Design, synthesis and evaluation of 4-substituted anthra[2,1-c][1,2,5]thiadiazole-6,11-dione derivatives as novel non-camptothecin topoisomerase I inhibitors

Article abstract of DOI:10.1016/j.bmcl.2017.03.039

Previously, 4-tosylanthra[1,2-c][1,2,5]thiadiazole-6,11-dione (1) was identified as a novel non-camptothecin topoisomerase I (Top1) inhibitor by structure-based virtual screening. Herein, a series of 4-substituted derivatives were designed and synthesized. Most of them showed potent Top1 inhibitory activity. Their in vitro antiproliferative activity was also evaluated in A549, HCT-116 and ZR-75-30 human cancer cell lines. Compound 8s showed good antiproliferative activity with IC₅₀ of 0.52?μM and 0.42?μM against HCT-116 and ZR-75-30 cell line, respectively. Top1 unwinding assay and molecular modeling studies rationalized the mode of action of this new class of inhibitors.

Full text of DOI:10.1016/j.bmcl.2017.03.039

Accepted Manuscript
Design, Synthesis and Evaluation of 4-Substituted Anthra[2,1-c][1,2,5]thiadia-
zole-6,11-dione Derivatives as Novel Non-camptothecin Topoisomerase I In-
hibitors
Guoqiang Dong, Yuxin Fang, Yang Liu, Na Liu, Shanchao Wu, Wannian Zhang,
Chunquan Sheng
PII:
S0960-894X(17)30279-2
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.03.039
BMCL 24791
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 September 2016
10 March 2017
16 March 2017
Please cite this article as: Dong, G., Fang, Y., Liu, Y., Liu, N., Wu, S., Zhang, W., Sheng, C., Design, Synthesis
and Evaluation of 4-Substituted Anthra[2,1-c][1,2,5]thiadiazole-6,11-dione Derivatives as Novel Non-
camptothecin Topoisomerase I Inhibitors, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/
10.1016/j.bmcl.2017.03.039
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Design, Synthesis and Evaluation of 4-Substituted
Anthra[2,1-c][1,2,5]thiadiazole-6,11-dione Derivatives as Novel
Non-camptothecin Topoisomerase I Inhibitors
Guoqiang Dong1, §, Yuxin Fang 1, §, Yang Liu2, §, Na Liu1, Shanchao Wu1, Wannian
Zhang1 and Chunquan Sheng1, *
1. School of Pharmacy, Second Military Medical University, 325 Guohe Road,
Shanghai 200433, People’s Republic of China
2. Department of Pharmacy, No. 401 Hospital of Chinese People's Liberation Army,
Qingdao 266071, People’s Republic of China.
§These authors contributed equally to this work.
* To whom correspondence should be addressed. Phone/Fax, 86-21-81871239, E-mail,
shengcq@hotmail.com.
1

Abstract
Previously, 4-tosylanthra[1,2-c][1,2,5]thiadiazole-6,11-dione (1) was identified as a
novel non-camptothecin topoisomerase I (Top1) inhibitor by structure-based virtual
screening. Herein, a series of 4-substituted derivatives were designed and synthesized.
Most of them showed potent Top1 inhibitory activity. Their in vitro antiproliferative
activity was also evaluated in A549, HCT-116 and ZR-75-30 human cancer cell lines.
Compound 8s showed good antiproliferative activity with IC50 of 0.52 µM and 0.42
µM against HCT-116 and ZR-75-30 cell line, respectively. Top1 unwinding assay and
molecular modeling studies rationalized the mode of action of this new class of
inhibitors.
Keywords: Topoisomerase I inhibitors, Anthrathiadiazole, Antiproliferative activity,
Structure-activity relationship.
2

