop-2-ynyl
ester (3c). Prepared from 2c (0.53 g); 79% (0.49 g); recrystallized
from methylene chloride:cyclohexane (1:3, v/v); colorless crystals;
m.p.: 44–45 ꢀC; Rf 0.67 (EtOAc/cyclohexane 3:7); IR nmax (KBr):
(300 MHz), internal SiMe4 at
d
¼ 0.00 ppm, 13C (75 MHz),
OAc
OAc
6
2
4
N
O
3
O
5
N
N
6
2
4
AcO
AcO
3
1
O
N
5
1
N
4
N
AcO
AcO
2
1
N
H
OAc
3
O
1
4
N
5
2
OAc
H
3
5
H
O
O
H
nOe
O
O
5a
Hypothetic 1,5-regioisomer
N
(1,4-regioisomer)
A
B
N
Fig. 1. Possible isomers formed in the copper-catalyzed [3 þ 2] cycloaddition reaction between 4 and 3a. The 1,4-regioisomer (left) was the only isolated product. No detection of
the 1,5-regioisomer was found in the 1H NMR and nOe difference spectra.

3574
J.V. dos Anjos et al. / European Journal of Medicinal Chemistry 44 (2009) 3571–3576
Fig. 2. 1H NMR and nOe diff spectra of the compound 5a, O-{[1-(2,3,4,6-tetra-O-acetyl-
propanoate in DMSOd6
b-D-glucopyranosyl)-1H-1,2,3-triazol-4-yl]methyl}-3-[3-phenyl-1,2,4-oxadiazol-5-yl]
.
1173, 1343, 1590, 1752, 2930, 3243 cmꢂ1; 1H NMR (CDCl3):
d
2.41 (s,
3-[3-(4-Bromophenyl)-1,2,4-oxadiazol-5-yl]propionic acid prop-
3H, CH3), 2.50 (t, 1H, J 2.3 Hz, C^CH), 3.00 (t, 2H, J 7.3 Hz, CH2), 3.27
(t, 2H, J 7.3 Hz, CH2), 4.73 (d, 2H, J 2.3 Hz, CH2O); 7.29 (d, 1H, J 7.5 Hz,
2-ynyl ester (3e). Prepared from 2e (0.68 g); 93% (0.71 g); recrystal-
lized from methylene chloride:cyclohexane (1:2, v/v); colorless
crystals; m.p.: 61–62 ꢀC; Rf 0.67 (EtOAc/cyclohexane 3:7); IR nmax
Harom), 7.35 (d, 1H, J 7.5 Hz, Harom); 7.86 (d, 2H, J 9.3 Hz, Harom); 13
C
NMR (CDCl3):
d
21.2, 21.8, 30.1, 52.4, 75.2, 77.2, 124.4, 126.4, 127.8,
(KBr): 1186,1363,1591,1744, 2941, 3252 cmꢂ1; 1H NMR (CDCl3):
d 2.50
128.6, 131.9, 138.5, 168.3, 170.5, 177.9. Anal. Calcd. for C15H14N2O3
(C,H,N): C, 66.66%; H, 5.22%, N, 10.36%. Found: C, 66.73%; H, 5.09%;
N, 10.67%.
(t, 1H, J 2.5 Hz, C^CH), 3.00 (t, 2H, J 7.0 Hz, CH2), 3.28 (t, 2H, J 7.0 Hz,
CH2), 4.74 (d, 2H, J 2.5 Hz, CH2O), 7.60 (d, 2H, J 8.7 Hz, Harom, AA0BB0
system), 7.92 (d, 2H, J 8.7 Hz, Harom, AA0BB0 system); 13C NMR (CDCl3):
3-[3-(4-Tolyl)-1,2,4-oxadiazol-5-yl] propionic acid prop-2-ynyl
ester (3d). Prepared from 2d (0.53 g); 74% (0.46 g); recrystallized
from methylene chloride:cyclohexane (1:3, v/v); colorless crystals;
m.p.: 43–44 ꢀC; Rf 0.64 (EtOAc/cyclohexane 3:7); IR nmax (KBr):
d 21.8, 30.1, 52.4, 75.2, 77.1,125.5,125.6,128.8,132.0,167.5,170.5,178.2;
Anal. Calcd. for C14H11BrN2O3 (C,H,N): C, 50.17%; H, 3.31%; N, 8.36%.
Found: C, 50.09%; H, 3.18%; N, 8.47%.
