Synthesis and biological evaluation of novel isothiazoloquinoline quinone analogues

Article abstract of DOI:10.1016/j.bmcl.2020.127286

Natural quinones and their analogues have attracted growing attention because of their novel anticancer activities. A series of novel isothiazoloquinoline quinone analogues were synthesized and evaluated for antitumor activities against four different kind of cancer cells. Among them, isothiazoloquinolinoquinones inhibited cancer cells proliferation effectively with IC₅₀ values in the nanomolar range, and isothiazoloquinolinoquinone 13a induced the cell apoptosis. Further exploration of possible mechanism of action indicates that 13a not only activates ROS production through NQO1-directed redox cycling but also inhibits the phosphorylation of STAT3. These findings indicate that 13a has potential use for the development of new skeleton drug candidate as an efficient substrate of NQO1 and STAT3 inhibitor.

Full text of DOI:10.1016/j.bmcl.2020.127286

Journal Pre-proofs
Synthesis and Biological Evaluation of Novel Isothiazoloquinoline Quinone
Analogues
Ling Chen, Yuan-Zhu Xie, Zhi-Yong Luo, Li-Jun Liu, Zi-Zheng Zou, Hong-
Dou Liu, Fan-Rong Kong, Ying Hao, Jin-Lei Gao, Liu-Liu Wang, Da-You
Ma, Su-You Liu
PII:
S0960-894X(20)30396-6
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127286
BMCL 127286
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Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
26 March 2020
11 May 2020
23 May 2020
Please cite this article as: Chen, L., Xie, Y-Z., Luo, Z-Y., Liu, L-J., Zou, Z-Z., Liu, H-D., Kong, F-R., Hao, Y.,
Gao, J-L., Wang, L-L., Ma, D-Y., Liu, S-Y., Synthesis and Biological Evaluation of Novel Isothiazoloquinoline
Quinone Analogues, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.
2020.127286
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Synthesis and Biological Evaluation of Novel
Isothiazoloquinoline Quinone Analogues
Ling Chen a, 1, Yuan-Zhu Xie b, 1, Zhi-Yong Luo b, Li-Jun Liu b, Zi-Zheng Zou b, Hong-Dou Liu b,
Fan-Rong Kong b, Ying Hao a, Jin-Lei Gao a, Liu-Liu Wang a, Da-You Ma a, *, Su-You Liu a, *
a School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
b School of Life Sciences, Central South University, Changsha 410013, China
*Corresponding authors: suyouliu@csu.edu.cn (S. Y. Liu), madayou@hotmail.com (D. Y. Ma)
1 Both authors contributed equally to this work
Abstract： Natural quinones and their analogues have attracted growing attention
because of their novel anticancer activities. A series of novel isothiazoloquinoline
quinone analogues were synthesized and evaluated for antitumor activities against
four different kind of cancer cells. Among them, isothiazoloquinolinoquinones
inhibited cancer cells proliferation effectively with IC50 values in the nanomolar
range, and isothiazoloquinolinoquinone 13a induced the cell apoptosis. Further
exploration of possible mechanism of action indicates that 13a not only activates ROS
production through NQO1-directed redox cycling but also inhibits the
phosphorylation of STAT3. These findings indicate that 13a has potential use for the
development of new skeleton drug candidate as an efficient substrate of NQO1 and
STAT3 inhibitor.
Keyword: isothiazoloquinoline quinone analogues; synthesis; antitumor activities;
structure-activity relationship; NQO1 substrate; ROS production; STAT3 inhibitor.