DNA topoisomerase I (Top1) is an essential enzyme that regulates the cellular
processes such as replication, transcription, recombination, chromatin and
chromosomal segregation by altering DNA topology.1, 2 It catalyzes the breakage and
religation of DNA, maintaining the topological changes of DNA and various DNA
metabolic processes.3 Due to its important role in DNA metabolism, the ability to
interfere with the function of Top1 or generate Top1-mediated DNA damage is an
effective strategy for cancer chemotherapy, which makes Top1 inhibitors as a widely
used class of antiproliferative agents.4, 5 Camptothecin (CPT, Fig. 1) was the first
Top1 inhibitor isolated from the Chinese tree Camptotheca acuminata and showed
potent antiproliferative activity.6 Further optimization of CPT led to the development
of two CPT derivatives, topotecan (TPT) and irinotecan (IRT, Fig. 1), with better
8
pharmacokinetic profiles and improved water solubility.7,
Clinically, both
compounds are currently used for the treatment of ovarian cancer and colorectal
cancer.7, 9 Moreover, belotecan was also approved in South Korea for the treatment of
ovarian cancer and small cell lung cancer.10, 11 Unfortunately, their therapeutic
application is hampered by several disadvantages such as poor chemical stability, drug
resistance, long infusions and significant side effects.12 In particular, CPT derivatives
share a common structural feature of highly electrophilic α-hydroxylactone of the E
ring, which can be rapidly hydrolyzed to inactive carboxylate form under the
physiological conditions.13 To overcome the drawbacks of the CPTs, the discovery of
non-CPT Top1 inhibitors has recently emerged as a promising field to find better
antiproliferative agents.14-16 Two families of non-CPT Top1 inhibitors are in clinical
3

development (Fig. S1 in Supplementary Data): indenoisoquinolines (LMP400 and
LMP776) and dibenzonaphthyridinones (Genz-644282).1 These derivatives overcame
the E-ring instability of CPTs and the drug efflux-associated resistance of CPTs.17
They also produced less bone marrow suppression and appeared active and relatively
well tolerated in phase I clinical trials.1, 18
Fig. 1. Chemical structures of camptothecin, topotecan, irinotecan and lead compound
1.
In our previous studies, a novel non-CPT Top1 inhibitor with a new
anthrathiadiazole scaffold, 4-tosylanthra[1,2-c][1,2,5]thiadiazole-6,11-dione (1), was
discovered by structure-based virtual screening, which showed potent Top1 inhibitory
activity and moderate in vitro antiproliferative potency.19 However, the in vitro
antiproliferative activity of 1 remains to be further improved (Table 1) and its
structure-activity relationship (SAR) is still unknown. Herein, a series of 4-substituted
derivatives were designed and synthesized based on the following strategies. First,
4

various substituted 4-thiophenyl or 4-sulfonyl groups were introduced. Secondly, to
improve the solubility of lead compound 1, aliphatic amine, alicyclic amine and
piperazine were introduced to afford 4-amine substituted derivatives.
Scheme 1
O
NH2
O
NH2
S
N
O
N
NH2
NH2
Br
a
b
Br
O
2
O
O
4
3
S
O
N
S
N
O
N
N
d
c
R
O
R
S
S
O
O
O
5a-q
6a-p
a
b
c
d
e
f
g
h
i
R = Ph
R = 3-FPh
R = 3-ClPh
R = 3-CH3Ph
R = 3-OC2H5Ph
R = 4-FPh
R = 4-ClPh
R = 4-BrPh
R = 4-OCH3Ph
j
k
l
R = 4-CH(CH3)2Ph
R = 4-C(CH3)3Ph
R = CH2Ph
m
R = 2-ClPhCH2
n
o
p
q
R = naphthalen-2-yl
R = thiophen-2-yl
R = benzo[d]thiazol-2-yl
R = 4-CH3Ph
Scheme 1. Reagents and conditions: (a) CH3COOH, Br2, 50 ºC, 1 h, yield 70%; (b)
thionyl chloride, 1,4-dioxane, 70 ºC, 1 h, yield 65%; (c) mercaptan, DMF, 110 ºC, 2 h,
yield 17-71%; (d) H2O2, CH3COOH, 100 ºC, 0.5 h, yield 31-93%.
5

