Synthesis and in vitro anti-tumor activity of a new class of acyclic thioglycosides

Article abstract of DOI:10.1080/15257770.2015.1016168

The reaction of sodium 2-cyano-ethylene-1-thiolate salts with 2,3,4,6-tetra-O-acetyl-D-gluco- and D-galactopyranosyl bromides and with 2,3,4-tri-O-acetyl-D-xylo-. and L-arabinopyranosyl bromides, respectively, afforded new thioglycosides. Heating of the resultout glycosides with hydrazine produced pyrazole derivatives. The cytotoxicities toward the hepatoma cell line (HEPG2) of some synthesized compounds were tested. Some compounds showed high cytotoxic activity against (HEPG2) cell line. The OH moieties in the free glycosides were vital for potency. The synthesis procedures, spectroscopic data and antitumor activities for the prepared compounds are reported herein.

Full text of DOI:10.1080/15257770.2015.1016168

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Synthesis and in Vitro Anti-Tumor
Activity of A New Class of Acyclic
Thioglycosides
G. H. Elgemeiea & N. M. Saberb
a Chemistry Department, Faculty of Science, Helwan University,
Helwan, Cairo, Egypt
b Chemistry Department, Faculty of Science, Suez Canal University,
Suez, Egypt
Published online: 09 Jul 2015.
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To cite this article: G. H. Elgemeie & N. M. Saber (2015) Synthesis and in Vitro Anti-Tumor Activity
of A New Class of Acyclic Thioglycosides, Nucleosides, Nucleotides and Nucleic Acids, 34:7, 463-474,
DOI: 10.1080/15257770.2015.1016168
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Nucleosides, Nucleotides and Nucleic Acids, 34:463–474, 2015
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770.2015.1016168
SYNTHESIS AND IN VITRO ANTI-TUMOR ACTIVITY OF A NEW
CLASS OF ACYCLIC THIOGLYCOSIDES
G. H. Elgemeie1 and N. M. Saber2
1Chemistry Department, Faculty of Science, Helwan University, Helwan, Cairo, Egypt
2Chemistry Department, Faculty of Science, Suez Canal University, Suez, Egypt
The reaction of sodium 2-cyano-ethylene-1-thiolate salts with 2,3,4,6-tetra-O-acetyl-D-gluco- and
2
D-galactopyranosyl bromides and with 2,3,4-tri-O-acetyl-D-xylo-. and L-arabinopyranosyl bromides,
respectively, afforded new thioglycosides. Heating of the resultout glycosides with hydrazine produced
pyrazole derivatives. The cytotoxicities toward the hepatoma cell line (HEPG2) of some synthesized
compounds were tested. Some compounds showed high cytotoxic activity against (HEPG2) cell line.
The OH moieties in the free glycosides were vital for potency. The synthesis procedures, spectroscopic
data and antitumor activities for the prepared compounds are reported herein.
Keywords
Acyclic thioglycosides; sodium 2-cyano-ethylene-1-thiolates; antitumor
activity; HEPG2
1. INTRODUCTION
As a part of our program directed toward the development of new, ef-
ficient, and simple procedures for the synthesis of antimetabolites,[1,2] we
have reported different successful approaches for the synthesis of folic acid,
pyrimidine nucleoside, and mercaptopurine analogues.[3,4] Recently, there
is increasing interest in the synthesis of nucleoside analogues and their incor-
poration into DNA sequences for the study of ligand–DNA and protein–DNA
interactions.[5] A variety of nucleoside derivatives has been prepared that
result in the deletion, or change in the nature of the functional groups
present on the heterocyclic bases. Such analogues permit the synthesis of
oligodeoxynucleotides in which a single functional goup at a preselected
position has been deleted or otherwise altered.[6] Recently, we reported the
Received 1 July 2014; accepted 31 January 2015.
Address correspondence to G. H. Elgemeie, Chemistry Department, Faculty of Science, Helwan
University, Helwan, Cairo, Egypt. E-mail: elgemeie@yahoo.com
Color versions of one or more of the figures in the article can be found online at
www.tandfonline.com/lncn.
463