3-[3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl]propionic
acid
1173, 1349, 1586, 1745, 2920, 3252 cmꢂ1; 1H NMR (CDCl3):
d
2.40 (s,
prop-2-ynyl ester (3f). Prepared from 2f (0.58 g); 93% (0.62 g);
recrystallized from methylene chloride:cyclohexane (1:2, v/v);
colorless crystals; m.p.: 49–50 ꢀC; Rf 0.67 (EtOAc/cyclohexane 3:7);
3H, CH3), 2.49 (t, 1H, J 2.4 Hz, C^CH), 2.99 (t, 2H, J 7.3 Hz, CH2), 3.26
(t, 2H, J 7.3 Hz, CH2), 4.73 (d, 2H, J 2.4 Hz, CH2O), 7.27 (d, 2H, J 8.4 Hz,
Harom, AA0BB0 system), 7.94 (d, 2H, J 8.4 Hz, Harom, AA0BB0 system);
IR nmax (KBr): 1186, 1357, 1586, 1743, 2934, 3243 cmꢂ1 1H NMR
;
13C NMR (CDCl3):
d
21.5, 21.8, 30.1, 52.4, 75.1, 77.2, 123.7, 127.2,
(CDCl3): d 2.49 (t,1H, J 2.4 Hz, C^CH), 3.00 (t, 2H, J 7.2 Hz, CH2), 3.28
129.4, 141.4, 168.2, 170.5, 177.7. Anal. Calcd. for C15H14N2O3 (C,H,N):
C, 66.66%; H, 5.22%, N, 10.36%. Found: C, 66.67%; H, 5.15%; N, 10.65%.
(t, 2H, J 7.2 Hz, CH2), 4.74 (d, 2H, J 2.4 Hz, CH2O), 7.45 (d, 2H, J 8.7 Hz,
Harom, AA0BB0 system), 8.00 (d, 2H, J 8.4 Hz, Harom, AA0BB0 system);
13C NMR (CDCl3):
d 21.8, 30.1, 52.5, 75.2, 125.1, 128.7, 129.1, 137.3,
167.4, 170.5, 178.2. Anal. Calcd. for C14H11ClN2O3 (C,H,N): C, 57.84%;
H, 3.81%; N: 9.64%. Found: C, 57.59%; H, 3.73%; N, 9.65%.
Table 2
3-[3-(4-Nitrophenyl)-1,2,4-oxadiazol-5-yl]propionic acid prop-
2-ynyl ester (3g). Prepared from 2g (0.6 g); 87% (0.6 g); recrystal-
lized from methylene chloride:cyclohexane (1:3, v/v); yellow
crystals; m.p.: 82–84 ꢀC; Rf 0.55 (EtOAc/cyclohexane 3:7); IR nmax
Neoplastic cell growth inhibition and IC50 of compounds 3a and 5a–g.
Compound
Cell Growth Inhibition (%)
IC50
(mg/mL)
NCI-H292
HEp-2
NCI-H292
HEp-2
(KBr): 1211, 1352, 1580, 1745, 2940, 3272 cmꢂ1 1H NMR (CDCl3):
;
3a
5a
5b
5c
5d
5e
5f
3.6
10.4
9.2
–
>50.0
>50.0
>50.0
>50.0
>50.0
>50.0
>50.0
>50.0
4.5
6.7
7.5
1.2
24.1
4.9
22.4
d
2.49 (t, 1H, J 2.4 Hz, C^CH), 3.01 (t, 2H, J 7.2 Hz, CH2), 3.30 (t, 2H, J
7.2 Hz, CH2), 4.73 (d, 2H, J 2.4 Hz, CH2O), 8.22 (d, 2H, J 9.0 Hz, Harom,
9.5
AA0BB0 system), 8.30 (d, 2H, J 9.0 Hz, Harom, AA0BB0 system), 13C NMR
10.2
24.8
15.0
23.1
(CDCl3): d 21.8, 30.0, 52.5, 75.2, 77.1, 124.0, 128.3, 132.5, 149.3, 166.7,
170.4, 179.0. Anal. Calcd. for C14H11N3O5 (C,H,N): C, 55.82%; H,
3.68%; N, 13.95%. Found: C, 55.86%; H, 3.70%; N, 13.93%.
5g

J.V. dos Anjos et al. / European Journal of Medicinal Chemistry 44 (2009) 3571–3576
3575
3.1.2. Synthesis of glycosyl–triazole linked 1,2,4-oxadiazoles
(5a–g)
Harom), 8.49 (s, 1H, Htriazole); 13C NMR (DMSOd6):
d
19.9, 20.3, 20.4,
20.9, 21.6, 29.7, 57.4, 61.8, 67.5, 70.1, 72.1, 73.3, 83.8, 123.9, 124.2,
126.1,127.4,129.2,132.2,138.7,142.5, 167.5,168.5,169.4,169.6, 170.1,
171.1, 179.2. Anal. Calcd. for C29H33N5O12 (C,H,N): C, 54.12%; H,
5.17%; N, 10.88%. Found: C, 53.83%; H, 5.12%; N, 10.92%.