Scheme 2. Reagents and conditions: (a) thionyl chloride, 1,4-dioxane, 70 ºC, 1 h,
yield 78%; (b) CuOAc, DMF, microwave, 110 ºC, 0.5 h, yield 12-83%.
These analogs can be classed into two types, 4-thio/sulfonyl (compounds 5a-q and
6a-p) and 4-amine (8a-u) substituted derivatives, whose synthetic procedures are
depicted in Scheme 1 and 2, respectively. 1,2-Diaminoanthraquinone (2) was reacted
with bromine in acetic acid at 50 ºC to give intermediate 3.20 Cyclization of 3 was
then accomplished in the presence of thionyl chloride and dioxane, and the resulting
intermediate 4 was subsequently coupled with various substituted mercaptans to
afford compounds 5a-q. Oxidation of 5a-p using hydrogen peroxide under acidic
condition gave the sulphones 6a-p. Anthra[1,2-c][1,2,5]thiadiazole-6,11-dione (7)
was prepared using the method similar to that of intermediate 4, which was
subsequently coupled with copper acetate under microwave condition to yield target
compounds 8a-u.
The Top1 inhibitory activity of several target compounds was investigated using
6

Top1-mediated supercoiled pBR322 relaxation assay.19, 21 As shown in Fig. 2A, all the
tested compounds were found to be active against Top1-mediated DNA relaxation.
Several of them showed comparable or superior Top1 inhibitory activity to CPT. For
the 4-thio/sulfonyl substituted compounds, 4-sulfonyl compounds (6m-o) exhibited
better activity against Top1 than their corresponding 4-thio substituted derivatives
(5m-o). In particular, compounds 6n and 6o were more active than CPT. 4-Amine
substituted derivatives were found to have moderate to good Top1 inhibitory potency.
Among them, compound 8r bearing the 4-methylpiperazin substitution was the best
one. Compound 8s inhibited Top1-mediated relaxation of pBR322 DNA in a
concentration-dependent manner (Fig. 2B). It showed good inhibitory activity at 100
µM and lower potency at 10 µM. Both CPT and compound 8s showed weak inhibition
against Top1 at 1 µM. In order to investigate whether these derivatives could
intercalate into DNA, Top1 unwinding assay was also performed.21-23 Supercoiled
pBR322 DNA was treated by an excess amount of Top1 in the presence of the tested
compounds, and then the compounds were removed by phenol extraction after DNA
relaxation. If the compound is a DNA intercalator, the positively supercoiled state of
DNA could be observed in agarose gel. As shown in Fig. 3, DNA intercalator
ethidium bromide induced the formation of supercoiled DNA after Top1 treatment.
The same DNA state was obtained for compound 8s, suggesting that compound 8s
was also a DNA intercalator. Conversely, DNA remained relaxed in the presence of
compounds 5o and 6o, indicating that they failed to intercalate into DNA.
7

Fig. 2. Top1 inhibitory activity. (A) Inhibition of Top1 at 100 µM. Lane 1: supercoiled
plasmid DNA (pBR322); Lane 2: DNA + Top1; Lane 3: DNA + Top1 + CPT; Lane
4-13: DNA + Top1 + compound (5m, 5n, 5o, 6m, 6n, 6o, 8i, 8j, 8r and 8s). (B)
Inhibition of Top1 ranging from 1 µM to 100 µM. Lane 1: supercoiled plasmid DNA
(pBR322); Lane 2: DNA + Top1; Lane 3-5: DNA + Top1 + CPT (1, 10 and 100 µM);
Lane 6-8: DNA + Top1 + 8s (1, 10 and 100 µM).
Fig. 3. Investigation of the intercalating ability of the target compounds. Lane 1,
supercoiled plasmid DNA (pBR322); Lane 2, DNA + Top1; Lane 3, DNA + Top1 +
EtBr (1 µg/mL); Lanes 4-7, DNA + Top1 + target compounds (5o, 6o and 8s at 100
µM, respectively). The position of nicked DNA (Nck), Relaxed DNA (Rel) and
Supercoiled pBR322 (SC) was indicated.
8

