Synthesis and cytotoxic evaluation of new colchicine derivatives bearing 1,3,4-thiadiazole moieties

Article abstract of DOI:10.1016/j.cclet.2013.01.052

In search of novel anticancer agents, a series of N-methyl colchiceinamide derivatives (7a-7i) containing 1,3,4-thiadiazole moieties were synthesized, and their structures were confirmed by spectral analysis. Cytotoxicity of these compounds was evaluated by MTT assay in vitro against four human tumor cell lines, i.e. A2780, A549, BEL7402, and MCF-7. The results indicated that most of the derivatives showed significant anticancer activities, particularly, compounds 7h and 7i showed more potent cytotoxic activities of all screened cancer cells than colchicine.

Full text of DOI:10.1016/j.cclet.2013.01.052

Chinese Chemical Letters 24 (2013) 299–302
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Synthesis and cytotoxic evaluation of new colchicine derivatives
bearing 1,3,4-thiadiazole moieties
a
a
a
b
c
Li-Hong Shen a, , Hong-Yu Li , Hui-Xia Shang , Shu-Ting Tian , Yi-Sheng Lai , Li-Jie Liu
*
a Handan Key Laboratory of Organic Small Molecule Materials, Handan College, Handan 056005, China
b Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
c Hebei Yiling Medicine Corporation Ltd., Shijiazhuang 050035, China
A R T I C L E I N F O
A B S T R A C T
Article history:
In search of novel anticancer agents, a series of N-methyl colchiceinamide derivatives (7a–7i) containing
1,3,4-thiadiazole moieties were synthesized, and their structures were confirmed by spectral analysis.
Cytotoxicity of these compounds was evaluated by MTT assay in vitro against four human tumor cell
lines, i.e. A2780, A549, BEL7402, and MCF-7. The results indicated that most of the derivatives showed
significant anticancer activities, particularly, compounds 7h and 7i showed more potent cytotoxic
activities of all screened cancer cells than colchicine.
Received 12 December 2012
Received in revised form 9 January 2013
Accepted 21 January 2013
Available online 15 March 2013
Keywords:
ß 2013 Li-Hong Shen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Colchicine
N-Methyl colchiceinamide
1,3,4-Thiadiazole
Cytotoxicity
1. Introduction
with the apoptotic mechanisms and angiogenesis, which is a
crucial step in the tumorigenesis, seems to be very promising in
Colchicine (1 in Fig. 1) and many of its derivatives are powerful
mitotic poisons, anti-inflammatories, and inhibitors of tumor
growth [1,2]. Most biological effects of colchicine are probably
related to the formation of a colchicine–tubulin complex which
prevents microtubule polymerization [3,4]. Although colchicine is
a potent antimitotic agent, its medical uses in cancer chemother-
apy are limited due to its high toxicity. Therefore, many attempts
have been made to discover more effective and less toxic
analogues of colchicine by modifying the substituents of its basic
structure [5]. N-Methyl colchiceinamide (2 in Fig. 1), a semisyn-
thetic derivative of colchicine, showed considerably higher
stability toward acid hydrolysis and is a slightly less active
antitumor and toxicity agent than colchicine [6].
In recent years, different classes of thiadiazole compounds
have been investigated, many of which have been found to be
important scaffolds with broad spectrum of pharmacological
activities [7–9]. Particularly, 1,3,4-thiadiazoles are much ex-
plored for their broad spectrum of biological activities including
anti-inflammatory, antiviral, antimicrobial, antidepressants,
antileishmanial and anticancer [10–13]. The action connected
anticancer therapy [14,15].
With these facts, and in order to obtain compounds with better
anticancer activities, in this study we synthesized a variety of novel
colchicine derivatives by combining N-methyl colchiceinamide
and differently substituted 1,3,4-thiadiazole moieties and tested
their anticancer activities against a selected panel of human cancer
cell lines.
2. Experimental
2.1. Chemistry
Solvents and reagents were analytical reagents and when
necessary, were purified and dried by standard methods. IR spectra
(KBr) were recorded on a Nicolet Impact 410 spectrometer. The 1H
NMR spectra were recorded on a Brucker spectrometer (300 MHz)
with CDCl3 as the solvent and TMS as the internal standard.
Chemical shifts reported in
d (parts per million) values. Mass
spectra were performed on Agilent 1100 series LC/MSD Trap (SL)
spectrometer. Elemental analyses were performed with an
Elementar Vario EL III instrument and analyses for C, H, and N
were within ꢀ0.4% of the theoretical values. Flash column
chromatography was performed on a column packed with silica
gel 60 (200–300 mesh).
* Corresponding author.
E-mail address: lhshen1974@gmail.com (L.-H. Shen).
1001-8417/$ – see front matter ß 2013 Li-Hong Shen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.01.052

[
L.-H. Shen et al. / Chinese Chemical Letters 24 (2013) 299–302
CH3O
CH3O
CH3O
CH3O
N-Deacetyl-N-({5-[(4-methylbenzyl)sulfanyl]-1,3,4-thiadiazol-2-
yl}carbamoyl pionyl) N-methyl colchiceinamide (7e): Yellow syrup,
yield 60%. IR (KBr, cmꢁ1):
3328, 2925, 1710, 1695, 1612, 1511,
1396. 1H NMR (300 MHz, CDCl3):
1.50–2.35 (m, 5H), 3.09 (d, 3H,
N-CH3), 3.63 (s, 3H, MeO-1), 3.89 (s, 3H, MeO-2), 3.94 (s, 3H, MeO-
3), 4.30 (m, 4H, SCH2, OCH2), 4.46 (m, 2H, OCH2), 4.63 (m, 1H, H-7),
6.59 (s, 1H, H-4), 7.16 (m, 2H, H-11 and H-12), 7.50 (s, 1H, H-8),
7.62–7.66 (m, 2H), 7.84–7.90 (m, 2 H), 13.12 (brs, 2H, NHCO); MS
(ESI, m/z): 675.2 [M]+; Anal. calcd. for C34H37N5O6S2: C 60.43, H
5.52, N 10.36; found: C 60.24, H 5.49, N 10.48.
NHCOCH3
O
NHCOCH3
O
n
OCH3
OCH3
d
OCH3
1
NHCH3
2
Fig. 1. Structures of colchicine (1) and N-methyl colchiceinamide (2).
2.2. General procedure for the synthesis of compounds (7a–7i)
N-Deacetyl-N-({5-[(3-methoxybenzyl)sulfanyl]-1,3,4-thiadiazol-
2-yl}carbamoyl pionyl) N-methyl colchiceinamide (7f): Yellow syrup,
The reaction mixture of succinate 4 (18 mg, 0.04 mmol),
compounds 6a–6i (0.06 mmol), 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDC) (25 mg, 0.13 mmol),
DMAP (2 mg, 0.019 mmol) and dry dichloromethane (5 mL)
was stirred at room temperature for 24 h. Then, additional
dichloromethane (20 mL) was added. The organic layer was
washed with water and brine, and then dried over MgSO4. After
the solvent was removed in vacuo, the residue was separated by
column chromatography (eluent: ethyl acetate/petroleum
ether = 1/1) to yield the target compounds 7a–7i (shown in
Scheme 1).
yield 58%. IR (KBr, cmꢁ1):
1462. 1H NMR (300 MHz, CDCl3):
n
3326, 2923, 1705, 1692, 1632, 1561,
1.50–2.34 (m, 5H), 3.07 (d, 3H,
d
N-CH3), 3.68 (s, 3H, MeO-1), 3.95 (sꢂ2, 6H, MeO-2 and MeO-3),
4.38 (m, 4H, SCH2, OCH2), 4.45 (m, 2H, OCH2), 4.63 (m, 1H, H-7),
6.59 (s, 1H, H-4), 7.16 (m, 2H, H-11 and H-12), 7.50 (s, 1H, H-8),
7.51–7.54 (m, 1H), 7.60–7.65 (m, 1H), 7.73–7.79 (m, 2H), 13.14
(brs, 2H, NHCO); MS (ESI, m/z): 691.2 [M]+; Anal. calcd. for
C
34H37N5O7S2: C 59.03, H 5.39, N 10.12; found: C 60.14, H 5.59, N
10.08.
N-Deacetyl-N-({5-[(4-methoxybenzyl)sulfanyl]-1,3,4-thiadia-
zol-2-yl}carbamoyl pionyl) N-methyl colchiceinamide (7g): Yel-
low syrup, yield 50%. IR (KBr, cmꢁ1):
3327, 2923, 1707, 1696,
1639, 1562, 1461. 1H NMR (300 MHz, CDCl3):
1.50–2.34 (m,
n
2.3. Selected data of the target compounds 7a–7i
d
5H), 3.07 (d, 3H, N-CH3), 3.58 (s, 3H, MeO-1), 3.90 (s, 3H, MeO-
2), 3.96 (s, 3H, MeO-3), 4.32 (m, 4H, SCH2, OCH2), 4.44 (m, 2H,
OCH2), 4.63 (m, 1H, H-7), 6.54 (s, 1H, H-4), 7.12 (m, 2H, H-11
and H-12), 7.53 (s, 1H, H-8), 7.60–7.65 (m, 2H), 7.74–7.79 (m,
2H), 13.10 (brs, 2H, NHCO); MS (ESI, m/z): 691.1 [M]+; Anal.
calcd. for C34H37N5O7S2: C 59.03, H 5.39, N 10.12; found: C
60.16, H 5.28, N 10.06.
N-Deacetyl-N-{[5-(benzylsulfanyl)-1,3,4-thiadiazol-2-yl]carba-
moyl pionyl} N-methyl colchiceinamide (7a): Yellow syrup, yield
n
48%. IR (KBr, cmꢁ1): 3329, 1704, 1692, 1615, 1600, 1580, 1492. 1H
NMR (300 MHz, CDCl3):
d 1.50–2.35 (m, 5H), 3.07 (d, 3H, N-CH3),
3.67 (s, 3 H, MeO-1), 3.91 (s, 3H, MeO-2), 3.95 (s, 3H, MeO-3), 4.25–
4.29 (t, 2H, OCH2), 4.44–4.48 (m, 4H, SCH2, OCH2), 4.60–4.72 (m,
1H, H-7), 6.54 (s, 1H, H-4), 7.14 (m, 2H, H-11 and H-12), 7.49 (s, 1H,
H-8), 7.45–7.78 (m, 5H), 12.80 (brs, 2H, NHCO); MS (ESI, m/z):
661.2 [M]+; Anal. calcd. for C33H35N5O6S2: C 59.89, H 5.33, N 10.58;
found: C 60.07, H 5.49, N 10.64.
N-Deacetyl-N-({5-[(3-nitrobenzyl)sulfanyl]-1,3,4-thiadiazol-2-
yl}carbamoyl pionyl) N-methyl colchiceinamide (7h): Yellow syrup,
yield 55%. IR (KBr, cmꢁ1):
1491. 1H NMR (300 MHz, CDCl3):
n
3327, 2923, 1707, 1691, 1635, 1552,
1.50–2.35 (m, 5H), 3.08 (d, 3H,
d
N-Deacetyl-N-({5-[(3-chlorobenzyl)sulfanyl]-1,3,4-thiadiazol-2-
yl}carbamoyl pionyl) N-methyl colchiceinamide (7b): Yellow syrup,
N-CH3), 3.62 (s, 3H, MeO-1), 3.89 (s, 3H, MeO-2), 3.95 (s, 3H, MeO-
3), 4.32 (m, 2H, OCH2), 4.46 (m, 4H, SCH2, OCH2), 4.63 (m, 1H, H-7),
6.53 (s, 1H, H-4), 7.09 (m, 2H, H-11 and H-12), 7.53 (s, 1H, H-8),
7.49–7.54 (m, 1H), 7.60–7.66 (m, 1H), 7.75–7.80 (m, 1H), 8.04–8.08
(m, 1H), 12.60 (brs, 2H, NHCO); MS (ESI, m/z): 706.1 [M]+; Anal.
calcd. for C33H34N6O8S2: C 56.08, H 4.85, N 11.89; found: C 56.21, H
4.98, N 11.67.
yield 50%. IR (KBr, cmꢁ1):
1394. 1H NMR (300 MHz, CDCl3):
n
3325, 2932, 1700, 1692, 1613, 1507,
1.50–2.40 (m, 5H), 3.07 (d, 3H,
d
N-CH3), 3.69 (s, 3H, MeO-1), 3.95 (sꢂ2, 6H, MeO-2 and MeO-3),
4.25–4.29 (t, 2H, OCH2), 4.45–4.49 (m, 4H, SCH2, OCH2), 4.67 (m,
1H, H-7), 6.52 (s, 1H, H-4), 7.12 (m, 2H, H-11 and H-12), 7.49 (s, 1H,
H-8), 7.70–7.75 (m, 2H), 8.04–8.06 (m,2H), 12.56 (brs, 2H, NHCO);
MS (ESI, m/z): 695.1 [M]+; Anal. calcd. for C33H34ClN5O6S2: C 56.93,
H 4.92, N 10.06; found: C 57.06, H 5.09, N 10.18.
N-Deacetyl-N-({5-[(4-nitrobenzyl)sulfanyl]-1,3,4-thiadiazol-2-
yl}carbamoyl pionyl) N-methyl colchiceinamide (7i): Yellow syrup,
yield 56%. IR (KBr, cmꢁ1):
1492. 1H NMR (300 MHz, CDCl3):
n
3325, 2925, 1709, 1698, 1637, 1565,
1.50–2.35 (m, 5H), 3.08 (d, 3H,
N-Deacetyl-N-({5-[(4-chlorobenzyl)sulfanyl]-1,3,4-thiadiazol-2-
yl}carbamoyl pionyl) N-methyl colchiceinamide (7c): Yellow syrup,
d
N-CH3), 3.62 (s, 3H, MeO-1), 3.89 (s, 3H, MeO-2), 3.95 (s, 3H, MeO-
3), 4.30 (m, 2H, OCH2), 4.45 (m, 4H, SCH2, OCH2), 4.63 (m, 1H, H-7),
6.53 (s, 1H, H-4), 7.09 (m, 2H, H-11 and H-12), 7.53 (s, 1H, H-8),
7.74–7.78 (m, 2H), 8.02–8.06 (m, 2H), 13.02 (brs, 2H, NHCO); MS
(ESI, m/z): 706.2 [M]+; Anal. calcd. for C33H34N6O8S2: C 56.08, H
4.85, N 11.89; found: C 56.02, H 4.78, N 11.96.
yield 46%. IR (KBr, cmꢁ1):
1467. 1H NMR (300 MHz, CDCl3):
n
3330, 2919, 1703, 1692, 1606, 1546,
1.50–2.38 (m, 5H), 3.08 (d, 3H,
d
N-CH3), 3.65 (s, 3H, MeO-1), 3.90 (s, 3H, MeO-2), 3.96 (s, 3H, MeO-
3), 4.35 (t, 2H, OCH2), 4.48 (m, 4H, SCH2, OCH2), 4.65 (m, 1H, H-7),
6.55 (s, 1H, H-4), 7.10 (m, 2H, H-11 and H-12), 7.52 (s, 1H, H-8),
7.74–7.79 (m, 2H), 8.04–8.07 (m, 2H), 13.01 (brs, 2H, NHCO); MS
(ESI, m/z): 695.2 [M]+; Anal. calcd. for C33H34ClN5O6S2: C 56.93, H
4.92, N 10.06; found: C 57.09, H 5.07, N 9.90.
2.4. Biological activity
N-Deacetyl-N-({5-[(3-methylbenzyl)sulfanyl]-1,3,4-thiadiazol-2-
yl}carbamoyl pionyl) N-methyl colchiceinamide (7d): Yellow syrup,
Human cancer cell lines were purchased from the Key Gen
Serving Science Company (Nanjing, China). Cancer cells were
cultured in RPMI-1640 medium supplemented with 10% heat-
inactivated fetal bovine serum (FBS) and cells were routinely
cultured in a humidified incubator at 37 8C with 5% carbon dioxide.
Cancer cells were seeded in 96-well microtiter plates and
attached to the bottom of the well overnight. After 24 h, the
compounds (10ꢁ4–10ꢁ8 mol/L) dissolved in DMSO (5%) were
added to each well and incubated for 3 days. At the end of 3
days incubation, the medium in each well was replaced by fresh
yield 54%. IR (KBr, cmꢁ1):
1496. 1H NMR (300 MHz, CDCl3):
n
3326, 2927, 1708, 1693, 1602, 1567,
1.50–2.36 (m, 5H), 3.08 (d, 3H,
d
N-CH3), 3.68 (s, 3H, MeO-1), 3.91 (s, 3H, MeO-2), 3.97 (s, 3H, MeO-
3), 4.35 (m, 4H, SCH2, OCH2), 4.48 (m, 2H, OCH2), 4.65 (m, 1H, H-7),
6.58 (s, 1H, H-4), 7.15 (m, 2H, H-11 and H-12), 7.43–7.47 (m, 2 H),
7.60–7.65 (m, 2H), 7.74–7.79 (m, 1 H), 13.02 (brs, 2H, NHCO); MS
(ESI, m/z): 675.2 [M]+; Anal. calcd. for C34H37N5O6S2: C 60.43, H
5.52, N 10.36; found: C 60.66, H 5.47, N 10.18.

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L.-H. Shen et al. / Chinese Chemical Letters 24 (2013) 299–302
301
CH3O
CH3O
CH3O
NH2
NHCO(CH2)2CO2H
O
H2SO4
CH3O
succinic anhydride
2
OCH3
OCH3
N
O
NHCH3
NHCH3
3
4
S
N
N
N
1) KOH/CS2
2) HCl
R-PhCH2Br
NaOH
H2N
SH
H2N
SCH2
H2N
C NHNH2
S
5
S
6a-6i
R
N
N
CH3O
4
+
NHCO(CH2)2CONH
O
SCH2
EDC, DMAP
S
R
CH3O
6a-6i
OCH3
NHCH3
7a-7i
Scheme 1. Synthesis of the target compounds 7a–7i.
medium (200
m
L) containing 5 mg/mL of 3-(4,5-dimethylthiazol-
3.2. Biological studies
2-yl)-2,5-diphenyl-2H-tetrazolium hydrobromide (MTT). The for-
mazan product of MTT reduction was dissolved in DMSO 3 h later,
and absorbance was measured using an ELISA micro-plate reader.
Growth of tumoral cells was quantitated by the ability of living
cells to reduce the yellow dye MTT to a purple formazan product.
Drug effect was quantified as the percentage of control absorbance
of reduced dye at 570 nm.
In vitro evaluation of the target compounds 7a–7i for their
cytotoxic properties was performed by means of MTT assays in
triplicate using four different human cancer cell lines: A2780
(human ovary cancer), A549 (human lung cancer), BEL7402
(human hepatoma), and MCF7 (human breast carcinoma). Colchi-
cine was the positive control for the cytotoxic effect. The biological
activity data are presented in Table 1.
3. Results and discussion
As shown in Table 1, these novel derivatives 7a–7i showed
superior or comparable cytotoxic activity to colchicine and 2
against four tumor cells. Among these compounds 7d, 7e, 7f and 7g
exhibited potent anticancer activities similar to that of colchicine,
while the activities of 7h and 7i are stronger than that of colchicine.
The preliminary structure–activity relationships (SARs)
revealed that the substituent on benzene ring of benzene alkyl
groups plays an important role in activity. The compounds with
nitro or methoxy groups displayed more potent anticancer
activities than those with chlorine or methyl groups. In particular,
electron-withdrawing substituents such as a nitro group (7h and
7i) showed better anti-tumor activity than 7f and 7g with electron-
donating groups. Furthermore, the anti-tumor activities were
governed by the position of substituents. para-Substituted
compounds as 7c, 7e, 7g and 7i showed higher antitumor activities
than 7b, 7d, 7f, and 7h with meta-substituents.
3.1. Chemistry
The synthetic route of these target compounds is outlined in
Scheme 1. N-Methyl colchiceinamide (2) was refluxed with
concentrated H2SO4 in water to give N-methyl deacetyl colchi-
ceinamide (3). Compound 3 was acylated by succinic anhydride in
dry pyridine at 60 8C to give succinate 4 in 95% yield. The physical
and spectral properties of compounds 3 and 4 were in accordance
with the literature [16,17]. The compound 5-amino-1,3,4-
thiadiazole-2-thiol (5) was prepared by cyclization of thiosemi-
carbazide with CS2. Treatment of 5 with corresponding benzyl
bromides (RPhCH2Br) in presence of NaOH in 80% EtOH at room
temperature afforded S-benzyl intermediates 6a–6i according to
the literature [18,19] in 68%–90% yields.
By the acylation of compounds 6a–6i with succinate 4 in the
presence of a coupling agent EDC and a catalyst, 4-(dimethyla-
mino)pyridine (DMAP), in CH2Cl2 at room temperature, nine new
final compounds 7a–7i were synthesized. All of the newly
synthesized compounds 7a–7i were identified by IR, 1HNMR
and MS spectra and confirmed by elemental analysis.
Table 1
The cytotoxicity data of the target compounds.
Compounds
R
IC50
(
m
mol/L)/cell line
A2780
A549
BEL7402
MCF7
The elemental analysis data for each compound were in good
agreement with the empirical formula proposed. In the IR spectra,
newly synthesized compounds 7a–7i exhibited characteristic
7a
H
0.134
0.112
0.109
0.097
0.096
0.095
0.092
0.024
0.023
0.102
0.094
0. 156
0.108
0.106
0.085
0.082
0.080
0.078
0.015
0.011
0.082
0.078
0.212
0.125
0.113
0.086
0.084
0.080
0.079
0.016
0.009
0.085
0.080
0.163
0.235
0.208
0.108
0.085
0.084
0.082
0.018
0.014
0.090
0.084
7b
3-Cl
7c
4-Cl
y
(C55O) bands at 1690–1695 cmꢁ1 and 1700–1710 cmꢁ1 for
7d
3-Me
4-Me
3-MeO
4-MeO
3-NO2
4-NO2
7e
amide side chains and tropolone rings, respectively. The
stretching bands were centered at 3324–3330 cmꢁ1
y (N–H)
7f
.
7g
The 1H NMR spectral data of compounds 7a–7i are presented in
Section 2. The 1H NMR spectra of all complexes were consistent
with their corresponding protons as chemical shift values and
numbers of hydrogen.
7h
7i
2
Colchicine

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L.-H. Shen et al. / Chinese Chemical Letters 24 (2013) 299–302
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4. Conclusion
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In summary, a series of colchicine analogues (7a–7i) by
hybridization of N-methyl colchiceinamide with 1,3,4-thiadiazole
were investigated. Preliminary bioassay data indicated that all of
the target compounds exhibited cytotoxic activity against the
tumor cells to varied extent. Compared with colchicine, com-
pounds 7h and 7i were more potent. Our results may provide some
guidance for the development of novel colchicine anticancer
agents. Further SARs and mechanistic studies on this new class of
anticancer compounds are currently in progress and will be
reported in due course.
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