Synthesis and antitumor activity of new 1,2,4-triazine and [1,2,4]triazolo[4,3-b][1,2,4]triazine derivatives and their thioglycoside and acyclic C-nucleoside analogs

Article abstract of DOI:10.1002/jhet.522

New 1,2,4-triazine and their derived 1,2,4-triazolo[3,4-b][1,2,4]triazine derivatives were synthesized starting from 5,6-diphenyl-1,2,4-triazine-3-thiol. Furthermore, the corresponding 1,2,4-triazolo[3,4-b][1,2,4]-triazine thioglycosides and acyclic C-nuc

Full text of DOI:10.1002/jhet.522

January 2011
Synthesis and Antitumor Activity of New 1,2,4-Triazine and
[1,2,4]Triazolo[4,3-b][1,2,4]triazine Derivatives and Their
Thioglycoside and Acyclic C-Nucleoside Analogs
135
Wael A. El-Sayed,a* Ibrahim F. Nassar,b and Adel A.-H. Abdel-Rahmanc*
aDepartment of Photochemistry, National Research Centre, Cairo, Egypt
bFaculty of Education, Ain Shams University, Abbassia, Cairo, Egypt
cDepartment of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt
*E-mail: adelnassar63@hotmail.com (or) waelshendy@gmail.com
DOI 10.1002/jhet.522
Published online 10 September 2010 in Wiley Online Library (wileyonlinelibrary.com).
New 1,2,4-triazine and their derived 1,2,4-triazolo[3,4-b][1,2,4]triazine derivatives were synthesized
starting from 5,6-diphenyl-1,2,4-triazine-3-thiol. Furthermore, the corresponding 1,2,4-triazolo[3,4-b]
[1,2,4]-triazine thioglycosides and acyclic C-nucleoside analogs were synthesized. The newly synthe-
sized compounds were evaluated for their antitumor activity and some of them showed high inhibition
activities.
J. Heterocyclic Chem., 48, 135 (2011).
INTRODUCTION
interesting broad spectrum of antiproliferative activity
and a pronounced growth inhibitory activity against leu-
kemic cell lines and a wide range of cancer cells [8,9]
revealing in vitro antitumor and antifungal activities
[10,11]. It is noteworthy that many potential antiviral
and anticancer drugs have been modeled on them
[12,13]. 1,2,4-Triazine derivatives are known to possess
antitubercular, antibacterial, fungicidal, insecticidal,
herbicides hypotensive, and hypothermic activities
[6,14–17]. Many 1,2,4-triazines have been screened
in vitro supporting their anti-HIV and anti-cancer activ-
ities [18,19]. On the other hand, the glycosylthio hetero-
cycles [20–23] and the acyclic nucleoside analogs with
modification of both the glycon part and the heterocyclic
base have stimulated extensive research as biological
1,2,4-Triazines and their condensed derivatives
occupy a pivotal position in modern medicinal chemis-
try, because of their high potential biological activities.
The 1,2,4-triazine ring is a prominent structural motif
found in numerous natural and synthetic biologically
active compounds. For example, the well-known antivi-
ral drug azaribine is structurally based on the 1,2,4-tria-
zine scaffold [1]. In addition, certain azanucleosides, for
example, 6-azacytosine and 6-azauracil, bearing the
1,2,4-triazine heterocycle, have displayed an impressive
array of biological activities, among which antiviral
[2,3] and antitumor [4,5] activities. Condensed 1,2,4-tri-
azines found various applications as pharmaceuticals,
herbicides, pesticides, and dyes [6,7]. They showed an
C
V
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136
W. A. El-Sayed, I. F. Nassar, and A. A.-H Abdel-Rahman
Vol 48
inhibitors [24–27]. Owing to the above facts and our in-
terest in the attachment of carbohydrate moieties to
newly synthesized heterocycles [28–32], our aim is the
synthesis of new 1,2,4-triazine and [1,2,4]triazolo[4,3-
b][1,2,4]triazine derivatives and their thioglycoside and
acyclic C-nucleoside analogs in an ongoing search for
new biologically active leads with potential antitumor
activity.
adjacent C¼¼S, was reported [29,34–37] to appear at
higher chemical shift because of the anisotropic
deshielding effect of the C¼¼S. The 13C NMR spectra of
6a,b showed a signal at d 88.98 and 88.56 ppm corre-
sponding to the anomeric C-1, which also confirmed the
b-configuration. The absence of a peak corresponding to
the C¼¼S group indicates that the attachment of the
sugar has taken place at the sulfur atom and not on the
nitrogen atom.
When compounds 6a,b were treated with methanolic
ammonia at 0ꢀC, the deacetylated thioglycoside deriva-
tives 7a,b were obtained in moderate yields. The struc-
tures of the deprotected glycosides 7a,b were conformed
RESULTS AND DISCUSSION
The starting compound 5,6-diphenyl-1,2,4-triazine-3-
thiol (1) was synthesized according to a reported proce-
dure [33] by Saxena et al. Methylation of 1 with methyl
iodide in acetone in the presence of K2CO3 at room
temperature afforded 3-(methylthio)-5,6-diphenyl-1,2,4-
triazine (2) in 80% yield. Reaction of 2 with hydrazine
hydrate in ethanol gave 3-hydrazinyl-5,6-diphenyl-1,2,4-
1
by IR, H- and 13C NMR, and elemental analysis (see
experimental part). When 3-hydrazinyl-5,6-diphenyl-
1,2,4-triazine (3) was allowed to react with D-galactose,
or D-ribose in an aqueous ethanolic solution and a cata-
lytic amount of acetic acid, the corresponding sugar
hydrazones 8a,b were obtained, respectively. The IR
spectra of 8a,b showed the presence of characteristic
absorption bands corresponding to the hydroxy groups
in the region 3478–3448 cmꢁ1. The 1H NMR spectra
showed the signals of the sugar chain protons at d 3.30–
5.79 ppm and the C-1 methine proton as doublet in the
range d 7.48–7.52 ppm in addition to the aromatic pro-
tons in the region d 7.27–7.73 ppm.
1
triazine (3). The H NMR spectrum of 2 revealed the
presence of the S-CH3 signal at d 2.44 ppm, which
disappeared in the H NMR spectrum of the hydrazine
1
derivative 3 and instead two signals appeared at d 5.52
and 9.94 ppm corresponding to the NH2 and NH groups,
respectively.