464
G. H. Elgemeie and N. M. Saber
synthesis of different novel pyridine thioglycosides, which revealed antago-
nistic activity.[7] We have also reported the use of dihydropyridine thiogly-
cosides as substrates or inhibitors of protein glycosylation.[8] Additionally,
pyrazole derivatives are one important class of heterocyclic compounds that
may possess antibacterial, antifungal, anti-inflammatory, and tumor necrosis
inhibitory activity.[9,10] On the basis of these findings, it was of interest to
synthesize modified and acyclic thioglycosides to search for more effective
agents.
1.1. Chemistry
This work reports the synthesis of acrylamide thioglycoside deriva-
tives as a new class of thioglycosides through a one-pot synthesis. The
sodium 2-cyanoethylene-1-thiolate salts 3a–d were chosen as the key in-
termediates. The sequences of reactions are summarized in the following
chart (Chart 1).
Thus, it has been found that substituted anilide derivatives 1a–d were
refluxed with thioacetamide 2 in EtONa/EtOH to give the correspond-
ing stable sodium 2-cyano-ethylene-1-thiolate salts 3a–d. These salts reacted
with 2,3,4,6-tetra-O-acetyl-α-d-gluco- and galactopyranosyl bromides 4a,b and
with 2,3,4-tri-O-acetyl-α-d-xylo- and β-l-arabinopyranosyl bromides 4c,d in
ethanol at room temperature to give in a high yield the corresponding
S-glucosides 5a–d, S-galactosides 5e-h, S-xylosides 5i–l, and S-arabinosides
5m–p, respectively (Chart 1).
The structures of the compounds 5a–p were established by their elemen-
1
tal analyses and spectral data (IR, H NMR). For example, the analytical
data for 5a revealed a molecular formula C25H28N2O10S. The 1H NMR spec-
trum showed the anomeric proton as a doublet at δ 4.85 ppm. The other six
glucose protons resonated at δ 3.70–5.50 ppm and the four acetyl groups ap-
peared as four singlets at δ 2.00–2.15 ppm. The spectral data of the derivative
5i also confirmed its expected structure. The 1H NMR spectrum showed the
anomeric proton as a doublet at δ 4.80 ppm. The other five xylose protons ap-
peared as a multiplet at δ 3.40–5.25 ppm, the three acetyl groups appeared as
singlets at δ 2.00–2.20 ppm. Deacetylation of 5a–p using a saturated solution
of methanolic ammonia at room temperature afforded the corresponding
free glycosides 6a-p (Chart 1). We suggested that 5a–d should be present
in the E and not in the Z form. This was shown by refluxing of 5a–d with
hydrazine in ethanol to give the corresponding 5-aminopyrazole derivatives
8a–d (Chart 1). Alternatively, 8a–d could be prepared by reaction of 7a–d
with hydrazine hydrate. Compounds 7a–d were prepared by the reaction
of the sodium 2-cyano-ethylene-1-thiolate salts 3a–d with methyl iodide in
ethanol at room temperature (Chart 1).
To sum up, we have achieved the synthesis of acyclic thioglycosides by the
reaction of the sodium 2-cyanoethylene-1-thiolate salts with glycosyl halides.

Synthesis and In Vitro Anti-Tumor Activity
465
CHART 1
These thioglycosides can be utilized as starting materials for the synthesis of
other novel carbohydrate derivatives.
2. BIOLOGICAL ACTIVITY
Sixteen of the newly synthesized compounds were screened for their
anticancer activities (Tables 1–3, Figs. 1–3). Pharmacological evaluation of

466
G. H. Elgemeie and N. M. Saber
CHART 2

Synthesis and In Vitro Anti-Tumor Activity
467
CHART 3
TABLE 1 Cytotoxcity of the synthesized acetyled acyclic thioglycosides on liver (HEPG2) cancer cell line
Comp.
IC50 (μg/mL) Liver
No.
5a
5e
5i
5g
cell line (HEPG2)
19
13.5
11.7
23.1
19
5m
5n
23.9
25
(5FU)b
b5FU (5-flurouracil), standard drug for liver cancer.
TABLE 2 Cytotoxcity of the synthesized free acyclic thioglycosides on liver (HEPG2) cancer cell line
Comp.
IC50 (μg/mL) Liver
No.
6a
6e
6i
6g
cell line (HEPG2)
13.7
16.7
19.4
12.5
16
6m
6n
22.5
25
(5FU)b
b5FU (5-flurouracil), standard drug for liver cancer.
TABLE 3 Cytotoxcity of the synthesized pyrazole derivatives on liver (HEPG2) cancer cell line
Comp.
IC50 (μg/mL) Liver
No.
8a
8b
cell line (HEPG2)
19
13.5
11.7
19
8c
8d
(5FU)b
25
b5FU (5-flurouracil), standard drug for liver cancer.