O-{[1-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-1H-1,2,3-tri-
azol-4-yl]methyl}-3-[3-(4-tolyl)-1,2,4-oxadiazol-5-yl]propanoate
A solution of sodium ascorbate (14 mg, 0.072 mmol, 15 mol%)
and copper acetate (5 mg, 0.024 mmol, 5 mol%) in water (3.0 mL)
was added individually to a mixture of the corresponding acety-
lenic oxadiazole 3a–g (0.53 mmol) and the azidosugar 4 (0.18 g,
0.48 mmol) in CH2Cl2 (3.0 mL). The contents were stirred for 20 h at
room temperature. The progress of the reaction was monitored by
TLC. The organic layer was separated and the aqueous phase was
extracted with CH2Cl2 (2 ꢁ 10 mL) followed by washing the organic
layer with aqueous NaHCO3, saturated brine solution and water.
The combined organic layers were dried over anhydrous Na2SO4,
filtered and the solvent evaporated under reduced pressure. The
resulting yellow oil was chromatographed over silica gel using 1:1
cyclohexane:EtOAc as eluant, which after work-up furnished
colorless crystals. The final product was recrystallized from meth-
ylene chloride:cyclohexane.
(5d). Prepared from 3d (0.14 g); 84% (0.26 g); recrystallized from
methylene chloride:cyclohexane (1:2, v/v); colorless crystals; m.p.:
20
154–155 ꢀC; [
a
]
ꢂ20 ꢃ 2 (c 0.26, CH2Cl2); Rf 0.46 (EtOAc/cyclo-
D
hexane 1:1); IR nmax (KBr): 1042,1248,1373,1590,1750, 2958 cmꢂ1
;
1H NMR (DMSOd6):
d
1.78 (s, 3H, OAc), 1.96 (s, 3H, OAc), 1.99 (s, 3H,
OAc), 2.03 (s, 3H, OAc), 2.37 (s, 3H, CH3), 2.95 (t, 2H, J 6.9 Hz, CH2),
3.24 (t, 2H, J 6.9 Hz, CH2), 4.05 (dd, 1H, J 12.3, 2.4 Hz, H6), 4.13 (dd,
1H, J 12.3, 5.4 Hz, H60), 4.36 (ddd, 1H, J 9.9, 5.4, 2.4 Hz, H5), 5.18 (dd,
1H, J 9.9, 9.3 Hz, H4), 5.18 (s, 2H, CH2O), 5.55 (dd, 1H, J 9.3, 9.3 Hz,
H3), 5.65 (dd, 1H, J 9.3, 9.0 Hz, H2), 6.34 (d, 1H, J 9.0 Hz, H1), 7.36 (d,
2H, J 8.1 Hz, Harom, AA0BB0 system), 7.86 (d, 2H, J 8.1 Hz, Harom,
O-{[1-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-1H-1,2,3-tri-
azol-4-yl]methyl}-3-[3-phenyl-1,2,4-oxadiazol-5-yl] propanoate
AA00BB0 system), 8.47 (s, 1H, Htriazole); 13C NMR (DMSOd6):
d 20.0,
(5a). Prepared from 3a (0.14 g); 83% (0.25 g); recrystallized from
20.3, 20.5, 20.7, 21.2, 21.6, 29.7, 57.4, 61.8, 67.5, 70.2, 72.2, 73.3, 83.9,
123.5,124.0,127.0,129.9,141.5,142.6,167.5,168.6,169.5,169.7,170.1,
171.2, 179.2. Anal. Calcd. for C29H33N5O12 (C,H,N): C, 54.12%; H,
5.17%; N, 10.88%. Found: C, 54.34%; H, 5.16%; N, 10.72%.