Natural products have been the most productive source for new drug development.
[1, 2, 3]
Quinones are ubiquitous in nature, and showed a wide range of biological
activities.[4, 5] Specially, some natural quinones and its derivatives containing quinone
core have been developed as antitumor agents with different modes of action, [6] such
[7, 8]
as DNA topoisomerase inhibition (e.g., salvicine, doxorubicin),
DNA alkylation
(e.g., mitomycin C),[9] ROS production (e.g., -lapachone),[10] signal transducer and
activator of transcription 3 (STAT3) inhibition (napabucasin, BBI608).[11] In addition,
some quinones are involved in other targets, including HSP90[12,13,14] and indoleamine
2,3-dioxygenase 1 (IDO1).[15, 16, 17] Aulosirazole (Fig. 1) was firstly isolated from the
blue-green alga Aulosira fertilissima and shown to exhibit tumor-selective
cytotoxicity although the mechanism of action remains unclear.[18] Recently it was
reported that aulosirazole was identified as effective IDO inhibitor. [19] To the best of
our knowledge, only a few synthetic aulosirazole derivatives (e.g., LOM604, Fig. 1)
was reported so far.[19, 20] Its unusual quinone structure, selective antitumor activity
and unique action modes impelled us to explore new compounds aulosirazole-based
and investigate their Structure-activity relationships in the hope of discovering novel
potent antitumor agents with new skeleton. In this paper, we report a series of novel
synthetic isothiazole-fused quinones with strong antiproliferation activities against
several cancer cell lines as efficient NQO1 substrates and inhibitor of STAT3.
O
OH
O
O
O
OCH3
N
N
O
O
S
S
O
O
napabucasin (BBI608)
LOM604
aulosirazole
Fig. 1. The structure of BBI608, aulosirazole and LOM604
The synthesis of isothiazoloquinone derivatives are depicted in Scheme 1. Firstly,
the 1,3,4-oxathiazol-2-ones 3 was readily prepared from carboxamides 1 and
chlorocarbonylsulfenyl chloride 2 according to literature procedure.[21] Then,
isothiazoloquinones
5
was obtained by 1,3-dipolar cycloaddition of
1,4-naphthquinone 4 and nitrile sulfides, generated in situ by thermal decarboxylation
of the corresponding precursor 3 according to the reported method.[22] Alternatively,

5-hydroxyl-1,4-naphthquinone 7 was prepared from the dihydroxynaphthalene 6 by
m-CPBA oxidation. Further methylation of gave the corresponding
7
5-methoxyl-1,4-naphthquinone 8 in the presence of silver oxide. Oxathiazolone 3 and
1,4-naphthquinones 7 or 8 were refluxed in xylene affording two regioisomeric
isothiazolonaphthoquinones 9 and 10, respectively. Similarly, 8-hydroxyquinoline 11
was oxidized to form 5,8-quinolinoquinone 12 using the Stork reagent PhI(O2CCF3)2
in high yield, followed by cycloaddition giving the two regioisomeric
isothiazoloquinoline-4,9-diones 13 and 14 in almost the same ratio. The structure of
regioisomers were further determined by 13C NMR and HMBC spectrum
(Supplementary materials).
O
O
S
N
a
3c R1 = Ph
3d R1 = 4-OMePh
3a R1 = CH3
3b R1 = C2H5
Cl
+
R1
NH2
O
Cl
S
R1
O
O
2
1
3
R1
O
5
4
3
5a R1 = CH3
2
N
b
6
7
5b R1 = C2H5
5c R1 = Ph
1
9
S
8
5d R1 = 4-OMePh
O
O
4
5
OR2
O
4
R1
N
OR2
O
O
OH
R1
5
3
1
2
N
c
6
b
+
9
S
7
S
8
OR2
O
OH
O
O
7 R2 = H
8 R2 = CH3
9a R1 = CH3, R2 = H
10a R1 = CH3, R2 = H
6
d
9b R1 = C2H5, R2 = H
10b R1 = C2H5, R2 = H
10c R1 = 4-OMePh, R2 = H
10d R1 = Ph, R2 = CH3
10e R1 = 4-OMePh, R2 = CH3
9c R1 = 4-OMePh, R2 = H
9d R1 = 4-OMePh, R2 = H
9e R1 = 4-OMePh, R2 = CH3
O
O
R1
O
R1
N 5
4
3
6
2
e
b
+
N
N
1
S
9
7
N
S
N
N
8
OH
O
O
O
13a R1 = CH3
13b R1 = C2H5
13c R1 = Ph
14a R1 = CH3
14b R1 = C2H5
14c R1 = Ph
11
12
14d R1 = 4-OMePh
Reagents and conditions: (a) toluene, 100℃, 5 h, 50%~89%; (b) 3, xylene, 138℃, 12 h, 8%~66%; (c)
m-CPBA, ACN, 25℃, 2 h, 60%; (d) CH3I, Ag2O, DCM, 40℃, 40 h, 95%; (e) PhI(O2CCF3)2,
H2O/MeCN, 0℃ - rt, 3 h, 95%.
Scheme 1. Synthesis of aulosirazole analogues
To evaluate in vitro tumor cell growth inhibitory activity, MTT assays were