468
G. H. Elgemeie and N. M. Saber
FIGURE 1 Representative Graph showing survival of (HEPG2) cell grown compared to 5-Flurouracil
(5FU) in the presence of increasing concentrations of compounds 5a, 5e, 5g, 5i, 5m, and 5n.
those compounds against a hepatoma cell line (HEPG2) revealed them to
possess high or moderate anti-tumor activities. One dose assay has been
tested for compounds 5a, 5e, 5i, 5g, 5m, 5n, 6a, 6e, 6i, 6g, 6m, 6n, 8a, 8b,
8c and 8d. IC50 values ranging from 11.7 to 23.9 (μg/mL) compared with
standard drug 5-fluorouracil. Acyclic free thioglycosides 6a showed higher
anticancer activity than their corresponding acetylated derivative 5a. Fur-
thermore, compounds 5e, 6a, and 8b exhibited high activity against tumor
(HEPG2) cell line, as well as compounds 5i, 6g, and 8c. The OH moieties in
the free glycosides were vital for potency.
FIGURE 2 Representative Graph showing survival of (HEPG2) cell grown compared to 5-Flurouracil
(5FU) in the presence of increasing concentrations of compounds 6a, 6e, 6g, 6i, 6m, and 6n.

Synthesis and In Vitro Anti-Tumor Activity
469
FIGURE 3 Representative Graph showing survival of (HEPG2) cell grown compared to 5-Flurouracil
(5FU) in the presence of increasing concentrations of compounds 8a, 8b, 8c, and 8d.
3. EXPERIMENTAL
All melting points were uncorrected on a Gallenkamp melting point
apparatus. The IR spectra were recorded (KBr disk) on a Perkin Elmer 1650
FT-IR instrument. The 1H NMR spectra were measured on a Varian 400 MHz
spectrometer for solution (CD3)2SO using Si(CH3)4 as an internal standard.
Elemental analyses were obtained from The Micro analytical Data Center at
Cairo University, Egypt.
Progress of the reactions was monitored by TLC using Aluminum sheets
coated with silica gel F254 (Merck). Viewing under a short-wavelength UV
lamp effected detection. All evaporations were carried out under reduced
pressure at 40◦C.
3.1. 3-Methyl-N-aryl-2-cyano-3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-
or galactopyranosylthio) or (2ꢀ,3ꢀ,4ꢀ-tri-O-acetyl-β-D-xylo- and
β-L-arabinopyranosylthio)acrylamides (5a–p)
A mixture of N -substituted cyanoacetamide derivatives 1a–d (0.01 mol)
and thioacetamide 2 (0.01 mol) were stirred for 30 min. at room temper-
ature in ethoxide (0.01 mol) then were refluxed for 1 h. After cooling, a
solution of 2,3,4,6-tetra-O-acetyl-α-d-gluco-or galactopyranosyl bromide and
2,3,4-tri-O-acetyl-α-d-xylo- or β-L-arabinopyranosyl bromide 4a,b,c,d, respec-
tively (0.01 mol) in acetone (20 mL) was added. The reaction mixture was
stirred at room temperature overnight until completion (TLC), and then was
poured on distilled ice cold water to remove the formed sodium bromide.
The resulting solid product was dried and crystallized from ethanol.
5a: As orange crystals, mp 150◦C, yield (25%). IR (KBr) νmax/cm−1, 3334
(NH); 2194 (CN); 1752 (COCH3). 1H NMR: δ 1.60 (s, 3H, CH3); 2.00–2.15
(m, 12H, 4CH3CO); 3.70–5.50 (m, 6H of acetyled glucose); δ 4.85 (d, 1H,