When 3 was reacted with carbon disulphide in ethanol
in the presence of potassium hydroxide, 6,7-diphenyl-
[1,2,4]triazolo[4,3-b][1,2,4]triazine-3(2H)-thione (4) was
obtained in 78% yield. The 1H NMR spectrum of 4
showed the signals of the aromatic protons and the NH
group and the 13C NMR spectrum reveled the presence
of the C¼¼S signal at d 172.35 ppm. The signals at d
156.48, 157.94, 158.12 ppm corresponding to three
C¼¼N groups in the 13C NMR spectrum of 4 indicate
that the cyclization has taken place to afford the tria-
zolo[4,3-b][1,2,4]triazin-3(2H)-thione structure and not
1,2,4-triazolo[3,4-c][1,2,4]triazin-3(2H)-thione structure.
In the later structure two of these signals will corre-
spond to CAN and not to C¼¼N and would appear at
lower chemical shifts.
It is well known that the reaction of sugar hydrazinyl
derivatives with acetic anhydride give the respective
per-O-acetyl derivatives. However, it has been reported
[38–42] that when the reaction was carried out at high
temperature in boiling acetic anhydride, cyclization usu-
ally takes place in addition to per-O-acetylation to
afford C-nucleoside analogs. We reported previously
[38] the synthesis of 1,2,4-triazolo[1,3,4]oxadiazole acy-
clic nucleoside analogous by the reaction of hydrazinyl
sugars with boiling acetic anhydride. Thus, when the
hydrazinyl sugars 8a,b were heated in acetic anhydride
at 100ꢀC they gave the triazolotriazine acyclic nucleo-
sides 9a,b, respectively. The structures of compounds
9a,b were confirmed by their IR, 1H NMR, and 13C
NMR spectra. The IR spectra of 9a,b showed character-
istic absorption bands in the carbonyl frequency region
at 1668–1662 cmꢁ1 and 1742–1738 cmꢁ1 corresponding
to the carbonyl amide and the carbonyl ester groups,
respectively indicating the presence of N-acetyl group in
Reaction of 4 with 2,3,4,6-tetra-O-acetyl-a-D-gluco-
pyranosyl bromide (5a) or 2,3,4-tri-O-acetyl-a-D-xylo-
pyranosyl bromide (5b) gave the corresponding acety-
lated thioglycoside derivatives 6a,b, respectively. The
assignments of sugar protons were based on the chemi-
cal shift equivalences to the assigned structures of
1
addition to the O-acetyl groups. The H NMR spectra of
1
related sugar thioglycosides [29,32]. Thus, the H NMR
9a,b showed the signals of the O-acetyl-methyl protons
each as singlet in the range d 1.85–2.18 ppm and the
N-acetyl-methyl protons in the range d 2.23–2.28 ppm.
The rest of the alditolyl chain protons appeared in the
range d 4.16–5.77 ppm. The 13C NMR spectrum of 9a,b
showed the resonances of the acetyl-methyl carbons at d
20.32–29.70 ppm. The value of the chemical shift of the
CAN-Ac (C-1 in the original sugar chain moiety)
spectra of the glycosides 6a,b showed signals corre-
sponding to the acetyl-methyl signals and the sugar pro-
tons in addition to the aromatic protons. The anomeric
protons appeared at d 5.70 and 5.72 ppm with coupling
constants J ¼ 10.2 and 9.8 Hz for 6a and 6b, respec-
tively, indicating the b-orientation of the thioglycosidic
bond. The anomeric proton of b-N-glucosides having an
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2011
Synthesis and Antitumor Activity of New 1,2,4-Triazine and [1,2,4]Triazolo[4,3-b]-
[1,2,4]triazine Derivatives and Their Thioglycoside and Acyclic C-Nucleoside Analogs
137
Scheme 1. Synthesis of [1,2,4]triazolo[4,3-b][1,2,4]triazine thioglycosides and acyclic C-nucleosides.
appeared at d 92.12 and 92.24 ppm whose value indi-
cated its N,N-acetal nature rather than being a C¼¼N.
The signals at d 152.46–153.58 ppm in 9a and 9b indi-
cated the presence of C-6 and C-7 as C¼¼N and not
CAN confirming the triazolino[4,3-b][1,2,4]triazine
and not triazolino[4,3-cb][1,2,4]triazine; the later will
contain C-6 and C-7 as CAN, which would appear at
lower chemical shift. The signals at d 169.12–171.10
ppm correspond to the carbonyl groups (Scheme 1).
Reaction of 1 with ethyl chloroacetate in acetone
afforded the corresponding S-substituted ethyl ester
derivative 10 in 82% yield. Hydrazinolysis of the ester
Journal of Heterocyclic Chemistry
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138
W. A. El-Sayed, I. F. Nassar, and A. A.-H Abdel-Rahman
Vol 48
10 in ethanol gave the corresponding hydrazide deriva-
tive 11. The IR spectrum of the ester 10 showed an
absorption band at 1738 cmꢁ1, which disappeared in the
corresponding spectrum of acid hydrazide 11 and
instead showed characteristic absorption bands at 3476
and 1678 cmꢁ1 for the NH2 and C¼¼O, respectively.
with 10 lL of the cell suspension. Within 5 min, the
mixture was spread onto haemocytometer, covered with
a cover slip and then the cells were examined under
microscope. Dead cells are blue stained but viable
cells are not [44]. Cell suspension was adjusted to con-
tain 2.5 ꢂ 106 viable cells/mL.
1
The H NMR spectrum of the hydrazide 11 showed sig-
EAC cells, RPMI medium, drugs, and DMSO were
added in sterile test tubes according to trypan blue
exclusion method [44]. The cells were incubated for 1
and 24 h at 37ꢀC under a constant over lay of 5% CO2.
EAC viable cells were counted by trypan blue exclusion
using haemocytometer as mentioned above. The cell
surviving fraction was calculated from the relation T/C;
where, T and C represent the number of viable cells in a
unit volume and the number of total (viable þ dead)
cells in the same unit volume, respectively.
nals corresponding to the NH2, the two CH2 in addition
to the aromatic protons and the NH signal. The 13C
NMR of compound 10 revealed the presence of the CH2
signals at d 41.14 and 48.14 ppm in addition to the
C¼¼O group at d 169.45 ppm.