methylene chloride:cyclohexane (1:2, v/v); colorless crystals; m.p.:
20
140–141 ꢀC; [
a
]
ꢂ25 ꢃ1 (c 0.33, CH2Cl2); Rf 0.41 (EtOAc/cyclo-
D
hexane 1:1); IR nmax (KBr): 1038, 1236, 1374, 1590, 1751, 2948 cmꢂ1
;
1H NMR (DMSOd6):
d
1.78 (s, 3H, OAc), 1.96 (s, 3H, OAc), 1.99 (s, 3H,
O-{[1-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-1H-1,2,3-tri-
OAc), 2.03 (s, 3H, OAc), 2.96 (t, 2H, J 6.9 Hz, CH2), 3.25 (t, 2H, J 6.9 Hz,
CH2), 4.06 (dd, 1H, J 12.6, 2.4 Hz, H6), 4.13 (dd, 1H, J 12.6, 5.1 Hz,
H6’), 4.36 (ddd, 1H, J 10.2, 5.1, 2.4 Hz, H5); 5.17 (dd,1H, J 9.3, 10.2 Hz,
H4), 5.18 (s, 2H, CH2O), 5.55 (dd, 1H, J 9.3, 9.3 Hz, H3), 5.65 (dd, 1H, J
9.0, 9.3 Hz, H2), 6.34 (d, 1H, J 9.0 Hz, H1), 7.52–7.61 (m, 3H, Harom),
7.98 (d, 2H, J 9.0 Hz, Harom), 8.47 (s,1H, Htriazole); 13C NMR (DMSOd6):
azol-4-yl]methyl}-3-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]propa-
noate (5e). Prepared from 3e (0.18 g); 73% (0.25 g); recrystallized
from methylene chloride:cyclohexane (1:1, v/v); colorless crystals;
20
m.p.: 105–107 ꢀC; [
a
]
ꢂ18 ꢃ 2 (c 0.26, CH2Cl2); Rf 0.44 (EtOAc/
D
cyclohexane 1:1); IR nmax (KBr): 1040, 1231, 1368, 1585, 1745,
2945 cmꢂ1; 1H NMR (DMSOd6):
d
1.80 (s, 3H, OAc), 1.98 (s, 3H, OAc),
d
20.0, 20.3, 20.4, 20.6, 21.6, 29.7, 57.4, 61.8, 67.5, 70.1, 72.1, 73.3,
2.00 (s, 3H, OAc), 2.04 (s, 3H, OAc), 2.97 (t, 2H, J 6.9 Hz, CH2), 3.27 (t,
2H, J 6.9 Hz, CH2), 4.07 (dd, 1H, J 12.6, 2.4 Hz, H6), 4.14 (dd, 1H, J
12.6, 5.1 Hz, H6’), 4.38 (ddd, 1H, J 9.6, 5.1, 2.4 Hz, H5), 5.19 (dd, 1H, J
9.6, 9.6 Hz, H4), 5.19 (s, 2H, CH2O), 5.57 (dd, 1H, J 9.6, 9.3 Hz, H3),
5.67 (dd, 1H, J 9.3, 9.0 Hz, H2), 6.37 (d, 1H, J 9.0 Hz, H1), 7.78 (d, 2H, J
8.7 Hz, Harom, AA0BB0 system), 7.92 (d, 2H, J 8.4 Hz, Harom, AA0BB0
83.9, 124.0, 126.2, 127.0, 129.4, 131.6, 142.6, 167.5, 168.6, 169.5, 169.7,
170.1, 171.2, 179.4. Anal. Calcd. for C28H31N5O12 (C,H,N): C, 53.42%;
H, 4.96%; N, 11.12%. Found: C, 53.46%; H, 4.94%; N, 10.79%.
O -{[1-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-1H-1,2,3-tri-
azol-4-yl]methyl}-3-[3-(2-tolyl)-1,2,4-oxadiazol-5-yl]propanoate
(5b). Prepared from 3b (0.14 g); 77% (0.24 g); recrystallized from
system), 8.49 (s, 1H, Htriazole); 13C NMR (DMSOd6):
d 19.9, 20.3, 20.4,
methylene chloride:cyclohexane (1:2, v/v); colorless crystals; m.p.:
20.5, 21.5, 29.7, 57.4, 61.8, 67.5, 70.1, 72.1, 73.3, 83.9, 123.9, 125.1,
125.4, 129.0, 132.4, 142.5, 166.8, 168.5, 169.4, 169.6, 170.1, 171.1,
179.6. Anal. Calcd. for C28H30BrN5O12 (C,H,N): C, 47.47%; H, 4.27%;
N: 9.89%. Found: C, 47.25%; H, 4.32%; N, 9.86%.