470
G. H. Elgemeie and N. M. Saber
anomeric); 7.20–7.65 (m, 6H, C6H5, NH). C25H28N2O10S, Calcd: C, 54.73%;
H, 5.15%; N, 5.11%. Found: C, 54.75%; H, 5.15%; N, 5.15%.
5b: As orange crystals, mp 124◦C, yield (25%). IR (KBr) νmax/cm−1, 3327
(NH); 2209 (CN); 1748 (COCH3).1H NMR: δ 2.00–2.20 (m, 12H, 4CH3CO);
2.35 (s, 3H, CH3); 2.50 (s, 3H, CH3); 3.70–5.25 (m, 6H of acetyled glucose);
4.85 (d, 1H, anomeric); 7.20–7.80 (m, 5H, C6H4, NH). C26H30N2O10S, Calcd:
C, 55.50%; H, 5.37%; N, 4.98%. Found: C, 55.53%; H, 5.42%; N, 5.08%.
5c: As orange crystals, mp 148◦C, yield (24%). IR (KBr) νmax/cm−1,
1
3463 (NH), 2359 (CN), 1746 (COCH3). H NMR: δ 1.60 (s, 3H, CH3);
2.00–2.20 (m, 12H, 4CH3CO); 3.80 (s, 3H, OCH3); 3.65–5.30 (m, 6H, of
acetyled glucose); 4.85 (d, 1H, anomeric); 6.90–7.70 (m, 5H, C6H4, NH).
C26H30N2O11S, Calcd: C, 53.96%; H, 5.22%; N, 4.84%. Found: C, 53.99%;
H, 5.24%; N, 4.87%.
5d: As orange crystals, mp 126◦C, yield (25%). IR (KBr) νmax/cm−1,
1
3321 (NH), 2225 (CN), 1747 (COCH3). H NMR: δ 1.60 (s, 3H, CH3);
2.00–2.20 (m, 12H, 4CH3CO); 3.70–5.30 (m, 6H, of acetyled glucose); 4.85
(d, 1H, anomeric); 7.30-7.80 (m, 5H, C6H4, NH). C25H27ClN2O10S, Calcd:
C, 51.50%; H, 4.66%; N, 4.80%. Found: C, 51.51%; H, 4.69%; N, 4.85%.
5e: As orange crystals, mp 166◦C, yield (40%). IR (KBr) νmax/cm−1. 3478
(NH); 2255 (CN); 1747 (COCH3). 1H NMR: δ 1.60 (s, 3H, CH3); 2.00–2.20
(m, 12H, 4CH3CO); 3.90–5.50 (m, 6H, of acetyled galactose); 4.85 (d, 1H,
anomeric); 7.20–7.60 (m, 6H, C6H5, NH). C25H28N2O10S, Calcd: C, 54.73%;
H, 5.15%; N, 5.11%. Found: C, 54.74%; H, 5.17%; N, 5.11%.
5f: As orange crystals, mp 106◦C, yield (35%). IR (KBr) νmax/cm−1,
1
3325 (NH), 2214 (CN), 1747 (COCH3). H NMR: δ1.70 (s, 3H, CH3); δ
2.00–2.30 (m, 12H, 4CH3CO); 2.50 (s, 3H, CH3); 3.80–5.40 (m, 6H, of
acetyled galactose); 4.85 (d, 1H, anomeric); 7.20–7.80 (m, 5H, C6H4, NH).
C26H30N2O10S, Calcd: C, 55.50%; H, 5.37%; N, 4.98%.Found: C, 55.50%; H,
5.36%; N, 5.00%.
5g: As orange crystals, mp 196◦C, yield (55%). C26H30N2O11S, Calcd: C,
53.96%; H, 5.22%; N, 4.84%. Found: C, 53.99%; H, 5.22%; N, 4.86%.
5h: As orange crystals, mp 112◦C, yield (25%). IR (KBr) νmax/cm−1.
1
3328 (NH); 2199 (CN); 1748 (COCH3). H NMR: δ 1.60 (s, 3H, CH3);
2.00–2.25 (m, 12H, 4CH3CO); 3.80-5.40 (m, 6H, of acetyled galactose); 4.85
(d, 1H, anomeric); 7.20–7.48 (m, 5H, C6H4, NH). C25H27ClN2O10S, Calcd:
C, 51.50%; H, 4.66%; N, 4.80%.Found: C, 51.53%; H, 4.70%; N, 4.82%.
5i: As orange crystals, mp 140◦C, yield (23%). IR (KBr) νmax/cm−1.
1
3271 (NH), 2194 (CN), 1755 (COCH3). H NMR: δ 1.60 (s, 3H, CH3);
2.00–2.20 (m, 9H, 3CH3CO); 3.40-5.25 (m, 5H, of acetyled xylose); 4.80
(d, 1H, anomeric); 7.10–7.60 (m, 6H, C6H5, NH). C22H24N2O8S, Calcd: C,
55.45%; H, 5.08%; N, 5.88%. Found: C, 55.58%; H, 4.87%; N, 5.90%.
5j: As orange crystals, mp 144◦C, yield (25%). IR (KBr) νmax/cm−1. 3271
(NH), 2194 (CN), 1747 (COCH3). 1H NMR: δ 1.25 (s, 3H, CH3); 2.00–2.40
(m, 9H, 3CH3CO); 2.50 (s, 3H, CH3); 3.45-5.20 (m, 5H, of acetyled xylose);