When the hydrazide 11 was allowed to react with car-
bon disulphide in ethanol in the presence of potassium
hydroxide the corresponding 1,3,4-oxadiazole-2-thione
derivative 12 was afforded in 80% yield. Reaction of
thione derivative 12 with 2,3,4,6-tetra-O-acetyl-a-D-glu-
copyranosyl bromide (5), the corresponding acetylated
The in vitro studies. The effects of the newly synthe-
sized compounds were assessed on the viability of EAC
cells using trypan blue exclusion test. The anti-tumor
efficacy of the compounds against ESC cell lines was
demonstrated compared with doxorubicin. The obtained
results revealed that compounds 3, 4, 7b, 9b, 10, and 11
were the most active derivatives among the series of
tested compounds and affected the EAC cell viability on
a dose dependent manner whereas other compounds
exhibited little or no activity. The effective dose calcu-
lated as IC50, which correspond to the compound con-
centration resulted in 50% mortality in the total cells
count and presented in (Table 1). The 1,2,4-triazine
derivatives 4, 9b, and 10 displayed the highest activity
with IC50 values 40, 44, and 45 lg/mL, respectively,
followed by compounds 3 and 11.
From the antitumor activity results and structure ac-
tivity relationship, it could be concluded that the attach-
ment of acyclic ribotetritolyl sugar moiety to the
[1,2,4]triazolo[4,3-b][1,2,4]triazine ring system displayed
higher activity than the corresponding analogous with
galactopentitolyl moiety. Furthermore, the [1,2,4]tria-
zolo[4,3-b][1,2,4]triazine thioglycoside with the free
hydroxyl xylopyranosyl sugar moiety revealed higher
activity than the corresponding acetylated analog or the
thioglycoside with the glucopyranosyl sugar moiety.
Moreover, the [1,2,4]triazolo[4,3-b][1,2,4]triazine thio-
glycosides displayed higher inhibition activity the 1,3,4-
oxadiazole thioglycoside derivatives. The substituted
hydrazine derivative of the 1,2,4-triazine ring system 3
displayed relatively higher activity than the correspond-
ing acid hydrazide 11, which revealed lower activity.
1
thioglycoside 13 was obtained. The H NMR spectrum
of the latter compound showed signals corresponding to
the acetyl-methyl signals and the sugar protons in addi-
tion to the aromatic protons. The anomeric proton signal
appeared at d 5.72 ppm with a coupling constant 9.8
indicating the b-orientation of the thioglycosidic bond.
The 13C NMR spectrum of 13 showed a signal at d
89.12 ppm corresponding to the anomeric C-1, which
also confirmed the b-configuration. The absence of a
peak corresponding to the C¼¼S group indicates that the
attachment of the sugar has taken place at the sulfur
atom and not on the nitrogen atom. Treatment of the
acetylated thioglycoside 13 with methanolic ammonia
gave the deacetylated thioglycoside derivative 14
1
(Scheme 2). Its structure was conformed by IR, H- and
13C NMR, and elemental analysis, which agreed with
the assigned structure (see experimental part).
Antitumor activity. The antitumor activity of the
newly synthesized compounds was investigated against
Ehrlich Ascites Carcinoma cells (EAC). These cells
were maintained by weekly intraperitoneal transplanta-
tion of 2.5 ꢂ 106 cells in female Swiss albino mice.
The tumor is characterized by a moderately rapid
growth, which leads to the death of the mice in about
20 days due to the distal metastasis. EAC is of mam-
mary origin; as spontaneous breast cancer served as the
original tumor from which an ascites variant was
obtained [43].
Cytotoxicity assay. Ascites fluid was withdrawn
under aseptic conditions (ultraviolet laminar flow sys-
tem) from the peritoneal cavity of tumor bearing mice
by needle aspiration after 7 days of EAC cells inocula-
tion. To adjust the number of EAC cells/mL, tumor cells
obtained were diluted several times with normal saline.
EAC viable cells were counted by trypan blue exclusion
method where, 10 lL trypan blue (0.05%) was mixed
EXPERIMENTAL
Melting points were determined with a kofler block appara-
tus and are uncorrected. The IR spectra were recorded on a
perkin-Elmer model 1720 FTIR spectrometer for KBr disc.
Journal of Heterocyclic Chemistry
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January 2011
Synthesis and Antitumor Activity of New 1,2,4-Triazine and [1,2,4]Triazolo[4,3-b]-
[1,2,4]triazine Derivatives and Their Thioglycoside and Acyclic C-Nucleoside Analogs
139
Scheme 2. Synthesis of (1,2,4-triazin-3-yl)methylthio-1,3,4-oxadiazole thioglycosides.
NMR spectra were recorded on a varian Gemini 200 NMR
2.34 g (80%), mp 130–131ꢀC; IR (KBr) m: 1608 (C¼¼N) cmꢁ1
;
1
Spectrometer at 300 MHz for H and 75 MHz for 13C or on a
1H NMR (DMSO-d6, 300 MHz): d 2.44 (s, 3H, SCH3), 7.26
(m, 3H, Ar-H), 7.31 (m, 3H, Ar-H), 7.37 (m, 2H, Ar-H), 7.71
(m, 2H, Ar-H); 13C NMR (DMSO-d6, 75 MHz): d 22.14
brucker Ac-250 FT spectrometer at 250 MHz for 1H and at
62.9 MHz for 13C. Chemical shifts were reported in d scale
(ppm) relative to TMS as a standard and the coupling con-
stants J values are given in Hz. The progress of the reactions
was monitored by TLC using aluminum silica gel plates
60 F245. Elemental analyses were determined on a Perkin
Elmer 240 (microanalysis) at the Microanalytical data centre
at Faculty of science, Cairo University, Egypt.
Table 1
The IC50 (lg/mL) of compounds 3 and 9–11.
Compound
IC50 (lg/mL)
3
4
7b
9b
10
11
51
40
3-Methylsulfanyl-5,6-diphenyl-1,2,4-triazine (2). To
a
solution of 5,6-diphenyl-1,2,4-triazine-3-thiol (1) (2.65 g,
10 mmol) and potassium carbonate (1.38 g, 10 mmol) in ace-
tone (25 mL), was added methyl iodide (1.42 g, 10 mmol).
