Synthesis and anticancer activity of thiosemicarbazones

Article abstract of DOI:10.1016/j.bmcl.2006.01.048

Twenty-six thiosemicarbazones (III-1-III-26) were synthesized via three steps starting from hydrazine hydrate and carbon disulfide. The testing of anticancer activity of these compounds in vitro against P-388, A-549, and SGC-7901 shows that compounds III-15 and III-16 possess a higher inhibitory ability for P-388 and SGC-7901. Further testing shows that the value of IC ₅₀ of compound III-16 against SGC-7901 reaches to 0.032 μM.

Full text of DOI:10.1016/j.bmcl.2006.01.048

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2213–2218
Synthesis and anticancer activity of thiosemicarbazones
Wei-xiao Hu,* Wei Zhou, Chun-nian Xia and Xi Wen
College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310032, PR China
Received 28 September 2005; revised 31 December 2005; accepted 10 January 2006
Available online 3 February 2006
Abstract—Twenty-six thiosemicarbazones (III-1–III-26) were synthesized via three steps starting from hydrazine hydrate and car-
bon disulfide. The testing of anticancer activity of these compounds in vitro against P-388, A-549, and SGC-7901 shows that com-
pounds III-15 and III-16 possess a higher inhibitory ability for P-388 and SGC-7901. Further testing shows that the value of IC50 of
compound III-16 against SGC-7901 reaches to 0.032 lM.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Thiosemicarbazones and its derivatives have attracted
considerable pharmaceutical interest due to their antivi-
ral,1 antibacterial,2–4 and antitumor activities.5–11 The
antitumor activity of these seems to be due to an inhibi-
tion of DNA synthesis produced by the modification in
the reductive conversion of ribonucleotides to deoxyri-
bonucleotides.12 Thiosemicarbazones have drawn great
interests for their high potential biological activity espe-
cially their antitumor activity. Recently, there have been
a number of reports involving the preparation and bio-
logical activity of the complexes formed by transition
metals coupled with thiosemicarbazones as ligands.
Although much attention has been paid to the complex-
es and the biological activities thereof, our interests have
been focused on the relationships between structures of
thiosemicarbazones and their antitumor activities. In the
present paper, we report the preparation of thiosemicar-
bazones, and their anticancer activities in vitro are also
evaluated.
or Me, and R3 were substituted aniline or piperazine.
Since norfloxacin has good anti-microbial activity,
piperazine substituents were chosen as R3.
The preparations are summarized in Table 1. The struc-
tures of all compounds were identified by IR, 1H NMR,
and elemental analysis (Table 2).
The antitumor activities in vitro for these compounds
were evaluated by the MTT method for P-388 cell,
SRB for A-549, and SGC-7901. The results are summa-
rized in Tables 3 and 4.
Comparing the structures of compounds III-12, III-14,
III-15, III-16 with those of compounds III-1–III-7, they
possess the same substituents R2 and R3, but the differ-
ent R1. From Table 3, it is obvious that compounds III-
12, III-14, III-15, and III-16 possess a higher inhibitory
activity against P-388 and A-549 than compounds III-1–
III-7. So, it shows that a heterocyclic substituent such as
2-pyridyl, 2-furyl, 2-thiazolyl or 2-pyrimidinyl as R1 is
more preferable than phenyl or substituted phenyl when
R2 and R3 are methyl and 2-pyridyl piperazine,
respectively.
In our previous papers, we have reported that some thi-
osemicarbazones have effective antitumor activities, and
the substituents in these compounds affect their antitu-
mor activities strongly.13–15 In a continuation of our
work on the structure–activity relationship, twenty-six
thiosemicarbazones were prepared17 according to Wil-
son’s method16 as Scheme 1. In compound (III), the
R1 were substituted phenyl or heterocyclics, R2 were H
Compounds III-3 and III-8 have the same R1 and R3,
but the different R2. Table 3 shows both of them display
a weak inhibitory activity against P-388 and A-549.