Synthesis and In Vitro Anti-Tumor Activity
471
4.75 (d, 1H, anomeric); δ 7.20–7.80 (m, 5H, C6H4, NH). C23H26N2O8S,
Calcd: C, 56.32%; H, 5.34%; N, 5.71%. Found: C, 56.44%; H, 5.15%; N,
5.75%.
1
5k: As orange crystals, mp 110◦C, yield (55%). H NMR: δ 1.90 (s, 3H,
CH3); 2.00–2.20 (m, 9H, 3CH3CO); 3.80 (s, 3H, OCH3); 3.40–5.25 (m, 5H,
of acetyled xylose); 4.75 (d, 1H, anomeric); 6.85–7.75 (m, 5H, C6H4, NH).
C23H26N2O9S, Calcd: C, 54.54%; H, 5.17%; N, 5.53%. Found: C, 54.65%; H,
4.97%; N, 5.59%.
1
5l: As orange crystals, mp 120◦C, yield (40%). H NMR: δ 1.60 (s, 3H,
CH3); 2.00–2.10 (m, 9H, 3CH3CO); 3.40–5.20 (m, 5H, of acetyled xylose);
4.75 (d, 1H, anomeric); 7.20–7.65 (m, 5H, C6H4, NH). C22H23ClN2O8S,
Calcd: C, 51.72%; H, 4.54%; N, 5.48%. Found: C, 51.83%; H, 4.35%; N,
5.50%.
5m: As yellow crystals, mp 114◦C, yield (30%). IR (KBr) νmax/cm−1.
3271 (NH), 2194 (CN), 1747 (COCH3). C22H24N2O8S, Calcd: C, 55.45%; H,
5.08%; N, 5.88%. Found: C, 55.54%; H, 4.89%; N, 5.92%.
5n: As orange crystals, mp 115◦C, yield (45%). IR (KBr) νmax/cm−1. 3274
(NH), 2210 (CN), 1747 (COCH3). 1H NMR: δ 1.95 (s, 3H, CH3); 2.00-2.20
(m, 9H, 3CH3CO); 2.50 (s, 3H, CH3); 3.40–5.20 (m, 5H, of acetyled Arabi-
nose); 4.90 (d, 1H, anomeric); 7.20–7.60 (m, 5H, C6H4+ NH). C23H26N2O8S,
Calcd: C, 56.32%; H, 5.34%; N, 5.71%. Found: C, 56.44%; H, 5.15%; N,
5.75%.
5o: As viscous orange oil, yield (20%). C23H26N2O9S, Calcd: C, 54.54%;
H, 5.17%; N, 5.53%. Found: C, 54.65%; H, 4.98%; N, 5.58%.
5p: As orange crystals, mp 118◦C, yield (45%). IR (KBr) νmax/cm−1.
3271 (NH), 2198 (CN), 1747 (COCH3).1H NMR: δ 1.90 (s, 3H, CH3);
2.00–2.20 (m, 9H, 3CH3CO); 3.70–5.20 (m, 5H, of acetyled Arabinose);
4.90 (d, 1H, anomeric); 7.40–7.70 (m, 5H, C6H4, NH). C22H23ClN2O8S,
Calcd: C, 51.72%; H, 4.54%; N, 5.48%. Found: C, 51.81%; H, 4.37%; N,
5.48%.
3.2. 3-Methyl-N-aryl-2-cyano-3-(β-D-gluco-or galactopyranosyl
thio)- or (-β-D-xylo-and β-L-arabinopyranosylthio)acrylamides
(6a-p)
Dry gaseous ammonia was passed through a solution of protected gly-
cosides 5a–p (0.5 gm) in dry methanol (20 mL) at room temperature for
10 min.The mixture was stirred overnight (followed by TLC). The result-
ing mixture was then evaporated under reduced pressure to afford a solid
residue that was crystallized from ether.
6a: As viscous brown oil, Yield (40%). C17H20N2O6S, Calcd: C, 53.66%;
H, 5.29%; N, 7.36%. Found: C, 53.67%; H, 5.30%; N, 7.38%.
6b: As brown crystals, mp 126◦C, yield (45%). IR (KBr) νmax/cm−1. 3401
1
(Broad band of OH); 2191(CN). H NMR: δ 2.10 (s, 3H, CH3); δ 2.50 (s,