The solution was stirred at room temperature for 2 h and the
solvent was evaporated under reduced pressure. The resulting
solid product was recrystallized from ethanol as yellow solid,
68.5
44
45
62.5
38
Doxorubicin
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W. A. El-Sayed, I. F. Nassar, and A. A.-H Abdel-Rahman
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(CH3), 127.73–141.05 (Ar-C), 152.60 (C-5), 153.44 (C-6),
156.87 (C-3). Anal. Calcd for C16H13N3S: C, 68.79; H, 4.69;
N, 15.04. Found: C, 68.60; H, 4.52; N, 14.78.
3-(2,3,4-Tri-O-acetyl-b-D-xylopyranosyl)-6,7-diphenyl-3,5-
dihydro-1,2,4-triazolo[4,3-b][1,2,4]triazine (6b). This com-
pound was obtained as yellow solid, 2.23 g (79%)ꢁ, 1143–
3-Hydrazino-5,6-diphenyl-1,2,4-triazine (3). A solution of
2 (2.79 g, 10 mmol) and hydrazine hydrate (0.5 g, 10 mmol)
in ethanol (20 mL) was heated under reflux for 6 h. The solu-
tion was cooled and the resulting precipitate was filtered and
recrystallized from ethanol as yellow crystals, mp 188–189ꢀC;
2.15 g (82%), IR (KBr) m: 3363 (NH2), 3310 (NH), 1610
144ꢀC, IR (KBr) m: 1740 (C¼¼O), 1610 (C¼¼N) cm
;
1H
NMR (CDCl3, 300 MHz): d 1.88, 2.05, 2.10 (3s, 9H, 3CH3),
4.10 (dd, J ¼ 11.4 Hz, J ¼ 2.8 Hz, 1H, H-50), 4.14 (m, 1H,
H-500), 4.90 (t, J ¼ 9.4 Hz, 1H, H-40), 5.18 (dd, J ¼ 9.4 Hz,
J ¼ 9.2 Hz, 1H, H-30), 5.34 (t, J ¼ 9.2 Hz, 1H, H-20), 5.72
(d, J1 ,2 ¼ 9.8 Hz, 1H, H-10), 7.31 (m, 3H, Ar-H), 7.35
(m, 3H, Ar-H), 7.38 (m, 2H, Ar-H), 7.74 (m, 2H, Ar-H); 13C
NMR (CDCl3, 75 MHz): d 20.16, 20.26, 20.31 (3CH3), 65.87
(C-50), 67.21 (C-30), 68.62 (C-40), 70.34 (C-20), 88.56 (C-10),
128.26–143.25 (Ar-C), 154.88, 156.59, 157.94, 158.22
(4C¼¼N), 169.78, 170.14, 170.80 (3C¼¼O). Anal. Calcd for
C27H25N5O7S: C, 57.54; H, 4.47; N, 12.43. Found: C, 57.28;
H, 4.31; N, 12.55.
0
0
1
(C¼¼N) cmꢁ1; H NMR (DMSO-d6, 300 MHz): d 5.52 (s, 2H,
NH2), 7.24 (m, 3H, Ar-H), 7.33 (m, 3H, Ar-H), 7.41 (m, 2H,
Ar-H), 7.72 (m, 2H, Ar-H), 9.94 (s, 1H, NH); 13C NMR
(DMSO-d6, 75 MHz): d 126.88–141.12 (Ar-C), 152.65 (C-5),
153.76 (C-6), 156.89 (C-3). Anal. Calcd for C15H13N5: C,
68.42; H, 4.98; N, 26.60. Found: C, 68.22; H, 4.82; N, 26.42.
6,7-Diphenyl-1,2,4-triazolo[4,3-b][1,2,4]triazin-3(2H)-
thione (4). To a solution of 3 (2.63 g, 10 mmol) in ethanol
(20 mL) was added a solution of potassium hydroxide (0.56 g,
10 mmol) dissolved in water (2 mL) and carbon disulphide
(3 mL). The solution was heated under reflux for 15 h. The
solvent was evaporated and the residue was dissolved in water,
filtered off, and acidified with dilute hydrochloric acid. The
formed precipitate was filtered off, washed with water and
recrystallized from ethanol as yellow solid, mp 152–153ꢀC;
3-(b-D-Glycopyranosyl)-6,7-diphenyl-3,5-dihydro-1,2,4-tri-
azolo-[4,3-b][1,2,4]triazine (7a,b). General Procedure: Dry
gaseous ammonia was passed through a solution of a protected
nucleoside 6a,b (5 mmol) in dry methanol (15 mL) at 0ꢀC for
1 h, and then the mixture was stirred at 0ꢀC for about 5 h.
The solvent was evaporated under reduced pressure at 40ꢀC to
give a solid residue, which was recrystallized from ethanol.
3-(b-D-Glucopyranosyl)-6,7-diphenyl-3,5-dihydro-1,2,4-tri-
azolo[4,3-b][1,2,4]triazine (7a). This compound was obtained
as yellow solid, 2.08 g (82%), mp 192–193ꢀC; IR (KBr) m:
1
2.37 g (78%), IR (KBr) m: 3305 (NH), 1610 (C¼¼N) cmꢁ1; H
NMR (DMSO-d6, 300 MHz): d 7.27 (m, 3H, Ar-H), 7.33
(m, 3H, Ar-H), 7.39 (m, 2H, Ar-H), 7.75 (m, 2H, Ar-H), 12.14
(s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz): d 128.26–142.14
(Ar-C), 156.48, 157.94, 158.12 (3CAN), 172.35 (C¼¼S). Anal.
Calcd for C16H11N5S: C, 62.93; H, 3.63; N, 22.93. Found: C,
62.65; H, 3.54; N, 22.77.
3475–3451 (OH), 1614 (C¼¼N) cmꢁ1
;
1H NMR (DMSO-d6,
300 MHz): d 3.41 (m, 2H, H-60,600), 3.45 (m, 1H, H-50), 3.90
(m, 2H, H-30,40), 4.27 (t, J ¼ 9.4 Hz, 1H, H-20), 4.70 (t, J ¼
6.2, 1H, OH), 4.83 (d, J ¼ 6.4 Hz, 1H, OH), 5.15 (m, 1H,
OH), 5.24 (m, 1H, OH), 5.72 (d, J1 ,2 ¼ 10.2 Hz, 1H, H-10),
7.28 (m, 3H, Ar-H), 7.36 (m, 3H, Ar-H), 7.37 (m, 2H, Ar-H),
7.75 (m, 2H, Ar-H); 13C NMR (DMSO-d6, 75 MHz): d 61.46
(C-60), 64.14 (C-40), 68.83 (C-30), 71.33 (C-20), 72.18 (C-50),
88.70 (C-10), 128.25–143.68 (Ar-C), 154.85, 156.56, 157.84,
158.24 (4C¼¼N). Anal. Calcd for C22H21N5O5S: C, 56.52; H,
4.53; N, 14.98. Found: C, 56.41; H, 4.48; N, 14.72.