Then, the synthesized compounds were evaluated for antiproliferative activities
against three human cancer cell lines (i.e., A549 lung cancer cells, HCT116 colon
cancer cells and ZR-75-30 breast cancer cells) using CPT and irinotecan (IRT) as the
reference drugs. The antiproliferative activity (Table 1) was determined using the
standard MTT assay.19 For the 4-thio/sulfonyl substituted compounds, most of them
showed weak inhibitory activity against all the three cell lines. 4-Sulfonyl compounds
were more potent than their corresponding 4-thio substituted inhibitors, which was
closely correlated to their Top1 inhibitory activities. Compounds 6n and 6o showed
the best antiproliferative activity against the HCT116 cell line with an IC50 value of
6.7 µM and 1.5 µM, respectively. Introduction of substituted amines at the 4-positon
of anthrathiadiazole scaffold led to significantly improved antiproliferative activity as
compared to the 4-thio substituted derivatives. Most of them were found to have
moderate to good antiproliferative potency. For example, compound 8a with a
cyclohexylamino group showed good antiproliferative potency with IC50 values in the
range of 3.8 µM to 5.1 µM. 4-Benzylamino derivative (8f) displayed stronger
antiproliferative activity than IRT with IC50 values in the range of 1.9 µM to 4.5 µM.
Replacement of benzyl group with phenyl group afforded compound 8c, which was
less potent than compound 8f. Introduction of chlorine or trifluoromethyl onto the
benzyl ring of compound 8c led to complete loss of biological activity. Aliphatic
amine in 4-position of the anthrathiadiazole ring gave compounds (8h-n) with
moderate antiproliferative activity. When the carbon chain length of 4-aliphatic amino
9

substituted derivatives was adjusted to 2 or 3, compounds 8i and 8j displayed
increased antiproliferative activity with an IC50 value of 3.0 µM and 3.1 µM against
ZR-75-30 cell line, respectively. Compounds (8o-p) with alicyclic amine showed
moderate antiproliferative activity with IC50 values in the range of 8.1 µM to 68 µM.
For the piperazine derivatives, a large tail may significantly decrease the
antiproliferative potency. For example, compounds 8q, 8t and 8u were completely
inactive against all the cell lines. In contrast, a small substitution on piperazine would
dramatically improve the antiproliferative potency. In particular, compound 8s
showed the most potent antiproliferative activity with IC50 values ranging from 0.42
µM to 17 µM. It was significantly more active than the reference drug IRT against the
HCT116 and ZR-75-30 cell lines. Moreover, compound 8s exhibited dramatically
improved solubility as compared with compound 1 (7.98 mg/L vs 0.14 mg/L). Cell
cycle distribution of compound 8s was tested in HCT116 cells (Fig. 4). HCT116 cells
were treated with vehicle alone or compound 8s at 5 µM for 12 h and 36 h. The ratios
in G2 phase of the cell cycle were 34% at 12 h and 56% at 36 h, respectively. In
contrast, the ratios of cells with vehicle in G2 phase of the cell cycle were 19% and
21%, respectively. In comparison to the control group, HCT116 cells treated with
compound 8s appeared to accumulate in G2 phase.
10

Table 1. In vitro antiproliferative activity of target compounds (IC50, µM)
Compds
A549
HCT116
ZR-75-30
Compds
A549
HCT116
ZR-75-30
>100
>50
>100
>50
>100
>50
>100
>100
11 1.6
6.7 0.59
1.5 0.11
>100
>100
23 2.7
24 2.0
>100
5a
5b
5c
5d
5e
5f
6m
6n
6o
6p
8a
8b
8c
>100
>100
>50
>100
>100
>100
21 2.3
>50
49 3.9
>50
>100
3.8 0.23
37 3.8
>100
5.1 0.55
20 2.3
100
4.1 0.45
7.1 0.78
91 9.0
>100
>50
9.8 0.85
>100
20 2.3
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
97 9.3
>50
5g
5h
5i
>100
>100
>100
>100
8d
8e
>100
>100
>100
72 7.7
1.9 0.23
87 8.9
>100
98 8.9
4.5 0.48
12 1.0
>100
>100
>100
4.0 0.45
>100
5j
8f
>100
>100
5k
5l
8g
8h
8i
>100
>100
>100
5m
5n
5o
5p
5q
6a
6b
6c
6d
6e
6f
>100
>100
6.7 0.59
>100
7.0 0.59
6.3 0.55
58 5.2
50 5.2
34 3.5
54 5.9
68 6.6
>100
3.0 0.28
3.1 0.38
>100
>100
>100
8j
>100
>100
>100
8k
8l
>100
>100
>100
47 4.3
12 1.6
22 2.0
45 4.4
8.1 0.88
>100
26 2.8
35 3.0
24 2.8
>100
22 2.4
>100
44 4.8
31 3.6
>100
8m
8n
8o
8p
8q
8r
>100
>100
>100
78 8.0
>100
>100
>100
>100
>100
14 1.2
17 1.4
>100
3.3 0.38
0.52 0.03
>100
2.7 0.23
0.42 0.04
>100
23 2.5
15 1.2
18 1.9
>50
36 3.2
>100
8s
6g
6h
6i
8t
94 9.0
>50
>100
>100
>100
8u
1
50 2.1
0.26 0.23
20 2.5
84 7.1
0.12 0.03
6.3 0.43
90 9.7
0.24 0.01
18 1.2
>100
>50
27 2.1
34 3.7
68 5.8
83 8.6
>50
6j
CPT
IRT
6k
6l
>100
>100
11