20
125–126 ꢀC; [
a
]
ꢂ21 ꢃ2 (c 0.26, CH2Cl2); Rf 0.49 (EtOAc/cyclo-
D
hexane 1:1); IR nmax (KBr): 1038, 1233, 1370, 1598, 1747, 2960 cmꢂ1
;
1H NMR (DMSOd6):
d
1.79 (s, 3H, OAc), 1.97 (s, 3H, OAc), 2.00 (s, 3H,
OAc), 2.04 (s, 3H, OAc), 2.53 (s, 3H, CH3), 2.97 (t, 2H, J 6.9 Hz, CH2),
3.27 (t, 2H, J 6.9 Hz, CH2), 4.07 (dd, 1H, J 12.6, 2.4 Hz, H6), 4.14 (dd,
1H, J 12.6, 5.4 Hz, H60), 4.38 (ddd, 1H, J 9.9, 5.4, 2.4 Hz, H5), 5.18 (dd,
1H, J 9.9, 9.6 Hz, H4), 5.19 (s, 2H, CH2O), 5.57 (dd, 1H, J 9.6, 9.3 Hz,
H3), 5.67 (dd, 1H, J 9.3, 9.0 Hz, H2), 6.37 (d, 1H, J 9,0 Hz, H1), 7.34–
7.49 (m, 3H, Harom), 7.88 (dd, 1H, J 7.5, 1.5 Hz, Harom), 8.49 (s, 1H,
O-{[1-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-1H-1,2,3-tri-
azol-4-yl]methyl}-3-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]pro-
panoate (5f). Prepared from 3f (0.15 g); 66% (0.21 g); recrystallized
from methylene chloride:cyclohexane (1:1, v/v); colorless crystals;
20
m.p.: 106–107 ꢀC; [
a
]
ꢂ17 ꢃ 2 (c 0.31, CH2Cl2), Rf 0.39 (EtOAc/
D
cyclohexane 1:1); IR nmax (KBr): 1045, 1227, 1364, 1593, 1753,
Htriazole); 13C NMR (DMSOd6):
d
19.9, 20.3, 20.4, 20.5, 21.6, 29.7, 57.4,
2941 cmꢂ1; 1H NMR (DMSOd6):
d
1.79 (s, 3H, OAc), 1.97 (s, 3H, OAc),
61.8, 67.5, 70.1, 72.1, 73.3, 83.8,123.9,125.5,126.2,129.7,130.8,131.4,
137.5, 142.5, 168.1, 168.5, 169.4, 169.6, 170.0, 171.1, 178.2. Anal. Calcd.
for C29H33N5O12 (C,H,N): C, 54.12%; H, 5.17%; N, 10.88%. Found: C,
54.14%; H, 5.07%; N, 10.79%.
O -{[1-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-1H-1,2,3-tri-
azol-4-yl]methyl}-3-[3-(3-tolyl)-1,2,4-oxadiazol-5-yl]propanoate
2.00 (s, 3H, OAc), 2.04 (s, 3H, OAc), 2.97 (t, 2H, J 6.9 Hz, CH2), 3.27 (t,
2H, J 6.9 Hz, CH2), 4.07 (dd, 1H, J 12.6, 2.4 Hz, H6), 4.14 (dd, 1H, J
12.6, 5.3 Hz, H6’), 4.38 (ddd, 1H, J 9.9, 5.3, 2.4 Hz, H5), 5.19 (dd, 1H, J
9.9, 9.3 Hz, H4), 5.19 (s, 2H, CH2O), 5.57 (dd, 1H, J 9.3, 9.3 Hz, H3),
5.67 (dd, 1H, J 9.3, 9.0 Hz, H2), 6.37 (d, 1H, J 9.0 Hz, H1), 7.65 (d, 2H, J
8.4 Hz, Harom, AA0BB0 system), 7.99 (d, 1H, J 8.7 Hz, Harom, AA0BB0
(5c). Prepared from 3c (0.14 g); 74% (0.23 g); recrystallized from
system), 8.49 (s, 1H, Htriazole); 13C NMR (DMSOd6):
d 19.9, 20.3, 20.4,
methylene chloride:cyclohexane (1:2, v/v); colorless crystals; m.p.:
20.5, 21.5, 29.7, 57.4, 61.8, 67.5, 70.1, 72.1, 73.3, 83.8, 123.9, 125.0,
128.8, 129.4, 136.3, 142.5, 166.7, 168.5, 169.4, 169.6, 170.0, 171.1,
179.6. Anal. Calcd. for C28H30ClN5O12 (C,H,N): C, 50.65%; H, 4.55%; N,
10.55%. Found: C, 50.34%; H, 4.83%; N, 10.35%.