0
0
3-(2,3,4,6-Tetra-O-acetyl-b-D-glycopyranosyl)-6,7-diphenyl-
3,5-dihydro-1,2,4-triazolo[4,3-b][1,2,4]triazine (6a,b). General
procedure: To a solution of 4 (1.52 g, 5 mmol) in aqueous
potassium hydroxide [(0.28 g, 5 mmol) in distilled water
(16 mL)] was added a solution of 2,3,4,6-tetra-O-acetyl-a-D-
gluco (5a) or 2,3,4-tri-O-acetyl-a-D-Xylopyranosyl bromide
(5b) (5 mmol) in acetone (20 mL). The reaction mixture
was stirred at room temperature until reaction was judged
complete by TLC using chloroform/methanol 99.5:0.5. The
solvent was evaporated under reduced pressure at 40ꢀC and
the residue was washed with distilled water to remove potas-
sium bromide formed. The product was dried, and recrystal-
lized from ethanol.
3-(b-D-Xylopyranosyl)-6,7-diphenyl-3,5-dihydro-1,2,4-tria-
zolo[4,3-b][1,2,4]triazine (7b). This compound was obtained
as yellow solid, 1.91 g (80%), mp 195–196ꢀC; IR (KBr) m:
3470–34481 (OH), 1610 (C¼¼N) cmꢁ1
;
1H NMR (DMSO-d6,
300 MHz): d 3.44 (m, 2H, H-50,500), 3.97 (m, 2H, H-30,40),
4.29 (t, J ¼ 9.4 Hz, 1H, H-20), 4.61 (t, J ¼ 6.2, 1H, OH), 5.16
0
0
(m, 1H, OH), 5.25 (m, 1H, OH), 5.74 (d, J1 ,2 ¼ 9.8 Hz, 1H,
H-10), 7.32 (m, 3H, Ar-H), 7.37 (m, 3H, Ar-H), 7.40 (m, 2H,
Ar-H), 7.77 (m, 2H, Ar-H); 13C NMR (DMSO-d6, 75 MHz): d
62.41 (C-5), 64.66 (C-4), 68.98 (C-3), 71.30 (C-2), 88.75 (C-
1), 129.12-143.87 (Ar-C), 154.78, 156.52, 157.89, 158.34
(4C¼¼N). Anal. Calcd for C21H19N5O4S: C, 57.66; H, 4.38; N,
16.01. Found: C, 57.48; H, 4.29; N, 15.77.
3-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-6,7-diphenyl-
3,5-dihydro-1,2,4-triazolo[4,3-b][1,2,4]triazine (6a). This com-
pound was obtained as yellow solid, 2.58 g (81%), mp 139–
140ꢀC; IR (KBr) m: 1742 (C¼¼O), 1612 (C¼¼N) cmꢁ1
;
1H
NMR (CDCl3, 300 MHz): d 1.87, 1.89, 2.05, 2.10 (4s, 12H,
4CH3), 4.02 (m, 1H, H-50), 4.10 (dd, J ¼ 11.4 Hz, J ¼ 2.8
Hz, 1H, H-60), 4.14 (dd, J ¼ 11.4, 3.2 Hz, 1H, H-600), 4.90 (t,
J ¼ 9.3 Hz, 1H, H-40), 5.18 (dd, J ¼ 9.6 Hz, J ¼ 9.3 Hz, 1H,
General procedure for the synthesis of compounds
8a,b. To a well stirred solution of the respective monosaccha-
ride (5 mmol) in water (1 mL), and glacial acetic acid (1 mL)
was added 3-hydrazinyl-5,6-diphenyl-1,2,4-triazine (3) (1.32 g,
5 mmol) in ethanol (15 mL). The mixture was heated under
reflux for 3 h and the resulting solution was concentrated and
left to cool. The formed precipitate was filtered off, washed with
water and ethanol, then dried and recrystallized from ethanol.
3-(2-D-Galactopentitolylidenehydrazinyl)-5,6-diphenyl-1,2,4-
triazine (8a). This compound was obtained as white solid
1.81 g (85%), mp 197–198ꢀC; IR (KBr) m: 3478–3466 (OH),
H-30), 5.34 (t, J ¼ 9.6 Hz, 1H, H-20), 5.70 (d, J1 ,2 ¼ 10.2 Hz,
1H, H-10), 7.28 (m, 3H, Ar-H), 7.36 (m, 3H, Ar-H), 7.39
(m, 2H, Ar-H), 7.76 (m, 2H, Ar-H); 13C NMR (CDCl3, 75
MHz): d 19.31, 19.52, 20.16, 20.26 (4CH3), 62.87 (C-60),
64.21 (C-40), 68.62 (C-30), 70.34 (C-20), 71.82 (C-50), 88.98
(C-10), 127.26–143.14 (Ar-C), 154.78, 156.52, 157.92, 158.18
(4C¼¼N), 169.78, 170.14, 170.56, 170.84 (4C¼¼O). Anal. Calcd
for C30H29N5O9S: C, 56.69; H, 4.60; N, 11.02. Found: C,
56.37; H, 4.49; N, 10.89.
0
0
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2011
Synthesis and Antitumor Activity of New 1,2,4-Triazine and [1,2,4]Triazolo[4,3-b]-
[1,2,4]triazine Derivatives and Their Thioglycoside and Acyclic C-Nucleoside Analogs
141
3310 (NH), 1610 (C¼¼N) cmꢁ1
;
1H NMR (DMSO-d6, 300
(t, J ¼ 7.2 Hz, 1H, H-10), 5.75 (d, J ¼ 7.4 Hz, 1H, triazole-
H), 7.30 (m, 3H, Ar-H), 7.33 (m, 3H, Ar-H), 7.44 (m, 2H, Ar-
H), 7.78 (m, 2H, Ar-H); 13C NMR (CDCl3, 75 MHz): d 20.32,
20.52, 20.64, 20.78, 29.70 (5CH3), 62.90 (C-40), 65.38 (C-30),
68.41 (C-20), 71.18 (C-10), 92.24 (CAN-Ac), 128.12–143.45
(Ar-C), 152.46, 153.58, 156.25 (3C¼¼N), 169.14, 169.79,
170.12, 170.75, 171.10 (5CO). Anal. Calcd for C30H31N5O9:
C, 59.50; H, 5.16; N, 11.56. Found: C, 59.40; H, 5.11; N,
11.39.