472
G. H. Elgemeie and N. M. Saber
3H, CH3); 3.00–3.98 (m, 7H of glucose); 4.50–5.00 (m, 4H, 4OH groups of
glucose); 7.00–7.45 (m, 5H, C6H4, NH). C18H22N2O6S, Calcd: C, 45.80%; H,
5.62%; N, 7.10%. Found: C, 45.50%; H, 5.63%; N, 7.15%.
1
6c: As viscous brown oil, yield (25%). H NMR: δ 2.10 (s, 3H, CH3);
2.50 (s, 3H, OCH3); δ 3.00–3.90 (m, 7H of glucose); 4.50–5.15 (m, 4H, 4OH
groups of glucose); 6.90–7.50 (m, 5H, C6H4, NH). C18H22N2O7S, Calcd: C,
52.66%; H, 5.40%; N, 6.82%. Found: C, 52.68%; H, 5.44%; N, 6.83%.
6d: As brown crystals, mp 150◦C, yield (55%). IR (KBr) νmax/cm−1. 3274
(broad band of OH); 2194 (CN). 1H NMR: δ 2.50 (s, 3H, CH3); 3.00–3.98 (m,
7H of glucose); 4.50–5.10 (m, 4H, 4OH groups of glucose); 7.40–7.70 (m,
5H, C6H4+ NH). C17H19ClN2O6S, Calcd: C, 49.21%; H, 4.61%; N, 6.75%.
Found: C, 49.22%; H, 4.61%; N, 6.77%.
6e: As brown crystals, mp 186◦C, yield (55%). IR (KBr) νmax/cm−1.
3271 (broad band of OH); 2194 (CN). C17H20N2O6S, Calcd: C, 53.66%;
H, 5.299%; N, 7.36%. Found: C, 53.68%; H, 5.30%; N, 7.37%.
6f: As brown crystals, mp 204◦C, yield (45%). IR (KBr) νmax/cm−1. 3401
(broad band of OH); 2191 (CN). 1H NMR: δ 2.30 (s, 3H, CH3); 2.55 (s, 3H,
CH3); 3.00–3.80 (m, 7H of galactose); 4.20–5.05 (m, 4H, 4OH groups of
galactose); 7.10–7.50 (m, 5H, C6H4, NH). C18H22N2O6S, Calcd: C, 45.80%;
H, 5.62%; N, 7.10%. Found: C, 45.90%; H, 5.62%; N, 7.12%.
6g: As brown crystals, mp 206◦C, yield (35%). IR (KBr) νmax/cm−1. 3271
(broad band of OH); 2194 (CN). C18H22N2O7S, Calcd: C, 52.66%; H, 5.40%;
N, 6.82%. Found: C, 52.67%; H, 5.42%; N, 6.85%.
6h: As brown crystals, mp 196◦C, yield (45%). IR (KBr) νmax/cm−1. 3271
1
(broad band of OH); 2198 (CN). H NMR: δ 2.50 (s, 3H, CH3); 3.30–3.90
(m, 7H of galactose); 4.40–5.10 (m, 4H, 4OH groups of galactose); 7.30–7.70
(m, 5H, C6H4, NH). C17H19ClN2O6S, Calcd: C, 49.21%; H, 4.61%; N, 6.75%.
Found: C, 49.25%; H, 4.62%; N, 6.76%.
6i: As brown crystals, mp 192◦C, yield (45%). IR (KBr) νmax/cm−1. 3271
(broad band of OH); 2198 (CN). 1H NMR: δ 2.50 (s, 3H, CH3); 3.00–4.90 (m,
6H of xylose); 4.50–5.20 (m, 3H, 3OH groups of xylose); 7.30–7.70 (m, 6H,
C6H4+ NH). C16H18N2O5S, Calcd: C, 54.85%; H, 5.18%; N, 7.99%. Found:
C, 55.01%; H, 5.03%; N, 8.02%.
6j: As brown crystals, mp 174◦C, yield (50%). IR (KBr) νmax/cm−1. 3278
(broad band of OH); 2194 (CN). C17H20N2O5S, Calcd: C, 56.03%; H, 5.53%;
N, 7.69%. Found: C, 56.19%; H, 5.26%; N, 7.73%.
6k: As viscous brown oil, yield (25%). C17H20N2O6S, Calcd: C, 53.67%;
H, 5.30%; N, 7.36%. Found: C, 53.82%; H, 5.05%; N, 7.40%.
6l: As brown crystals, mp 174◦C, yield (50%). IR (KBr) νmax/cm−1. 3278
(broad band of OH); 2194 (CN). C16H17ClN2O5S, Calcd: C, 49.94%; H,
4.45%; N, 7.28%. Found: C, 50.10%; H, 4.25%; N, 7.20%.
6m: As brown crystals, mp 126◦C, yield (50%). IR (KBr) νmax/cm−1. 3271
(broad band of OH); 2194 (CN). C16H18N2O5S, Calcd: C, 54.85%; H, 5.18%;
N, 7.99%. Found: C, 55.01%; H, 5.01%; N, 8.01%.