performed in five different human cell lines, including human breast carcinoma
MDA-MB-231 cells, human breast carcinoma MCF-7 cells, human normal mammary
epithelial cells MCF-10A, the colorectal cancer HT-29 cells and human
non-small-cell lung carcinoma A549 cells with BBI608 as the positive control. As
shown in Table 1, most of the tested compounds displayed pronounced
anti-proliferative activity against four cancer cells. Among them, 3-alkyl substituted
naphthaquinones 5a, 5b, 9a, 9b showed much stronger cell growth inhibitory activity
compared with corresponding 3-aryl substituted naphthaquinones 5c (LOM604), 5d,
9c-9e, 10d, 10e. Besides, the anti-proliferation activity of 5- or 8-O-methylated
compounds 9d, 9e, 10d and 10e were markedly reduced compared to that of the
corresponding 5- or 8-hydroxyl compounds. It indicates that introduction of a
hydroxyl group peri at the carbonyls of the 1,4-naphthaquinone core could enhance its
activity. Interestingly, new skeleton isothiazoloquinolinoquinones 13a-13c, 14a-14d,
showed very strong activities against the selected cancer cell lines with the IC50
values in
the
nanomolar
range.
Furthermore, in
the
case
of
isothiazoloquinolinoquinones, alkyl or phenyl group at 3-position on the isothiazole
ring gave no obvious difference in antiproliferative effects. The structure-activity
relationship studies of these compounds suggest the replacement of naphthoquinone
nucleus with quinolinoquinone nucleus could significantly increase the
antiproliferative effects in vitro. More interestingly, 13a and 14a seem to show
tumor-selective cytotoxicity against breast cancer cells compared to HT-29 cells and
A549 cells. However, these synthetic compounds also show cytotoxicity against
normal cell MCF-10A and low selectivity between cancer cells and normal cell
similar to BBI608.
Table 1. Anti-proliferation on tumor cells (μM) and rate of NADH oxidation
Cytotoxicity IC50 (μM)
Cpd
MDA-MB
-231
Rate of NADH
oxidation
MCF-7
HT-29
A549
MCF-10A
5a
1.65 ± 0.06
2.59 ± 0.20
10.34 ± 0.47
35.23 ± 4.06
4.09 ± 0.24
2.34 ± 0.16
> 40
2.67 ± 0.17
2.92 ± 0.11
18.78 ± 2.62
36.78 ± 2.72
1.71 ± 0.41
0.70 ± 0.03
27.50 ± 2.63
> 40
1.11 ± 0.12
1.13 ± 0.18
17.64 ± 2.62
29.26 ± 1.85
68.05 ± 2.98
121.53 ± 8.26
5.59 ± 0.49
7.29 ± 0.18
5b
5c*
5d
37.48 ± 2.32

9a
9b
1.67 ± 0.55
2.72 ± 0.66
29.50 ± 1.86
9.80 ± 2.53
> 40
0.92 ± 0.08
0.71 ± 0.08
35.59 ± 2.31
6.22 ± 1.03
> 40
1.62 ± 0.31
1.66 ± 0.10
11.47 ± 1.54
27.87 ± 2.55
>40
1.96 ± 0.70
1.38 ± 0.17
10.59 ± 1.52
22.85 ± 2.54
>40
0.92 ± 0.05
3.06 ± 0.25
24.99 ± 5.12
10.04 ± 2.59
>40
121.53 ± 6.25
97.22 ± 4.55
38.89 ± 2.46
19.45 ± 1.06
8.75 ± 0.60
9c
9d
9e
10a
10b
10c
10d
10e
13a
13b
13c
14a
14b
14c
14d
BBI608
2.67 ± 0.32
5.81 ± 0.27
1.46 ± 0.28
21.97 ± 2.53
>40
1.58 ± 0.28
3.31 ± 0.18
1.41 ± 0.20
12.06 ± 2.52
>40
1.41 ± 0.35
3.80 ± 0.26
3.88 ± 0.24
28.82 ± 2.31
>40
1.36 ± 0.28
2.83 ± 0.38
4.80 ± 0.76
>40
1.37 ± 0.27
3.02 ± 0.30
1.51 ± 0.29
24.6 ± 4.21
>40
121.53 ± 9.66
111.80 ± 5.25
38.89 ± 1.69
14.59 ± 2.50
17.99 ± 2.67
218.75 ± 7.70
91.78 ± 5.80
175.00 ± 7.21
179.86 ± 7.04
28.42 ± 4.84
174.41 ± 5.03
209.03 ± 6.52
170.14 ± 5.56
>40
0.26 ± 0.04
1.53 ± 0.22
0.66 ± 0.06
0.23 ± 0.05
0.34 ± 0.06
0.40 ± 0.07
0.73 ± 0.09
1.29 ± 0.20
0.31 ± 0.07
0.36 ± 0.20
0.46 ± 0.05
0.64 ± 0.08
1.11 ± 0.10
0.26 ± 0.05
1.82 ± 0.09
0.63 ± 0.13
1.52 ± 0.27
0.91 ± 0.11
2.03 ± 0.08
3.03 ± 0.77
2.06 ± 0.29
1.20 ± 0.13
39.97 ± 3.12
0.14 ± 0.06
3.28 ± 0.19
1.38 ± 0.15
1.35 ± 0.17
1.69 ± 0.09
1.51 ± 0.12
0.81 ± 0.07
2.77 ± 0.24
6.69 ± 1.46
0.13 ± 0.02
0.17 ± 0.02
0.17 ± 0.03
0.88 ± 0.07
0.59 ± 0.05
0.88 ± 0.67
1.96 ± 0.28
0.54 ± 0.17
Notes: Rate of NADH oxidation by NQO1, μmol NADH /min/μmol NQO1. IC50, concentration of test
compound required for 50% inhibition of cell viability, as determined by the MTT assay after 48 h of
treatment. Values are the means (± SD) of three independent experiments. * 5c: LOM604
To investigate whether the anti-proliferative potency of compound 13a was
consistent with the induction of apoptosis, Annexin V-FITC/PI staining assay was
performed by flow cytometry. The results showed that 13a can induce A549 cell
apoptosis in a dose-dependent manner, and the apoptosis rates at 0, 1 and 2 μM were
3.95%, 6.70% and 13.73%, respectively (Fig. 2). The ability of 13a to induce
apoptosis of cancer cells is about 2.5-fold stronger than that of BBI608 (positive
control, 5.14%) at the same concentration (2 μM). In short ， the anti-proliferative
potency of 13a was in agreement with the induction of apoptosis.
Fig. 2. Apoptotic effects of compound 13a on A549 cells. A549 cells were incubated with indicated
compound 13a (1, 2 μM), BBI608 (2 μM) for 24 h, or vehicle control (DMSO), then stained with
Annexin V-FITC and propidium iodide for 15 min.