MHz): d 3.30–3.39 (m, 2H, H-60,600), 3.73 (m, 1H, H-50), 4.12
(m, 1H, H-40), 4.25 (t, J ¼ 7.4 Hz, 1H, H-30), 4.36 (dd, J ¼
7.4 Hz, J ¼ 7.8 Hz, 1H, H-20), 4.45 (m, 1H, OH), 4.48 (d, J ¼
6.4 Hz, 1H, OH), 5.19 (m, 1H, OH), 5.63 (t, J ¼ 4.6 Hz, 1H,
OH), 5.79 (t, J ¼ 4.6 Hz, 1H, OH), 7.27 (m, 3H, Ar-H), 7.34
0
0
(m, 3H, Ar-H), 7.42 (m, 2H, Ar-H), 7.48 (d, 1H, J1 ,2 ¼ 7.8
Hz, H-10), 7.73 (m, 2H, Ar-H), 9.94 (s, 1H, NH); 13C NMR
(DMSO-d6, 75 MHz): d 62.10 (C-60), 63.05 (C-50), 69.21
(C-40), 74.44 (C-20), 75.71 (C-30), 127.88–142.22 (Ar-C),
150.89 (C-10), 152.608 (C-5), 153.57 (C-6), 156.92 (C-3).
Anal. Calcd for C21H23N5O5: C, 59.29; H, 5.45; N, 16.46.
Found: C, 59.11; H, 5.30; N, 16.39.
Ethyl 2-(5,6-diphenyl-1,2,4-triazin-3-ylsulphanyl)acetate
(10). To a well stirred solution of 1 (2.65 g, 10 mmol) and
dry potassium carbonate (1.38 g, 10 mmol) in acetone (15
mL) was added ethyl chloroacetate (1.22 g, 10 mmol). The
reaction mixture was stirred at room temperature for 6 h and
then poured on ice-cold water. The precipitated solid was fil-
tered, washed with water and recrystallized from ethanol to
give compound 10 as white crystals, 2.73 g (78%), mp 141–
5,6-Dipheny-3-(2-D-ribotetritolylidenehydrazinyl)-1,2,4-tri-
azine (8b). This compound was obtained as white solid, 1.64
g (83%), mp 195–196ꢀC; IR (KBr) m: 3475–3448 (OH), 3325
1
(NH), 1612 (C¼¼N) cmꢁ1; H NMR (DMSO-d6, 300 MHz): d
1
142ꢀC IR (KBr) m: 1738 (C¼¼O), 1605 (C¼¼N) cmꢁ1; H NMR
3.49–3.53 (m, 2H, H-50,500), 3.73 (m, 1H, H-40), 4.12 (m, 1H,
H-30), 4.36 (dd, J ¼ 7.4 Hz, J ¼ 7.8 Hz, 1H, H-20), 4.45 (m,
1H, OH), 4.88 (d, J ¼ 6.4 Hz, 1H, OH), 5.60 (t, J ¼ 4.6 Hz,
1H, OH), 5.72 (t, J ¼ 4.6 Hz, 1H, OH), 7.28 (m, 3H, Ar-H),
(CDCl3, 300 MHz): d 1.84 (t, J ¼ 5.2 Hz, 1H, CH3), 3.92
(q, J ¼ 5.2 Hz, 2H, CH2), 4.88 (s, 2H, CH2), 7.30 (m, 3H,
Ar-H), 7.36 (m, 3H, Ar-H), 7.51 (m, 2H, Ar-H), 7.77 (m, 2H,
Ar-H); 13C NMR (CDCl3, 75 MHz): d 16.44 (CH3), 41.24,
48.14 (2CH2), 127.75–141.18 (Ar-C), 152.14 (C-5), 153.24
(C-6), 156.28 (C-3), 169.14 (C¼¼O). Anal. Calcd for
C19H17N3O2S: C, 64.94; H, 4.88; N, 11.96. Found: C, 64.72;
H, 4.69; N, 11.78.
0
0
7.36 (m, 3H, Ar-H), 7.42 (m, 2H, Ar-H), 7.52 (d, 1H, J1 ,2
¼
7.8 Hz, H-10), 7.73 (m, 2H, Ar-H), 9.98 (s, 1H, NH); 13C
NMR (DMSO-d6, 75 MHz): d 62.22 (C-50), 63.15 (C-40),
69.32 (C-30), 74.56 (C-20), 127.882–142.28 (Ar-C), 150.44
(C-10), 152.49 (C-5), 153.50 (C-6), 156.38 (C-3). Anal. Calcd
for C20H21N5O4: C, 60.75; H, 5.35; N, 17.71. Found: C,
60.65; H, 5.29; N, 17.58.
2-(5,6-Diphenyl-1,2,4-triazin-3-ylsulphanyl)acetohydrazide
(11). Hydrazine hydrate (0.5 g, 10 mmol) was added to a solu-
tion of 10 (3.51 g, 10 mmol) in ethanol (25 mL) and the reac-
tion mixture was heated under reflux for 3 h. After cooling,
the precipitated solid was filtered, washed with ethanol and
recrystallized from ethanol to afford compound 11 as white
crystals, 2.99 g (89%), mp 203–204ꢀC; IR (KBr) m: 3476
2-Acetyl-3-(O-acetylsugar)-6,7-diphenyl-2H,3H-1,2,4-triazo-
lino[4,3-b][1,2,4]triazine (9a,b). General procedure: A solution
of 8a,b (1 mmol) in acetic anhydride (5 mL) was boiled under
reflux for 1 h. The resulting solution was poured onto crushed
ice, and the product that separated out was filtered off, washed
with sodium hydrogen carbonate and water and then dried
well.