Synthesis and In Vitro Anti-Tumor Activity
473
6n: As brown crystals, mp 126◦C, yield (45%). IR (KBr) νmax/cm−1. 3287
(broad band of OH); 2199 (CN). C17H20N2O5S, Calcd: C, 56.03%; H, 5.53%;
N, 7.69%. Found: C, 56.20%; H, 5.29%; N, 7.72%.
6o: As viscous brown oil, yield (25%). C17H20N2O6S, Calcd: C, 53.67%;
H, 5.30%; N, 7.36%. Found: C, 53.83%; H, 5.06%; N, 7.39%.
6p: As viscous brown oil, yield (25%). C16H17ClN2O5S, Calcd: C, 49.94%;
H, 4.45%; N, 7.28%. Found: C, 50.06%; H, 4.22%; N, 7.33%.
3.3. 5-Amino-N-aryl-3-(methyl)-1H-pyrazole-4-carboxamides
(8a-f)
A mixture of compounds 5a–f (0.01 mol) and hydrazine (0.01 mol) in
ethanol (30 mL) were refluxed for 2 hours. After cooling, the resulting solid
product was filtered off and recrystallized from ethanol.
8a: As yellow crystals, mp 145◦C, yield (20%). C11H12N4O, Calcd: C,
61.09%; H, 5.59%; N, 25.91%. Found: C, 61.30%; H, 5.60%; N, 26.00%.
8b: As yellow crystals, mp 150◦C, yield (20%). C12H14N4O, Calcd: C,
62.58%; H, 6.128%; N, 24.33%. Found: C, 62.59%; H, 6.14%; N, 24.35%.
8c: As yellow crystals, mp 175◦C, yield (20%). C12H14N4O2, Calcd: C,
58.52%; H, 5.73%; N, 22.75%. Found: C, 58.53%; H, 5.74%; N, 22.80%.
8d: As yellow crystals, mp 160◦C, yield (25%). IR (KBr) νmax/cm−1. 3272
(NH2); 1665 (CONH); 3200 (NH). 1H NMR: δ 2.50 (s, 3H, CH3); 3.90 (s, 1H,
NH); 7.51–7.65 (m, 4H, C6H4); 10.40(s, 2H, NH2). C11H11ClN4O, Calcd: C,
52.69%; H, 4.42%; N, 22.35%. Found: C, 52.70%; H, 4.45%; N, 22.37%.
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