Figure 4. HCT116 cells treated with compound 8s (5 µM) for 12-36 h were assayed
by flow cytometry after staining with PI. Cells treated with vehicle were used for
comparison.
Molecular docking studies were performed using GOLD 5.024 to predict the
binding mode of compounds 8a and 8s with Top1-DNA complex. The crystal
structure of Top1-DNA-CPT ternary complex was retrieved from protein database
bank (PDB ID: 1T8I).25 After the docking process, molecular dynamics simulations
were performed on the docked complexes to further explore the stability and affinity
of the obtained binding poses using Desmond/Maestro non-commercial version
2016.3.26 The total simulation time was 2 ns (Fig. S3) and the average structure was
calculated. As depicted in Fig. 4, the binding mode of compounds 8a and 8s in the
active site of Top1 was the similar to that of CPT and lead compound 1 (Fig. S2).19
The planar anthrathiadiazole ring intercalates at the site of DNA cleavage and form
π-π stacking interactions with both the -1 (upstream) and +1 (downstream) base pairs.
The nitrogen atom in thiadiazole ring formed hydrogen-bonding interaction with
12

Arg364. 4-Substituted group was faced into the major groove and formed
hydrophobic interaction with the surrounding hydrophobic residues such as Ala351
and Met428.
Fig. 5. Docking of compound 8a (A) and 8s (B) in the active site of Top1 (PDB ID
1T8I). The figure was generated using PyMol (http://www.pymol.org/)
In summary, a series of new anthrathiadiazole analogs were designed and synthesized
on the basis of our previously identified novel non-CPT Top1 inhibitor. The SAR and
binding mode was preliminary clarified by the combination of biological assays and
molecular docking. Compound 8s showed potent activity for HCT-116 and ZR-75-30
cell lines, which provides a good starting point for the development of novel non-CPT
Top1 inhibitors. Further structural optimization is in progress.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grant
81373278 to G. D.), the Key Project of Science and Technology of Shanghai (Grant
14YF1405400 to G. D.), the 863 Hi-Tech Program of China (Grant
13

2014AA020525 to C. S.), and the Shanghai “ShuGuang” Project (Grant 14SG33
to C. S.
).
Supplementary data
Supplementary data associated (additional results, experimental protocols and
structural characterization of target compounds.) with this article can be found, in the
online version.
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15

Graphical Abstract
Design, Synthesis and Evaluation of 4-Substituted
Anthra[2,1-c][1,2,5]thiadiazole-6,11-dione Derivatives as Novel
Non-camptothecin Topoisomerase I Inhibitors
Guoqiang Dong1, §, Yuxin Fang 1, §, Yang Liu2, §, Na Liu1, Shanchao Wu1, Wannian
Zhang1 and Chunquan Sheng1, *
A series of non-camptothecin topoisomerase I (Top1) inhibitors were designed and
synthesized. Compound 8s showed good Top1 inhibitory activity and potent in vitro
antitumor activity.
16