1
(NH2), 3325 (NH), 1678 (C¼¼O), 1610 (C¼¼N) cmꢁ1; H NMR
(DMSO-d6, 300 MHz): d 4.88 (s, 2H, CH2), 5.48 (s, 2H,
NH2), 7.29 (m, 3H, Ar-H), 7.32 (m, 3H, Ar-H), 7.50 (m, 2H,
Ar-H), 7.75 (m, 2H, Ar-H), 10.05 (s, IH, NH); 13C NMR
(DMSO-d6, 75 MHz): 48.31 (CH2), 127.70–141.12 (Ar-C),
152.65 (C-5), 153.48 (C-6), 156.64 (C-3), 169.10 (C¼¼O).
Anal. Calcd for C17H15N5OS: C, 60.52; H, 4.48; N, 20.76.
Found: C, 60.38; H, 4.32; N, 20.59.
2-Acetyl-3-(2,3,4,5,6-penta-O-acetyl-D-galactopentitolyl)-6,7-
diphenyl-2H,3H-1,2,4-triazolino[4,3-b][1,2,4]triazine (9a). This
compound was obtained as white solid, 0.59 g (78%), mp
139–140ꢀC; IR (KBr) m: 1742 (C¼¼O), 1668 (C¼¼O), 1610
(C¼¼N) cmꢁ1
;
1H NMR (CDCl3, 300 MHz): d 1.85, 1.98,
2.03, 2.10, 2.18, 2.23 (6s, 18H, 6CH3), 4.16 (dd, J ¼ 11.4 Hz,
J ¼ 2.8 Hz, 1H, H-50), 4.21 (dd, J ¼ 11.4 Hz, J ¼ 3.2 Hz,
1H, H-500), 5.14 (m, 1H, H-40), 5.26 (dd, J ¼ 6.5 Hz, J ¼ 7.4
Hz, 1H, H-30), 5.52 (dd, J ¼ 7.4 Hz, J ¼ 7.2 Hz, 1H, H-20),
5.71 (t, J ¼ 7.2 Hz, 1H, H-10), 5.77 (d, J ¼ 7.6 Hz, 1H, tria-
zole-H), 7.29 (m, 3H, Ar-H), 7.34 (m, 3H, Ar-H), 7.42
(m, 2H, Ar-H), 7.74 (m, 2H, Ar-H); 13C NMR (CDCl3, 75
MHz): d 20.34, 20.52, 20.58, 20.67, 20.75, 29.69 (6CH3),
62.90 (C-50), 65.38 (C-40), 68.41 (C-30), 69.7 (C-20), 71.15
(C-10), 92.12 (CAN-Ac), 127.82-142.44 (Ar-C), 152.47,
153.55, 156.27 (3C¼¼N), 169.12, 169.77, 170.14, 170.48,
170.78, 171.05 (6CO). Anal. Calcd for C33H35N5O11: C,
58.49; H, 5.21; N, 10.33. Found: C, 58.31; H, 5.15; N, 10.29.
2-Acetyl-3-(2,3,4,5-tetra-O-acetyl-D-ribotetritolyl)-6,7-diphenyl-
2H,3H-1,2,4-triazolino[4,3-b][1,2,4]triazine (9b). This compound
was obtained as white solid, 0.48 g (75%) mp 141–142ꢀC; IR
3-[(1,3,4-Oxadiazolo-2(3H)-thion-5-yl)methylsulfanyl]-5,6-di-
phenyl-1,2,4-triazine (12). To a solution of 11 (3.37 g, 10
mmol) in ethanol (20 mL) was added a solution of potassium
hydroxide (0.56 g, 10 mmol) in water (2 mL) and carbon
disulphide (4 mL). The solution was heated under reflux for
12 h. The solvent was evaporated and the residue was dis-
solved in water, filtered, and acidified with dilute hydrochloric
acid. The precipitate was filtered off, washed with water, and
recrystallized from ethanol as yellow crystals, 3.03 g (80%),
mp 190–191ꢀC; IR (KBr) m: 3352 (NH), 1610 (C¼¼N) cmꢁ1
;
1H NMR (DMSO-d6, 300 MHz): d 4.95 (s, 2H, CH2), 7.28
(m, 3H, Ar-H), 7.30 (m, 3H, Ar-H), 7.33 (m, 2H, Ar-H), 7.71
(m, 2H, Ar-H), 12.78 (s, 1H, NH); 13C NMR (DMSO-d6, 75
MHz,): d 47.14 (CH2), 127.72–141.25 (Ar-C), 152.57 (C-5),
153.37 (C-6), 155.15 (oxadiazole C-5), 156.49 (C-3), 171.15
(C¼¼S). Anal. Calcd for C18H13N5OS2: C, 56.97; H, 3.45; N,
18.46. Found: C, 56.78; H, 3.41; N, 18.32.
(KBr) m: 1738 (C¼¼O), 1670 (C¼¼O), 1605 (C¼¼N) cmꢁ1
;
1H
NMR (CDCl3, 300 MHz): d 1.86, 1.97, 2.03, 2.12, 2.28 (5s,
15H, 5CH3), 4.18 (dd, J ¼ 11.2 Hz, J ¼ 2.8 Hz, 1H, H-40),
4.24 (dd, J ¼ 11.2 Hz, J ¼ 3.4 Hz, 1H, H-400), 5.15 (m, 1H,
H-30), 5.25 (dd, J ¼ 6.8 Hz, J ¼ 7.2 Hz, 1H, H-20), 5.54
3-{[2-(2,3,4,6-Tetra-O-acetyl-ꢀ-D-glucopyranosylsulfanyl)-
1,3,4-oxadiazolo-2(3H)-thion-5-yl]methylsulfanyl}-5,6-diphenyl-
1,2,4-triazine (13). To a solution of the thiol 12 (1.89 g, 5
Journal of Heterocyclic Chemistry
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142
W. A. El-Sayed, I. F. Nassar, and A. A.-H Abdel-Rahman
Vol 48
[4] Creasey, W. A.; Fink, M. E.; Handschumacker, R. E.;
Calabresi, P. Cancer Res 1963, 23, 444.
mmol) in aqueous potassium hydroxide [(0.28 g, 5 mmol) in
distilled water (15 mL)] was added a solution of 2,3,4,6-tetra-
O-acetyl-a-D-glucopyranosyl bromide (5a) (2.05 g, 5 mmol) in
acetone (20 mL). The reaction mixture was stirred at room
temperature until reaction was judged complete by TLC using
chloroform/methanol 99.5:0.5. The solvent was evaporated
under reduced pressure at 40ꢀC and the residue was washed
with distilled water to remove potassium bromide formed. The
product was dried, and recrystallized from ethanol as yellow
crystals 2.83 g (80%), mp 128–130ꢀC; IR (KBr) m: 1748
[5] Walters, T. R.; Aur, R. J. A.; Hernandez, K.; Vietti, T.;
Pinkel, D. Cancer 1972, 29, 1057.