NQO1 is upregulated in many human cancers,[23, 24] such as breast cancer,[25]
colocrectal cancer,[26] lung cancer,[27] and has been potential target for cancer therapy.
[28]
It has been known that quinones can be bioactivated by a cytosolic reductase,
NAD(P)H:quinone oxidoreductase-1 (NQO1) to produce excessive reactive oxygen
species (ROS) and induce cancer apoptosis.[28] We supposed that these novel
synthesized isothiazoloquinone derivatives affect cellular proliferation and apoptosis
by accumulating ROS through a futile redox cycle catalyzed by intracellular NQO1.
All of the isothiazoloquinone derivatives were first evaluated for their ability to act as
substrates for NQO1. The ability of NQO1 to process the isothiazoloquinones in vitro
at the concentration of 20 μM was assessed. The quinones were coincubated with
NADH in the presence or absence of human NQO1. For NQO1 the rate of NADH
oxidation is dependent on reduction of quinone. The results of the quinones reduction
were therefore presented as μmol NADH oxidized/min/μmol NQO1 protein. As
shown in Table 1 and Fig. 3, the results show that the isothiazoloquinones with
stronger anti-proliferative activities generally led to higher rate of NADH oxidation by
NQO1. In particular, more active isothiazoloquinoline quinones, such as 13a, 13c,
14a, 14c and 14d, showed much higher enzymatic conversion rates than the lead
compound 5c (LOM604, table 1, Fig. 3). Compound 13a (218.75 μmol NADH
/min/μmol NQO1, table 1, Fig. 3) showed the most efficient reduction rate by NQO1
compared with LOM604 (5.59 μmol NADH /min/μmol NQO1). The data indicates
some isothiazoloquinoline quinones are the efficient substrates for NQO1 and are
rapidly reduced to corresponding hydroquinones. These results are consistent with the
study on aulosirazole. [19]

Fig. 3. Rate of reduction of indicated compounds by NQO1. NQO1(-) and NQO1(+) represent the
absence and presence of NQO1, respectively.
To further determine whether the cell proliferation inhibition of these quinones was
associated with ROS production catalyzed by intracellular NQO1, the highly active
compound 13a and the poorly active compound 9e were used to investigate their
ability of promoting ROS in NQO1-rich cancer cell line A549. BBI608, an efficient
substrate of NQO1, was used as reference. As shown in Fig. 4, DCFH-DA positive
population of A549 cells treated with 13a (2 μM) had an increase of about three times
as compared with the cells by treatment with BBI608 (2 μM) for 24 h, whereas
DCFH-DA positive population had no significant change after treated with 9e (2 μM).
This result indicates that 13a is able to generate a higher amount of ROS through
NQO1-directed redox cycling, which is in good agreement with the cancer cells
proliferation assay.
Fig. 4. ROS production accessed by flow cytometry of A549 cells incubated with the cell
permeant probe reagent 2ʹ,7ʹ-dichlorofluorescein diacetate (DCFH-DA, 5 μM). A549 cells was
treated with the indicated compounds (2 μM) of 13a, 9e, BBI608 or vehicle control (DMSO) for
24 h.
STAT3 is overactivated in many tumors and has been an attractive molecular target
for the development of novel anticancer drugs.[29] We anticipated that
isothiazoloquinolinoquinone analogues may suppress the STAT3 activity in

accordance with naphthoquinones reported in literatures.[11, 30, 31, 32] We next examined
the effect of isothiazoloquinoline quinone 13a on the STAT3 in MDA-MB-231 cells
with BBI608 as a positive control by western blotting assays. As expected, 13a
treatment for 2 hours could inhibit the phosphorylation of STAT3 in a dose-dependent
manner while had no influence on the total level of STAT3 (Fig. 5). Moreover, 13a
showed stronger inhibition of p-STAT3 than BBI608. These results suggest that 13a
may be considered as a potent STAT3 inhibitor of phosphorylation.
Fig. 5. Effect of compound 13a on the phosphorylation of STAT3. MDA-MB-231 cells were incubated
with various concentrations of 13a (2, 4, 8 μM), BBI608 (8 μM), or vehicle control (DMSO) for 2 h,
respectively. The expressions of p-STAT3, STAT3 and GAPDH were determined by Western blotting
using specific antibodies.
To
gain
further
insight
of
the
interactions
between
these
isothiazoloquinolinoquinones and NQO1, molecular docking simulations were
performed using 13a with NQO1 (PDB code 1DXO) by MOE (version 2018)
software. The binding model of the 13a with NQO1 complex was carefully analyzed
and the results showed that compound 13a can fit into the active pocket completely
(Fig. 6). It is found that the π-stacking interaction between 13a and FAD is very
similar to that of duroquidone.[23] The direct hydride transfer from FADH2 cofactor in
NQO1 (atom N5 which transfer the hydride) to substrate (quinone carbonyl as the
hydride acceptor) has been confirmed previously.[23] In our docking model, the
distance between 13a and FAD is 3.84Å, within a reasonable distance for hydride
transfer (about 4Å), which shows that 13a is in an optimal position to receive a
hydride from FADH2 and is a potential substrate of NQO1. The carbonyl oxygen of
C-4 and C-9 form hydrogen bonds with amino acid residue Try126 and His161, with
distances of 2.14Å and 3.31Å respectively. π-H conjugation is formed between 3-CH3
of 13a and the residue of Trp105, with a distance of 3.82Å, further explained the high

activity of 13a.
Fig. 6. Docking conformation of 13a into the active site of NQO1 (PDB: 1DXO). The carbon atoms of
13a, duroquidone, the key residues in the active site of NQO1 and FAD were colored in red, grey,
green and yellow respectively.
In summary, we have synthesized a series of novel isothiazoloquinone analogues,
and evaluated their anticancer activities in vitro. Most isothiazoloquinoline quinones
strongly inhibited cancer cells proliferation in the nanomolar range and induced the
apoptosis. Studies on mechanism of action indicate that these compounds are efficient
substrates of NQO1 and produced ROS through NQO1-directed redox cycling. More
interestingly, 13a also markedly inhibited the phosphorylation level of STAT3. Our
findings suggest that new skeleton isothiazoloquinoline quinone may represent a
novel selective antitumor agent targeting NQO1 and STAT3. An in vivo study and
further insight into the effect on STAT3 inhibition is under the way.
Acknowledgements
This work was supported by the Fundamental Research Funds for the Central
Universities of Central South University (No. 1053320184103).
Declaration of interests
The authors declare that they have no known competing financial interests or

personal relationships that could have appeared to influence the work reported in this
paper.
Appendix A. Supplementary data
Experimental details, the 1D and 2D NMR of compounds are available in the
supplementary data.
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33.

Synthesis and Biological Evaluation of Novel
Isothiazoloquinoline Quinone Analogues
Hightlights
1. A series of unique isothiazole-fused quinolinoquinone analogues were
synthesized.
2. Some isothiazoloquinolinoquinones strongly inhibit proliferation of cancer cells
and may induce cancer cells apoptosis.
3. Isothiazoloquinolinoquinones are efficient substrates for NQO1 and induce ROS
production in vitro.
4. Isothiazoloquinolinoquinone inhibits the phosphorylation of STAT3.
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