When comparing the structures of compounds III-9
and III-10, they have the same R1 (phenyl) and R3
(piperazine substituted with norfloxacin), but the differ-
ent R2. Table 3 shows that the anticancer activity of
compound III-10 is higher than that of III-9, which indi-
cates that methyl as R2 is better than hydrogen.
Keywords: Thiosemicarbazones; Anticancer activity; SAR.
*
Corresponding author. Tel.: +86 571 88320557; fax: +86 571
88320557/85133199; e-mail: huyang@mail.hz.zj.cn
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.01.048

2214
W. Hu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2213–2218
Scheme 1. Synthetic route of thiosemicarbazones.
Table 1. Preparation of thiosemicarbazones
Entry
R1
R2
R3
mp (ꢁC)
Yield (%)
80.7
III-1
4-NO2C6H4
–CH3
180–181
III-2
III-3
III-4
III-5
III-6
III-7
III-8
4-Cl C6H4
–CH3
–CH3
–CH3
–CH3
–CH3
–CH3
–H
142–143
139–140
159–161
134–135
192–193
169–171
162–164
82.8
63.0
85.7
83.8
55.7
61.2
61.5
C6H5
4-CH3C6H4
4-CH3OC6H4
4-HOC6H4
4-NH2C6H4
C6H5
III-9
C6H5
–H
226–227
228–229
46.2
68.7
III-10
C6H5
–CH3
III-11
III-12
2-Pyridyl
2-Pyridyl
–CH3
241–242
174–176
48.5
73.5
–CH3

W. Hu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2213–2218
2215
Table 1 (continued)
Entry
R1
R2
R3
mp (ꢁC)
Yield (%)
III-13
III-14
III-15
III-16
III-17
III-18
III-19
III-20
III-21
III-22
III-23
2-Pyridyl
–CH3
147–148
67.0
27.3
58.0
66.0
84.3
60.3
68.4
75.5
82.6
43.5
62.5
2-Furyl
–CH3
–CH3
–CH3
–CH3
–CH3
–CH3
–CH3
–CH3
–CH3
–CH3
135–137
138–139
195–196
154–156
176–178
189–192
168–170
188–190
218–220
190–193
2-Thiazolyl
2-Pyrimidinyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
III-24
III-25
III-26
2-Thienyl
2-Thienyl
2-Thienyl
–CH3
–CH3
–CH3
155–157
166–169
198–200
60.4
59.4
74.1
From Table 1, comparing the structures of compounds
III-3 and III-10, they possess the same R1 (phenyl),
and the same R2 (methyl), but the different R3. The dif-
ference of their anticancer activity in Table 3 shows that
piperazine substituent bearing norfloxacin as R3 (III-10)
is preferable to that bearing piperidine (III-3). However,
interestingly, when their R1 substituent (phenyl) was
changed into 2-pyridyl, such as in compounds III-11
and III-12, the reverse result was given, that is, com-
pound III-12, which bears the piperidine in the pipera-
zine substituent as R3, possesses an anticancer activity
higher than that of compound III-11 which bears nor-
floxacin in piperazine as R3 (Table 3). According to this,
so we can conclude that the substituents R1 and R3
should match each other, and they should be considered
as a whole, not be considered separately.
From Tables 3 and 4, it has been found that compounds
III-15 and III-16 possess an excellent inhibitory activity
against P-388 and SGC-7901. More accurate two tests (a
and b) of IC50 of compound III-16 against SGC-7901
are listed in Table 5. It shows that the value of IC50
reaches to 0.032 lM. So this kind of thiosemicarbazone
is valuable for being further studied.

Table 2. Elemental analysis (calcd data in parentheses), IR, and 1H NMR data (III-1–III-26)
Compound
Elemental analysis (%)
IR (cmÀ1
)
1H NMR (d)
C
H
N
III-1
III-2
III-3
56.22 (56.23)
57.50 (57.82)
63.45 (63.68)
5.29 (5.24)
5.41 (5.39)
6.01 (6.24)
21.83 (21.86)
18.70 (18.73)
20.89 (20.63)
1598, 1520, 1490, 1443, 1345, 1293, 1180, 981, 856, 778
1600, 1492, 1473, 1464, 1363, 1265, 1236, 948, 835, 770
1600, 1485, 1440, 1360, 1297, 1236, 1030, 982, 756
8.56–6.64 (m, 8H), 4.23 (t, 4H), 3.76 (t, 4H), 2.34 (s, 3H)
8.23–6.60 (m, 8H), 4.20 (t, 4H), 3.80 (t, 4H), 2.44-2.68 (m, 3H)
8.22 (d, 1H), 7.44–7.26 (m, 6H), 6.24 (t, 2H), 4.23 (t, 4H), 3.63
(t, 4H), 2.25–2.62 (m, 3H)
III-4
III-5
65.00 (64.66)
61.77 (61.76)
6.53 (6.56)
6.04 (6.27)
19.94 (19.81)
18.96 (18.96)
1598, 1488, 1479, 1467, 1360, 1265, 1232, 976, 827, 763
1605, 1445, 1360, 1303, 1260, 1231, 1188, 983, 830, 770
8.23–6.60 (m, 8H), 4.20 (t, 4H), 3.65 (t, 4H), 2.38 (s, 3H), 2.67
(m, 3H)
8.23–6.70 (m, 8H), 4.18 (t, 4H), 3.85 (t, 4H), 3.64 (s, 3H), 2.52
(s, 3H)
III-6
III-7
60.77 (60.82)
60.75 (60.99)
5.91 (5.96)
6.55 (6.26)
19.89 (19.70)
23.83 (23.71)
1604, 1495, 1424, 1355, 1315, 1225, 1142, 989, 830, 783
1630, 1598, 1480, 1344, 1270, 1190, 1055, 950, 840, 775
8.16–6.58 (m, 3H), 4.40 (t, 4H), 3.60 (t, 4H), 2.42 (s, 3H)
8.12–6.64 (m, 8H), 5.64 (b, 2H), 4.40 (t, 4H), 3.85 (t, 4H), 2.54
(s, 3H)
III-8
63.06 (62.74)
60.09 (59.86)
60.75 (60.59)
57.71 (58.05)
5.86 (5.88)
5.22 (5.02)
5.39 (5.29)
5.28 (5.07)
21.63 (21.52)
14.55 (14.55)
14.05 (14.13)
16.95 (16.93)
1598, 1557, 1488, 1430, 1329, 1237, 1044, 947, 890, 750
1738, 1630, 1479, 1440, 1384, 1290, 1260, 1029, 850, 755
1744, 1633, 1480, 1437, 1358, 1255, 1235, 1030, 810, 762
1730, 1634, 1473, 1430, 1387, 1239, 1150, 1025, 980, 800
9.63 (s, 1H), 8.24–6.64 (m, 9H), 6.58 (s, 1H), 4.20 (t, 4H), 3.72
(t, 3H)
III-9
8.80 (s, 1H), 8.20 (s, 1H), 7.88–7.05 (m, 7H), 4.52 (q, 2H), 4.10
(t, 4H), 3.52 (t, 4H), 1.42 (s, 3H)
III-10
III-11
8.80–7.11 (m, 8H), 4.52 (q, 2H), 4.16 (t, 4H), 3.48 (t, 4H), 2.40
(s, 3H), 1.42 (s, 3H)
8.80 (s, 1H), 8.70–7.05 (m, 7H), 4.56 (q, 2H), 4.18 (t, 4H), 3.50
(t, 4H), 2.54 (s, 3H), 1.43 (t, 3H)
III-12
III-13
60.28 (59.97)
63.54 (63.47)
5.89 (5.92)
8.06 (8.13)
25.08 (24.69)
19.44 (19.48)
1600, 1490, 1471, 1433, 1368, 1264, 1231, 1154, 980, 784
1610, 1580, 1563, 1430, 1364, 1293, 1002, 979, 776
8.68–6.58 (m, 8H), 4.20 (t, 4H), 3.75 (t, 4H), 2.44 (s, 3H)
8.75–7.25 (m, 4H), 4.09 (t, 4H), 2.66 (s, 3H), 2.38–2.61 (m, 5H),
1.81–1.39 (m, 12H)
III-14
III-15
58.45 (58.34)
51.71 (52.00)
6.25 (5.81)
5.13 (5.24)
21.74 (21.27)
24.30 (24.26)
1598, 1479, 1435, 1359, 1300, 1268, 1229, 1158, 980, 750
1596, 1570, 1482, 1438, 1397, 1213, 981, 936, 781, 735
8.24–6.64 (m, 7H), 4.23 (t, 4H), 3.68 (t, 4H), 2.28 (s, 3H)
8.60–6.60 (m, 6H), 4.22 (t, 4H), 3.77 (m, 4H), 2.80–2.40
(m, 3H)
III-16
III-17
III-18
III-19
55.90 (56.28)
58.45 (58.34)
56.71 (56.69)
54.68 (55.05)
5.47 (5.61)
5.53 (5.54)
4.82 (4.75)
4.93 (4.95)
28.46 (28.72)
20.20 (20.26)
15.38 (15.25)
13.53 (13.75)
1593, 1561, 1479, 1364, 1297, 1213, 981, 936, 781, 735
1592, 1559, 1478, 1417, 1337, 1312, 1264, 1232, 1173, 1157
3299, 3227, 1530, 1496, 1362, 1291, 1196, 704, 688, 538
3292, 3217, 1521, 1487, 1297, 1242, 1192, 1027, 836, 715
8.83–6.66 (m, 7H), 4.25 (t, 4H), 3.66 (t, 4H), 2.70 (s, 3H)
8.22–6.63 (m,7H), 4.20 (t, 4H), 3.70 (t, 4H), 2.70 (s, 3H)
9.31 (s, 1H), 8.66 (s, 1H), 7.71–7.05 (m, 8H), 2.35 (s, 3H)
9.07 (s, 1H), 8.64 (s, 1H), 7.48 (d, 2H), 7.32–7.01 (m, 3H), 6.90
(d, 2H), 3.78 (s, 3H), 2.29 (s, 3H)
III-20
III-21
III-22
III-23
57.81 (58.10)
58.09 (58.10)
48.67 (48.69)
50.41 (50.39)
5.45 (5.22)
5.22 (5.22)
3.55 (3.77)
3.86 (3.90)
14.90 (14.52)
14.51 (14.52)
17.23 (17.47)
13.59 (13.56)
3295, 3218, 1518, 1488, 1292, 1258, 1191, 1046, 726,711
3294, 3217, 1522, 1486, 1293, 1259, 1192, 1048, 776, 709
3275, 1597, 1556, 1518, 1332, 1282, 1191, 1110, 851, 709
3288, 1519, 1291, 1200, 1087, 1044, 1016, 819, 788, 717
9.13 (s, 1H), 8.68 (s, 1H), 7.87–7.01 (m, 7H), 2.32 (s, 3H), 2.30
(s, 3H)
9.51 (s, 1H), 9.07 (s, 1H), 7.84 (d, 2H), 7.82–7.36 (m, 3H), 7.52
(d, 2H), 2.66 (s, 3H), 2.64 (s, 3H)
9.66 (s, 1H), 8.76 (s, 1H), 8.28 (d, 2H), 8.07 (d, 2H), 7.43–7.08
(m, 3H), 2.38 (s, 3H)
9.27 (s, 1H), 8.73 (s, 1H), 7.67 (d, 2H), 7.37 (d, 2H), 7.39–7.06
(m, 3H), 2.34 (s, 3H)
III-24
III-25
50.05 (50.39)
45.13 (45.38)
3.90 (3.90)
3.10 (3.22)
13.87 (13.56)
12.31 (12.20)
3298, 3231, 1578, 1516, 1416, 1255, 1200, 1045, 708, 528
3164, 1557, 1478, 1411, 1336, 1280, 1058, 1033, 711, 640
9.31 (s, 1H), 8.70 (s, 1H), 7.82–7.07 (m, 7H), 2.35 (s, 3H)
9.37 (s, 1H), 8.67 (s, 1H), 7.56 (s, 2H), 7.21 (s, 1H), 7.41–7.07
(m, 3H), 2.36 (s, 3H)
III-26
62.44 (62.73)
5.01 (4.64)
13.27 (12.91)
3304, 3204, 1597, 1530, 1514, 1488, 1360, 1291, 1249, 1208
9.58 (s, 1H), 8.88 (s, 1H), 8.03–7.06 (m, 10H), 2.40 (s, 3H)

W. Hu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2213–2218
Table 3. The inhibition rates for P-388 and A-549 in vitro (III-1–III-16)
2217
Compound
Inhibition rate of P-388 (%) concentration (mol/L)
Inhibition rate of A-549 (%) concentration (mol/L)
10À5
10À6
10À7
10À5
10À6
10À7
III-1
III-2
6.4
4.6
0.0
4.6
0.0
16.4
0.0
0.0
0.0
0.0
0.8
0.0
0.0
3.3
0.0
0.0
0.8
0.0
0.0
0.0
24.6
0.0
0.0
15.6
12.6
0.0
4.6
III-3
III-4
0.0
0.0
0.8
0.0
0.0
0.0
25.8
7.3
21.2
3.7
28.8
2.8
III-5
III-6
0.8
0.0
0.0
0.0
53.0
30.3
7.3
25.8
4.6
28.8
12.1
3.7
III-7
III-8
46.8
0.0
0.0
4.6
4.6
16.4
0.8
III-9
68.8
100.0
26.6
100.0
96.5
77.3
94.5
96.5
0.0
0.0
4.1
III-10
III-11
III-12
III-13
III-14
III-15
III-16
24.8
4.6
63.9
7.4
0.8
0.0
16.4
19.7
17.8
0.0
12.8
41.6
50.0
74.3
89.4
13.8
39.8
37.9
73.5
28.3
100.0
40.0
72.3
13.6
79.3
21.5
18.5
Table 4. The inhibition rates for P-388 and SGC-7901 in vitro (III-15–III-26)
Compound
Inhibition rate of P-388 (%) concentration (mol/L)
Inhibition rate of SGC-7901(%) concentration (mol/L)
10À4
10À5
10À6
10À7
10À8
10À4
10À5
10À6
10À7
10À8
III-15
III-16
III-17
III-18
III-19
III-20
III-21
III-22
III-23
III-24
III-25
III-26
—
—
94.5
96.5
0.0
1.2
5.2
1.3
9.2
0.0
9.9
6.5
20.9
4.3
74.3
89.4
15.0
1.6
6.9
0.0
5.7
2.1
0.0
3.7
7.0
7.2
73.5
28.3
0.0
—
—
—
—
92.5
90.0
94.9
0.0
60.8
90.0
7.2
14.3
81.7
1.6
—
—
100.0
48.0
25.9
91.9
8.4
0.0
8.5
0.0
0.0
0.0
10.3
0.0
0.0
0.0
0.0
96.4
39.2
65.1
73.5
67.8
51.7
56.7
86.8
72.9
55.9
12.8
0.0
0.0
7.1
8.8
9.1
0.0
0.0
0.0
20.0
6.2
3.6
0.0
0.0
0.0
0.0
29.2
41.6
33.9
35.7
12.7
39.7
27.9
24.3
5.9
5.5
0.0
9.6
10.8
3.6
15.0
8.3
8.6
14.5
0.0
21.6
51.0
90.1
30.3
0.0
8.3
0.0
0.0
0.0
0.0
17.6
0.9
0.0
13.5
16.5
Table 5. IC50 of III-16 for SGC-7901
Concentration (mol/L)
10À7
5 · 10À8
2.5 · 10À8
1.25 · 10À8
0.625 · 10À8
IC50 (lM)
III-16-a
III-16-b
65.1
83.9
60.1
68.9
48.4
51.8
31.7
49.8
18.4
38.8
0.032
0.012
4. Kasuga, N. C.; Sekino, K.; Ishikawa, M.; Honda, A.;
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Acknowledgments
The authors are thankful for the National Centre for
Drug Screening, Shanghai, PR China, to evaluate the
antitumor activities. We also thank the Natural and
Science Foundation of Zhejiang Province for funding
(Project M203027).
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Frampton, C. S.; Jasinski, J. P.; West, D. X. J. Inorg.
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W. Hu et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2213–2218
11. Quiroga, A. G.; Perez, J. M.; Lopez-Solera, I.; Masaguer,
J. R.; Luque, A.; Roman, P.; Edwards, A.; Alonso, C.;
Navarro-Ranninger, C. J. Med. Chem. 1998, 41, 1399.
12. Kovala-Demertzi, D.; Domopuolou, A.; Demertzi, M.;
Raptopoulou, C.; Tertzis, A. Polyhedron 1994, 13,
1917.
13. Hu, W. X.; Sun, N.; Yang, Z. Y. Chem. J. Chin. Univ.
2002, 23, 1877.
14. Hu, W. X.; Sun, N.; Yang, Z. Y. Chin. J. Med. Chem.
2001, 11, 129.
recrystallized with methylene dichloride to give 55.0 g
compound (I), yield 60.1%, mp 81–82 ꢁC [81–83 ꢁC lit18],
IR (KBr, cmÀ1): 3443, 3200, 2978, 1602, 1510, 1430, 1378,
1293, 1155, 1009, 948, 715, 666, 1H NMR (CDCl3-DMSO,
d): 5.51 (br, 2H), 4.49 (s, 1H), 2.61 (s, 3H). (b) 2.5g
(0.02 mol) compound (I) and 2.5g (0.02 mol) 2-acetylpyr-
imidine were dissolved in 20 mL isopropyl alcohol. The
mixture was stirred for 24 h at room temperature. Then
the resulted yellow precipitate was filtered, washed with
isopropyl alcohol, and recrystallized with 95% ethanol to
give 3.7 g compound (II), yield 81.8%, mp 132–134 ꢁC, IR
(KBr, cmÀ1): 3146, 2916, 1657, 1603, 1457, 1412, 1304,
1270, 1148, 1115, 1082, 1068, 986, 815, 1H NMR (CDCl3,
d): 8.94 (d, 2H), 7.38 (t, 1H), 2.66 (s, 3H), 2.53 (s, 3H). (c)
To a mixture of 2.3 g (0.01 mol) compound (II) in 50 mL
ethanol was added 1.6 g (0.01 mol) 1-(2-pyridyl) pipera-
zine. The mixture was refluxed for 24 h and the TLC test
showed the reaction is complete. The mixture was cooled
down to room temperature and concentrated under
vacuum. The residue was recrystallized with the mixture
of ethanol and chloroform (1/2) to give a 2.1 g brown
compound III-16, yield 66.0%, mp 195–196 ꢁC, the full
spectral analysis is given in Table 2.
15. Sun, N.; Yang, Z. Y.; Hu, W. X. Chin. J. Synth. Chem.
2001, 9, 148.
16. Wilson, H. R.; Revankar, G. R.; Tolman, R. L. J. Med.
Chem. 1974, 17, 760.
17. Representative procedure for compound III-16: (a) To a
mixture of 60 mL distilled water, 50 mL isopropyl alcohol,
and 49.5 g (0.75 mol) potassium hydroxide was added
39.0 g (0.75 mol) hydrazine hydrate at 20 ꢁC. The resulted
mixture was cooled down at 10 ꢁC with an ice-water bath,
then 57.5 g (0.75 mol) carbon disulfide was dropped slowly
over the course of 100 min. After the addition, the reaction
was continued for 2 h. Then 94.5 g (0.75 mol) dimethyl
sulfate was added to the mixture at 15 ꢁC and stirred for
1 h. The resulted precipitate was filtered, washed with
water, and dried in vacuum. The crude product was
18. Klayman, D. L.; Bartosevich, J. F.; Griffin, T. S.; Mason,
C. J. J. Med. Chem. 1979, 22, 1367.