20
123–124 ꢀC; [
a
]
ꢂ28 ꢃ 1 (c 0.22, CH2Cl2); Rf 0.46 (EtOAc/cyclo-
D
hexane 1:1); IR nmax (KBr): 1040, 1221, 1370, 1587, 1747, 2948 cmꢂ1
;
1H NMR (DMSOd6):
d
1.79 (s, 3H, OAc), 1.97 (s, 3H, OAc), 2.00 (s, 3H,
OAc), 2.04 (s, 3H, OAc), 2.40 (s, 3H, CH3), 2.97 (t, 2H, J 6.9 Hz, CH2),
3.26 (t, 2H, J 6.9 Hz, CH2), 4.06 (dd, 1H, J 12.6, 2.4 Hz, H6), 4.14 (dd,
1H, J 12.6, 5.4 Hz, H6), 4.37 (ddd, 1H, J 9.9, 5.4, 2.4 Hz, H5), 5.18 (dd,
1H, J 9.9, 9.3 Hz, H4), 5.19 (s, 2H, CH2O). 5.56 (dd, 1H, J 9.3, 9.3 Hz,
H3), 5.66 (dd, 1H, J 9.3, 9.0 Hz, H2), 6.38 (d, 1H, J 9.0 Hz, H1), 7.41 (d,
2H, J 7.5 Hz, Harom), 7.46 (d, 1H, J 7.5 Hz, Harom), 7.79 (d, 1H, J 7.5 Hz,
O-{[1-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-1H-1,2,3-tri-
azol-4-yl]methyl}-3-[3-(4-nitrophenyl)-1,2,4-oxadiazol-5-yl]pro-
panoate (5g). Prepared from 3g (0.16 g); 69% (0.22 g); recrystallized
from methylene chloride:cyclohexane (1:1, v/v); colorless crystals;
20
m.p.: 124–125 ꢀC; [
a
]
ꢂ24 ꢃ1 (c 0.30, CH2Cl2); Rf 0.28 (EtOAc/
D
cyclohexane 1:1); IR nmax (KBr): 1042, 1225, 1362, 1579, 1750,

3576
J.V. dos Anjos et al. / European Journal of Medicinal Chemistry 44 (2009) 3571–3576
[11] H.Z. Zhang, S. Kasibhatla, J. Kuemmerle, W. Kemnitzer, K. Ollis-Mason, L. Qiu,
2950 cmꢂ1; 1H NMR (DMSOd6):
d
1.80 (s, 3H, OAc), 1.97 (s, 3H, OAc),
C. Crogan-Grundy, B. Tseng, J. Drewe, S.X. Cai, J. Med. Chem. 48 (2005)
5215–5223.
[12] L.B. Clapp, in: K.T. Potts (Ed.), Comprehensive Heterocyclic Chemistry, vol. 6,
Pergamon Press, Oxford, 1984, pp. 365–392.
[13] L.B. Clapp, in: A.R. Katritzky, A.J. Boulton (Eds.), Advances in Heterocyclic
Chemistry, vol. 20, Academic Press, New York, 1976, pp. 65–116.
[14] J.C. Jochims, in: A.R. Katritzky, C.W. Rees, E.F.V. Scriven (Eds.), second ed,
Comprehensive Heterocyclic Chemistry, vol. 4, Pergamon Press, Oxford, 1996,
pp. 179–228.
2.00 (s, 3H, OAc), 2.04 (s, 3H, OAc), 2.97 (t, 2H, J 6.9 Hz, CH2), 3.31 (t,
2H, J 6.9 Hz, CH2), 4.07 (dd, 1H, J 12.6, 2.4 Hz, H6), 4.14 (dd, 1H, J
12.6, 5.4 Hz, H6’), 4.38 (ddd, 1H, J 9.9, 5.4, 2.4 Hz, H5), 5.18 (dd, 1H, J
9.9, 9.3 Hz, H4), 5.20 (s, 2H, CH2O), 5.57 (dd, 1H, J 9.3, 9.3 Hz, H3),
5.66 (dd,1H, J 9.3, 9.0 Hz, H2), 6.36 (d, 1H, J 9.0 Hz, H1), 8.24 (d, 2H, J
9.0 Hz, Harom, AA0BB0 system), 8.41 (d, 1H, J 9.0 Hz, Harom, AA0BB0
system), 8.49 (s, 1H, Htriazole), 13C NMR (DMSOd6):
d 19.9, 20.3, 20.4,
[15] K. Hemming, J. Chem. Res. (2001) 209–216.
20.5, 21.6, 29.7, 57.4, 61.8, 67.5, 70.1, 72.1, 73.3, 83.8, 123.9, 124.5,
128.4, 131.9,142.5, 149.2,166.2,168.5,169.4, 169.6,170.1,171.1,180.2.
Anal. Calcd. for C28H30N6O14 (C,H,N): C, 49.85%; H, 4.48%; N, 12.46%.
Found: C, 49.41%; H, 4.53%; N, 12.00%.
[16] Z. Jakopin, M.S. Dolenc, Curr. Org. Chem. 12 (2008) 850–898.
[17] K.E. Andersen, B.F. Lundt, A.S. Jørgensen, C. Braestrup, Eur. J. Med. Chem. 31
(1996) 417–425.
[18] C.B. Vu, E.G. Corpuz, T.J. Merry, S.G. Pradeepan, C. Bartlett, R.S. Bohacek,
M.C. Botfield, C.J. Eyermann, B.A. Lynch, I.A. MacNeil, M.K. Ram, M.R. van
Schravendijk, S. Violette, T.K. Sawyer, J. Med. Chem. 42 (1999) 4088–4098.
[19] T.L. Deegan, T.J. Nitz, D. Cebzanov, D.E. Pufko, J.A. Porco Jr., Bioorg. Med. Chem.
Lett. 9 (1999) 209–212.
3.2. Cytotoxic activity
[20] J. Yu, S. Zhang, Z. Li, W. Lu, R. Zhou, Y. Liu, M. Cai, Carbohydr. Res. 338 (2003)
257–261.