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[7] El Ashry, E. S. H.; Rashed, M.; Taha, E.; Ramadan, E. Adv
Heterocycl Chem 1994, 59, 39.
[8] Diana, P.; Barraja, P.; Lauria, A.; Almerico, A. M.; Dattolo,
G. Eur J Med Chem 2002, 37, 267.
(C¼¼O), 1608 (C¼¼N) cmꢁ1
;
1H NMR (CDCl3, 300 MHz): d
[9] Patil, S. A.; Otter, R. S.; Klein, R. S. Tetrahedron Lett
1994, 35, 5339.
1.86, 1.88, 2.05, 2.11 (4s, 12H, 4CH3), 4.05 (m, 1H, H-50),
4.14 (dd, J ¼ 11.4 Hz, J ¼ 3.2 Hz, 1H, H-60), 4.14 (dd, J ¼
11.4 Hz, J ¼ 3.4, 1H, H-600), 4.91 (t, J ¼ 9.2 Hz, 1H, H-40),
4.97 (s, 2H, CH2), 5.17 (dd, J ¼ 9.4 Hz, J ¼ 9.2 Hz, 1H, H-
30), 5.35 (t, J2,3 ¼ 9.4 Hz, 1H, H-20), 5.72 (d, J1,2 ¼ 9.8 Hz,
1H, H-10), 7.29 (m, 3H, Ar-H), 7.37 (m, 3H, Ar-H), 7.38 (m,
2H, Ar-H), 7.78 (m, 2H, Ar-H); 13C NMR (CDCl3, 75 MHz):
d 19.32, 19.54, 20.16, 20.25 (4CH3), 48.56 (CH2), 62.89 (C-
60), 64.22 (C-40), 68.64 (C-30), 70.35 (C-20), 71.81 (C-50),
89.12 (C-10), 127.25–143.48 (Ar-C), 152.22 (C-5), 153.45 (C-
6), 155.35 (oxadiazole C-2), 156.48 (C-3), 158.14 (oxadiazole
C-5), 169.77, 170.18, 170.59, 170.87 (4C¼¼O). Anal. Calcd for
C32H31N5O10S2: C, 54.15; H, 4.40; N, 9.87. Found: C, 53.89;
H, 4.29; N, 9.72.
[10] Partridge, M. W., Stevens, M. F. G. J Chem Soc (C) 1966,
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3-{[2-(ꢀ-D-Glucopyranosylsulfanyl)-1,3,4-oxadiazolo-2(3H)-
thion-5-yl]methylsulfanyl}-5,6-diphenyl-1,2,4-triazine (14). Dry
gaseous ammonia was passed through a solution of the acety-
lated thioglycosides 14 (3.55 g, 5 mmol) in dry methanol
(15 mL) at 0ꢀC for 1 h, and then the mixture was stirred at
0ꢀC for about 6 h. The solvent was evaporated under reduced
pressure at 40ꢀC to give a solid residue, which was recrystal-
lized from ethanol as yellow crystals 2.16 g (80%), mp 192–
[18] Abdel-Rahman, R. M.; Morsy, J. M.; El-Edfawy, S. Phar-
mazie 1999, 54, 667.
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[20] Brajeswar, P. Carbohydr Res 1984, 126, 27.
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2006, 62, 2943.
1
193ꢀC; IR (KBr) m: 3478–3450 (OH), 1608 (C¼¼N) cmꢁ1; H
NMR (DMSO-d6, 300 MHz): d 3.39 (m, 2H, H-60,600), 3.44
(m, 1H, H-50), 3.91 (m, 2H, H-30,40), 4.28 (t, J ¼ 9.2 Hz, 1H,
H-20), 4.72 (t, J ¼ 6.4, 1H, OH), 4.84 (d, J ¼ 6.6 Hz1H, OH),
5.05 (s, 2H, CH2), 5.22 (m, 1H, OH), 5.25 (m, 1H, OH), 5.74
[24] Awad, O. M. E.; Attia, W. E.; El Ashry, E. S. H. Carbo-
hydr Res 2004, 339, 469.
(d, J1 ,2 ¼ 9.8 Hz, 1H, H-10), 7.29 (m, 3H, Ar-H), 7.37 (m,
3H, Ar-H), 7.41 (m, 2H, Ar-H), 7.80 (m, 2H, Ar-H); 13C
NMR (DMSO-d6, 75 Hz): d 49.28 (CH2), 61.49 (C-60), 64.18
(C-40), 68.88 (C-30), 71.37 (C-20), 72.18 (C-50), 89.18 (C-10),
129.22–143.68 (Ar-C), 152.42 (C-5), 153.76 (C-6), 155.86
(oxadiazole C-2), 156.94 (C-3), 158.92 (oxadiazole C-5). Anal.
Calcd for C24H23N5O6S2: C, 53.22; H, 4.28; N, 12.93. Found:
C, 53.40; H, 4.22; N, 12.75.
0
0
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[28] El-Sayed, W. A.; Ramiz, M. M. M.; Abdel-Rahman, A. A.
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H. J Carbohydr Chem 2008, 27, 357.
Acknowledgments. Supply of Ehrlich Ascites Carcinoma Cells
(EAC) by National Cancer Institute (NCI) and performance of bi-
ological evaluation by the laboratory of biochemistry, radiation
research and technology center, Cairo, Egypt, Cairo University,
Egypt are gratefully acknowledged.
[30] El-Sayed, W. A.; Abdel-Rahman, A. A.-H.; Ramiz, M. M.
M. Z Naturforsch 2009, 64c, 323.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2011
Synthesis and Antitumor Activity of New 1,2,4-Triazine and [1,2,4]Triazolo[4,3-b]-
[1,2,4]triazine Derivatives and Their Thioglycoside and Acyclic C-Nucleoside Analogs
143
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet