Synthesis and antiprotozoal activity of 1,2,3,4-tetrahydro-2- thioxopyrimidine analogs of combretastatin A-4

Article abstract of DOI:10.1007/s00044-010-9334-1

Eighteen 1,2,3,4-tetrahydro-2-thioxopyrimidine analogs (5a-j, 6a-e, and 7a-c) of combretastatin A-4 were synthesized with the objective of discovering compounds capable of controlling the growth of Trypanosoma lewisii, Leishmania tarantole, Plasmodium fal

Full text of DOI:10.1007/s00044-010-9334-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:364–369
DOI 10.1007/s00044-010-9334-1
ORIGINAL RESEARCH
Synthesis and antiprotozoal activity of 1,2,3,4-tetrahydro-2-
thioxopyrimidine analogs of combretastatin A-4
•
Dereje Desta Robert Sjoholm Lauren Lee Megan Lee Kristin Dittenhafer
•
•
•
•
•
Sarah Canche Balaji Babu Sameer Chavda Christie Dewar
•
•
•
•
•
Stephanie Yanow Aaron A. Best Moses Lee
Received: 13 September 2009 / Accepted: 19 February 2010 / Published online: 9 March 2010
Ó Springer Science+Business Media, LLC 2011
Abstract Eighteen 1,2,3,4-tetrahydro-2-thioxopyrimidine
analogs (5a–j, 6a–e, and 7a–c) of combretastatin A-4 were
synthesized with the objective of discovering compounds
capable of controlling the growth of Trypanosoma lewisii,
Leishmania tarantole, Plasmodium falciparum, and Giar-
dia lamblia. Even though the target compounds demon-
strated differential cytotoxicity against mammalian cancer
cells, with IC50 values ranging from 0.5 to [100 lM, the
range of activity against Trypanosoma, Leishmania, and
Plasmodium, and to a good extent for Giardia, was narrow.
The IC50 values of ‘‘active’’ compounds against the para-
sites ranged from about 10 lM to slightly greater than
50 lL. Specifically, compounds 5a, 5g, 5h, 6c, 7a, and 7c
were not cytotoxic against mammalian cancer cells
(IC50 [ 100 lM) but showed good activity against the
parasites, except Giardia (e.g., compounds 6c and 7a),
suggesting that these compounds may act in a similar
mechanism in parasites. Compounds 5f and 6b were pre-
viously shown to promote microtubule depolymerization in
mammalian cells.
Keywords Combretastatin Á Microtubule Á Cytotoxicity Á
Antiparasite Á Trypanosoma Á Leishmania Á Plasmodium Á
Giardia
Introduction
Infections due to protozoan parasites are a major public
health concern for billions of people worldwide (Morris
et al., 2001). Trypanosoma, Leishmania, Plasmodium, and
Giardia are protozoa responsible for various tropical dis-
eases such as African sleeping sickness and Chagas dis-
ease, leishmaniasis (Zhai et al., 1995), malaria (Olliaro and
Wells, 2009), and giardiasis (Gardner and Hill, 2001;
Faubert, 2000), which cause considerable medical and
veterinary mortality and morbidity (De Souza, 2002).
Tubulin polymerization and microtubule depolymeriza-
tion are important targets for the discovery and design of
medicinal agents. Compounds that perturb microtubule
dynamics are currently among the most effective drugs to
treat medical conditions including cancer, gout, and hel-
minth infection (Belotti et al., 1996; Taraboletti et al.,
2002; Miller et al., 2001; Jordan et al., 1998). The anti-
cancer compound combretastatin-A4 (CA-4 1, Fig. 1) is
such an example. CA-4 inhibits tubulin polymerization by
binding the colchicine binding site of tubulin (Pettit et al.,
1987; Hsieh et al., 2003; Pettit et al., 1995; Gaukoger et al.,
2001). Unfortunately, CA-4 suffers from low bioavail-
ability and poor solubility in biological media (Galbraith
et al., 2003). These limitations have led to the development
of structural analogs including a water-soluble phosphate
prodrug (CA-4P, 2), an amino-containing analog (AC-
7739, 3) (Ohsumi et al., 1998) and its amino acid deriva-
tive (AVE-8062, 4) (Tozer et al., 2002) (Fig. 1).
D. Desta Á R. Sjoholm Á L. Lee Á M. Lee Á K. Dittenhafer Á
S. Canche Á B. Babu Á S. Chavda Á M. Lee (&)
Division of Natural and Applied Sciences, Department
of Chemistry, Hope College, 35 E 12th Street, Holland,
MI 49422, USA
e-mail: lee@hope.edu
D. Desta Á A. A. Best
Department of Biology, Hope College, Holland, MI 49422, USA
C. Dewar Á S. Yanow
Provincial Laboratory for Public Health, 8440-112th Street,
Edmonton, AB T6G 2J2, Canada
123

Med Chem Res (2011) 20:364–369
365
S
Fig. 1 Structures of
S
CH3O
combretastatin-A4 (C-A4, 1)
and its water-soluble derivates
2–4. The 1,2,3,4-tetrahydro-2-
thioxopyrimidine analogs are
5a–j, 6a–e, and 7a–c
HN
NH R1
B
HN
NH R1
H3CO
H3CO
OR
R2
R3
H3CO
H3CO
R2
R3
OCH3
OCH3
A
R5
R5
1. R=H (CA-4)
2. R=PO3-2 (CA-4P)
OCH3
R4
OCH3
Type I
R4
Type II
6a, R1=R2,R4=R5=H, R3=OCH3
6b, R2=R4=H; R1=R3=R5=OCH3
6c, R2=R3=R5=H; R1=R4=OCH3
6d, R1=R4=R5=H; R2=NO2; R3=OCH3
6e, R1=R5=H; R2=R3=R4=OCH3
5a, R1=R4=R5=H; R2=R3=R4=OCH3
5b, R2=R4=H; R1=R3=R5=OCH3
5c, R1=R4=R5=H; R2=R3=OCH3
5d, R2=R3=R5=H; R1=R4=OCH3
5e, R1=R3=R4=R5=H; R2=OCH3
5f, R1=R4=R5=H; R3=OCH3; R2=OH
5g, R1=R4=R5=H; R2=NO2; R3=OCH3
5h, R1=R2=R4=R5=H; R3=NO2
5i, R1=R2=R4=R5=H; R3=Cl
H3CO
H3CO
NHR
OCH3
OCH3
S
HN
NH R1
3. R=H (AC-7739)
4. R=amino acid (AVE-8062)
R2
R3
5j, R1=R2=R4=R5=H,R3=OCH3
H3CO
R5
Type III
R4
7a, R1=R2=R5=H; R3=R4=OCH3
7b, R2=R4=H; R1=R3=R5=OCH3
7c, R1=R2=R4=R5=H; R3=OCH3
As part of a program to develop heterocyclic analogs of
CA-4 with improved water solubility, a series of novel
1979). Compounds 5j, 6a, c, e, and 7a, b were newly
synthesized by reaction of the appropriate chalcone
(Dickson et al., 2006; Pati et al., 2005) with 2.5 mol
equivalents of thiourea and potassium carbonate in re-
fluxing ethanol (overnight). A similar reaction was recently
reported in the preparation of curcumin-based thioxopyr-
imidine analogs (Fadda et al., 2009). On completion, the
cooled reaction mixture was poured into ice water, and the
precipitate was collected. When needed, the precipitate was
recrystallized from methanol. The chemical yields of the
new compounds ranged from 52% to quantitative yield.
The structures of the new compounds were ascertained by
1,2,3,4-tetrahydro-2-thioxopyrimidine
analogs
were
designed with the purpose of examining their cytotoxic
properties (Lee et al., 2008). To date, the ability of thi-
oxopyrimidine analogs to inhibit the growth of protozoan
parasites has not been examined and is the focus of this
study. This investigation stems from recent reports that
chalcone analogs of CA-4 are endowed with significant
antiparasitic activity (Awasthi et al., 2009; Liu et al., 2001;
Go et al., 2004; Liu et al., 2003; Dominguez et al., 2001;
Narender et al., 2005). Eighteen thioxopyrimidine analogs
were selected and divided into three categories, types I–III,
and tested for their antiparasitic activity. Type I contains a
3,4,5-trimethoxyphenyl moiety in the A-ring (5a–j). Type
II contains a 2,5-dimethoxyphenyl group in the A-ring (6a–
e), and type III contains a 4-methoxyphenyl group in the
A-ring 7 (a–c). The conformation of analogs 5f and 6b
were previously assessed by molecular modeling studies
using MacSpartan (Johnson et al., 2007; Ruprich et al.,
2007). As reported earlier, compounds 5f and 6b adopt a
twisted geometry similar to that of CA-4 (Kong et al.,
2005; Ducki et al., 1998).
1
400 MHz H-NMR, infrared plus nominal and high reso-
lution mass spectrometry measurements (Scheme 1).
Biology
The cytotoxicity of the newly synthesized compounds
against the growth of murine cancer cells (murine L1210
lymphoma and B16 melanoma) were tested using an in
vitro 72-h continuous exposure MTT assay (Carmichael
et al., 1987). These experiments were conducted according
to a previously published procedure (Lee et al., 2008). The
concentration (lM) of each target compound required to
inhibit cell growth by 50% relative to an untreated control
(IC50 value) was determined. The cytotoxicity of the newly
synthesized thioxopyrimidine compounds are reported in
Table 1 along with previously disclosed results (Lee et al.,
2008). It is noteworthy that, in general, the compounds are
slightly more active against L1210 leukemia cells than B16
melanoma cells. Except for compound 6e, the other new
compounds (5j, 6a, 6c, 7a, and 7b) are significantly less
active (Table 1). Interestingly, only three compounds (5f,
6b, 6e) show significant cytotoxicity against mammalian
Results and discussion
Chemistry
The synthesis of 1,2,3,4-tetrahydro-2-thioxopyrimidine
analogs 5a–i, and 6b, d and their cytotoxic activity against
B16 and L1210 cell lines have been reported (Lee et al.,
2008). Compound 7c has also been reported, but its bio-
logical activity has not been examined (Al-Hajjar et al.,
123

366
Med Chem Res (2011) 20:364–369
Scheme 1 A representative
synthesis of 1,2,3,4-tetrahydro-
2-thioxopyrimidine 7a
S
O
HN
NH
Thiourea
K2CO3
H3CO
OCH3
OCH3
EtOH, reflux
overnight
OCH3
OCH3
H3CO
7a
cancer cells (IC50 \ 1 lM). However, more of the com-
pounds show very weak activity (IC50 [ 100 lM), e.g., 5a,
5e, 5g, 5h, 6e, 7a, and 7c.
were dissolved in media containing 0.03–0.5% DMSO.
This level of DMSO has no effect on the growth of the
parasites in culture (data not shown).
Since our objective is to discover compounds with poor
cytotoxicity against mammalian cells but exhibit high
activity against parasitic cells, the compounds were sub-
jected to testing against parasitic cells grown in culture.
The 18 targeted compounds were tested for their ability to
inhibit the growth of Trypanosoma lewisii, Leish-
mania tarantole, Plasmodium falciparum, and Giar-
dia lamblia in culture. Studies on Plasmodium were
conducted according to a published procedure (Yanow
et al., 2008). Trypanosoma, Leishmania, and Giardia were
cultured in RPMI, BHI, and TYI-S-33, respectively, and
the cytotoxicity results obtained after 72 h of continuous
exposure of the compounds. The activity was assayed using
an MTT assay. For the biological studies, the compounds
Results for the cytotoxicity studies against the growth of
four parasites are given in Table 1. Foremost, the com-
pounds are generally active against the parasites. Interest-
ingly, with a few exceptions for Giardia, the range of IC50
values fall within a narrow range from about 10 lM to
slightly greater than 50 lM. In order to confirm the validity
of the MTT-based cytotoxicity results, the effects of
compound 5f against the growth of Giardia and Trypano-
soma cells were examined microscopically. The micro-
graphs of Giardia and Trypanosoma cells treated with
compound 5f (21.5 and 12.1 lM, accordingly) for 72 h are
shown in Figs. 2b and 3b, respectively. For comparison,
the respective pictures of the untreated parasites are given
in Figs. 2a and 3a. Visually, it is clearly evident that the
Table 1 Cytotoxicity and antiprotozoal activity of 1,2,3,4-tetrahydro-2-thioxopyrimidine analogs 5–7
Agents Cytotoxicity
B16 IC50 (lM) L1210 IC50 (lM) Leishmania IC50 (lM)c Trypanosoma IC50 (lM)c Plasmodium IC50 (lM)c Giardia IC50 (lM)c
5aa
5ba
5ca
5da
5ea
5fa
5ga
5ha
5ia
5j
[100
6.3
[100
5.7
46.6
46.6
36.4
30.3
19.4
12.1
12.5
13.7
10.2
12.5
11.4
10.4
18.0
21.1
16.8
27.2
25.1
17.8
29.3
29.6
52.1
48.4
24.3
49.2
39.5
50.0
27.0
17.9
16.5
25.0
27.3
33.3
15.7
25.8
13.4
15.2
Ndb
Nd
24.8
20.3
22.7
23.5
40.4
21.5
24.3
21.0
46.7
22.3
[100
33.8
[100
57.8
[100
[100
[100
Nd
[100
36
56.3
32
Nd
Nd
59.5
6.0
[100
[100
55.5
[100
0.5
[100
[100
48.3
Nd
Nd
Nd
Nd
Nd
41.0
87
36
80
14.5
69.4
17.3
27.9
Nd
6a
6ba
6.1
0.4
[100
2.2
0.5
[100
6c
[100
42
6.0
6da
6e
13.3
31.0
14.6
25.0
7a
[100
85
7b
7cd
a
25
[100
[100
Cytotoxicity data against L1210 and B16 are taken from Lee et al. (2008)
b
c
d
Nd is not determined
The error for the antiparasitic studies is 10%
Taken from Al-Hajjar et al. (1979)
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Med Chem Res (2011) 20:364–369
367
number of viable parasites in wells of compound-treated
parasites is significantly lower than those in untreated
control wells.
on any of the parasites, the authors speculate that it is
possible that the target compounds also derive their anti-
parasitic activity by binding tubulin and causing microtu-
bule depolymerization.
Perhaps the most significant discovery from this study is
as follows. A number of the thioxopyrimidine compounds
(5c, 5g, 5h, 6c, 7a, and 7c) that show good activity against
the parasites exhibit low cytotoxicity against L1210 and
B16 cells (IC50 values [ 100 lM). Of particular interest
are the nitro-containing analogs (on the B-ring) 5g and 5h.
Both compounds have approximately eightfold enhanced
activity against Leishmania, approximately fourfold
increase in activity against Giardia, and two-times more
activity for Trypanosoma, when compared to L1210 and
B16 cells. Also of special interest are compounds 7a and
7c, the former agent being one of the newly synthesized
compounds. These two compounds were inactive against
mammalian cells but gave IC50 values in the range of
13–25 lM against L. tarantole, T. lewisii, and P. falcipa-
rum. Interestingly, the substitution pattern of functional
groups on these compounds is different from CA-4. Instead
of containing the 3,4,5-trimethoxyphenyl A-ring, which
makes CA-4 highly cytotoxic against mammalian cancer
cells, compounds 7a and 7c contain a para-substituted
methoxy on the phenyl moiety (A-ring). This difference
may explain why compounds 7a and 7c are not cytotoxic
(IC50 [ 100 lM) against L1210 and B16 cells. The results
also show that compounds 7a and 7c are not cytotoxic
against G. lamblia.
In summary, even though only three compounds, 5f, 6b,
and 6e, show significant cytotoxicity against B16 and
L1210 cells, almost all 18 1,2,3,4-tetrahydro-2-thioxopyr-
imidine compounds, 5a–j, 6a, e, and 7a–c, show good
antiprotozoal activity. Six of the compounds, 5c, 5g, 5h,
6c, 7a, and 7c, are worthy of further studies because of
their low cytotoxicity against mammalian cells and good
potency against the parasites. Additional benefits of the
target compounds 5–7 include their enhanced solubility in
aqueous biological media and ease of synthesis.
Characterization of the newly synthesized compounds
5j, Off white solid, quantitative yield; m.p. 222–224°C;
TLC (5% MeOH/CHCl3) Rf 0.22; IR (KBr) 3166, 2361,
1663, 1601, 1552, 1452, 1248, 1179, 1131, 1017, 816, 799;
1H-NMR (CDCl3) 7.49 (br s, 1H), 7.30 (d, J = 8 Hz, 2H),
6.93 (d, J = 8 Hz, 2H), 6.59 (s, 2H), 6.56 (br s, 1H), 5.24
(d, J = 8 Hz, 1H), 5.10 (d, J = 8 Hz, 1H), 3.88 (s, 6H),
3.86 (s, 3H), 3.83 (s, 3H); EI: M? 386 (100%); HRMS:
obsd: 386.1304; calcd: 386.1300.
6a, Off white solid, 88% yield; m.p. 152–154°C; TLC
(5% MeOH/CHCl3) Rf 0.62, IR (KBr) 3490, 3170, 3070,
2998, 2946, 2832, 1670, 1605, 1553, 1501, 1462, 1297,
Along with the cytotoxicity of compounds 5f and 6b
against L1210 and B16 cells, the ability of these agents to
cause microtubule depolymerization has been reported
earlier (Lee et al., 2008). The effects of these compounds
on interphase cellular microtubules were evaluated in A-10
aortic smooth muscle cells. With EC50 values of 4.4 and
2.9 lM, compounds 5f and 6b were concluded to be
effective in causing the loss of cellular microtubules,
suggesting that microtubule depolymerization might con-
tribute to the observed cytotoxicity against L1210 and B16
cells. Even though these studies have not been conducted
1
1242, 1221, 1176, 1030, 810, 747; H-NMR: DMSO-d6
9.80 (br s, 1H), 8.58 (br s, 1H), 7.28 (d, J = 8 Hz, 2H),
6.95 (d, J = 8 Hz, 2H), 6.92 (d, J = 8 Hz, 2H), 6.81 (s,
1H), 5.13 (d, J = 8 Hz, 1H), 5.05 (d, J = 8 Hz, 1H), 3.75
(s, 6H), 3.71 (s, 3H); EI: M? 356 (100%).
6c Off white solid, 65% yield; m.p. 210–212°C; TLC
(5% MeOH/CHCl3) Rf 0.59; IR (KBr) 3177, 2942, 1542,
1535, 1494, 1452, 1262, 1207, 1176, 1083, 1041, 799, 744;
1H-NMR: CDCl3: 8.20 (br s, 1H), 7.30 (d, J = 8 Hz, 2H),
6.92 (d, J = 8 Hz, 2H), 6.87 (s, 2H), 6.59 (br s, 1H), 5.23
Fig. 2 Giardia lamblia control
(a) and treated (b) with 21.5 lM
of 5f for 72 h (920)
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Med Chem Res (2011) 20:364–369
Fig. 3 Leishmania tarantole
control (a) and treated (b) with
12.1 lM of 5f for 72 h (940)
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4.80 (d, J = 8 Hz, 1H), 3.88 (s, 6H), 3.86 (s, 3H), 3.85 (s,
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416.1409 calcd: 416.1406.
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1663, 1601, 1552, 1452, 1248, 1179, 1131, 1017, 799; 1H-
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2942, 2838, 1670, 1601, 1552, 1511, 1463, 1324, 1297,
1
1181, 1151, 1120, 1031, 947, 817, 752; H-NMR: CDCl3
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