[21] Z. Jakopin, R. Roskar, M.S. Dolenc, Tetrahedron Lett. 48 (2007) 1465–1468.
[22] N.M.M. Bezerra, S.P. de Oliveira, R.M. Srivastava, J.R. da Silva, Farmaco 60
(2005) 955–960.
[23] A.C.L. Leite, R.F. Vieira, A.R. de Faria, A.G. Wanderley, P. Afiatpour,
E.C.P.A. Ximenes, R.M. Srivastava, C.F. Oliveira, M.V. Medeiros, E. Antunes,
D.J. Brondani, Farmaco 55 (2000) 719–724.
[24] W.D. Wu, L.T. Ma, L.H. Zhang, Y. Lu, F. Guo, Q.T. Zheng, Tetrahedron Asymm. 11
(2000) 1527–1536.
[25] J.W.H. Watthey, M. Desai, R. Rutledge, R. Dotson, J. Med. Chem. 23 (1980)
690–692.
[26] R.D. Haugwitz, A.J. Martinez, J. Venslavsky, R.G. Angel, B.V. Maurer, G.A. Jacobs,
V.L. Narayanan, L.R. Cruthers, J. Szanto, J. Med. Chem. 28 (1985) 1234–1241.
[27] C. Ainsworth, W.E. Buting, J. Davenport, M.E. Callender, M.C. McCowen, J. Med.
Chem. 10 (1967) 208–211.
[28] L. Cafici, T. Pirali, F. Condorelli, E. Del Grosso, A. Massarotti, G. Sorba,
P.L. Canonico, G.C. Tron, A.A. Genazzani, J. Comb. Chem. 10 (2008) 732–740.
[29] F. Lenda, F. Guenoun, J. Martinez, F. Lamaty, Tetrahedron Lett. 48 (2007)
805–808.
For cytotoxicity evaluation, HEp-2 (larynx carcinoma) and NCI-
H292 (lung carcinoma) cell strains with proven viability were used.
The cells were cultivated in MEM – Minimal Essential Medium with
10% bovine fetal serum containing 1% antibiotics solution (peni-
cillin 1000 UI/mL þ streptomycin 250 mg/mL) and 1% glutamine
solution (200 m
M). A cell suspension containing 5.104 cells/mL was
used and distributed in plates of 96 wells. The drugs 3a and 5a–g
were diluted in DMSO (0.15 mL) and added into each well. The
plates were incubated for 72 h at 37 ꢀC in humid atmosphere
enriched with 5% CO2. After incubation, MTT (15 mL) in phosphate
buffered saline solution (5 mg/mL) was added into each well. After
2 h, the culture medium was removed and DMSO (100 mL) were
added in the wells for formazan quantification. The measurements
were performed using a Multskan ELX 800 cell reader at 595 nm.
[30] M. Whiting, J.C. Tripp, Y.-C. Lin, W. Lindstrom, A.J. Olson, J.H. Elder,
K.B. Sharpless, V.V. Fokin, J. Med. Chem. 49 (2006) 7697–7710.
[31] T. Liebert, C. Ha¨nsch, T. Heinze, Macromol. Rapid Commun. 27 (2006) 208–213.
[32] H. Gallardo, G. Conte, F. Bryk, M.C.S. Lourenço, M.S. Costa, V.F. Ferreira, J. Braz.
Chem. Soc. 18 (2007) 1285–1291.
[33] M.S. Alam, J. Huang, F. Ozoe, F. Matsumura, Y. Ozoe, Bioorg. Med. Chem. 15
(2007) 5090–5104.
[34] R. Pe´rion, V. Ferrie`res, M.I. Garcı´a-Moreno, C.O. Mellet, R. Duval,
Acknowledgements
We are indebted to the Brazilian Research Council (CNPq) for
financial assistance. One of us (J.V. dos Anjos) is thankful to this
organization for a Doctoral Fellowship, which made possible to do
this work.
´
J.M.G. Fernandez, D. Plusquellec, Tetrahedron 61 (2005) 9118–9128.
[35] V.D. Bock, D. Speijer, H. Hiemstra, J.H. van Maarseveen, Org. Biomol. Chem. 5
(2007) 971–975.
Appendix. Supplementary materials
[36] H.C. Kolb, K.B. Sharpless, Drug Disc. Today 8 (2003) 1128–1137.
[37] V. Kren, L. Martinkova, Curr. Med. Chem. 8 (2001) 1313–1338.
[38] R.M. Srivastava, I.M. Brinn, J.O. Machuca-Herrera, H.B. Faria, G.B. Carpenter,
D. Andrade, C.G. Venkatesh, L.P.F. de Morais, J. Mol. Struct. 206 (1997) 159–167.
[39] R.M. Srivastava, M.B.A.B. Viana, L. Bieber, J. Heterocycl. Chem. 21 (1984)
1193–1195.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.ejmech.2009.03.002.
[40] A. Bianchi, A. Bernardi, J. Org. Chem. 71 (2006) 4565–4577.
[41] B.Y. Lee, S.R. Park, H.B. Jeon, K.S. Kim, Tetrahedron Lett. 47 (2006)
5105–5109.
References
[1] J.A. Rafferty, I. Hickson, L.S. Lashford, Cancer Metastasis Rev. 15 (1996)
365–383.
[42] J.V. dos Anjos, D. Sinou, S.J. de Melo, R.M. Srivastava, Carbohydr. Res. 342
(2007) 2440–2449.
[43] F. Himo, T. Lovell, R. Hilgraf, V.V. Rostovtsev, L. Noodleman, K.B. Sharpless,
V.V. Fokin, J. Am. Chem. Soc. 127 (2005) 210–216.
[2] J.R. de Freitas Filho, J.C.R. de Freitas, L.P. da Silva, J.R. de Freitas, G.Y.V. Kimura,
R.M. Srivastava, Tetrahedron Lett. 48 (2007) 6195–6198.
[3] J.V. dos Anjos, D. Sinou, S.J. de Melo, R.M. Srivastava, Lett. Org. Chem. 4 (2007)
4393–4397.
[4] R.A.W. Neves Filho, R.M. Srivastava, Molecules 11 (2006) 318–324.
[5] A.C.L. Leite, R.F.F. Vieira, D.R.D. Moreira, D.J. Brondani, R.M. Srivastava, V.F. da
Silva, M.A. de Morais Jr., Mutat. Res. Genet. Toxicol. Environ. Mutag. 588 (2005)
166–171.
[44] W.H. Binder, C. Kluger, Curr. Org. Chem. 10 (2006) 1791–1815.
[45] M.J. Frisch, G.W. Trucks, H.B. Schlegel, P.M.W. Gill, B.G. Johnson, M.A. Robb,
J.R. Cheeseman, T. Keith, G.A. Petersson, J.A. Montgomery, K. Raghavachari,
M.A. Al-Laham, V.G. Zakrzewski, J.V. Ortiz, J.B. Foresman, J. Cioslowski,
B.B. Stefanov, A. Nanayakkara, M. Challacombe, C.Y. Peng, P.Y. Ayala, W. Chen,
M.W. Wong, J.L. Andres, E.S. Replogle, R. Gomperts, R.L. Martin, D.J. Fox,
J.S. Binkley, D.J. Defrees, J. Baker, J.P. Stewart, M. Head-Gordon, C. Gonzalez,
J.A. Pople, Gaussian 94, Revision E.3, Gaussian, Inc., USA, 1995.
[6] V.M.L. Braga, S.J. de Melo, R.M. Srivastava, E.P.S. Falca˜o, J. Braz. Chem. Soc. 15
(2004) 603–607.
[46]
M.C. Alley, D.A. Scudiero, A. Monks, M.L. Hursey, M.J. Czerwinski, D.L. Fine,
B.J. Abbot, J.G. Mayo, R.H. Shoemaker, M.R. Boyd, Cancer Res. 48 (1988)
589–601.
[7] R.M. Srivastava, J.R. de Freitas Filho, M.J. da Silva, S.C.M. Souto, G.B. Carpenter,
W.M. Faustino, Tetrahedron 60 (2004) 10761–10769.
[8] R.M. Srivastava, A.D. Lima, O.S. Viana, M.J.C. Silva, M.T.J.A. Catanho, J.O.F. de
Morais, Bioorg. Med. Chem. 11 (2003) 1821–1827.
[9] R.M. Srivastava, L.P.F. de Morais, M.T.J.A. Catanho, G.M.L. de Souza, G.M. Seabra,
A.M. Simas, M.A.L. Rodrigues, Heterocycl. Commun. 6 (2000) 41–48.
[10] M.L. Boys, L.A. Schretzman, N.S. Chandrakumar, M.B. Tollefson, S.B. Mohler,
V.L. Downs, Y. Wang, C.R. Dalton, S.A. Norring, et al., Bioorg. Med. Chem. Lett.
16 (2006) 839–844.
[47] H. Eagle, Proc. Soc. Exp. Biol Med. 89 (1955) 362–364.
[48] H. Eagle, Science 174 (1959) 500–503.
[49] K.A. Jessen, N.M. English, J.Y. Wang, S. Maliartchouk, S.P. Archer, L. Qiu,
R. Brand, J. Kuemmerle, H.Z. Zhang, K. Gehlsen, J. Drewe, B. Tseng, S.X. Cai,
S. Kasibhatla, Mol. Cancer Ther. 4 (2005) 761–771.
[50] S. Kasibhatla, B. Tseng, Mol. Cancer Ther. 2 (2003) 573–580.