Natural product-based design, synthesis and biological evaluation of anthra[2,1-d]thiazole-6,11-dione derivatives from rhein as novel antitumour agents

Article abstract of DOI:10.1016/j.ejmech.2014.07.047

Two series of novel 2-substituted 5,7-dihydroxyanthra[2,1-d]thiazole-6,11- dione derivatives from natural rhein were designed, synthesized and evaluated for their antitumour activities against human cancer cell lines A549 and HeLa in vitro.

Full text of DOI:10.1016/j.ejmech.2014.07.047

European Journal of Medicinal Chemistry 84 (2014) 505e515
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Natural product-based design, synthesis and biological evaluation of
anthra[2,1-d]thiazole-6,11-dione derivatives from rhein as novel
antitumour agents
,
,
Yu-Kun Liang a b, Zhi-Zhou Yue a, Jia-Xin Li b, Cun Tan b, Ze-Hong Miao b *, Wen-Fu Tan c,
Chun-Hao Yang b
,
*
a Department of Pharmaceutical Engineering, School of Chemical Engineering, Wuhan University of Technology, 205 Luo Shi Road, Wuhan, Hubei 430070,
PR China
b State Key Laboratory of Drug Research, Shanghai Institute of MateriaMedica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203,
PR China
c School of Pharmacy, Fudan University, 826 Zhang Heng Road, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Two series of novel 2-substituted 5,7-dihydroxyanthra[2,1-d]thiazole-6,11-dione derivatives from natural
rhein were designed, synthesized and evaluated for their antitumour activities against human cancer cell
lines A549 and HeLa in vitro.
Received 23 January 2014
Received in revised form
14 July 2014
Accepted 15 July 2014
Available online 15 July 2014
© 2014 Elsevier Masson SAS. All rights reserved.
Keywords:
Rhein analogues
Anthra[2,1-d]thiazole-6,11-dione
Antitumour
SRB assay
1. Introduction
to DNA duplexes [10e13]. Rhein (Fig. 1), possessing an anthraqui-
none scaffold, which is a natural product isolated from Rheum pal-
Natural products (NPs), including semi-synthetic NPs and NP-
derived compounds, with great characteristics of high chemical
diversity and biochemical specificity, are all through major entities
among the FDA-approved drugs as anticancer, anti-infective agents
and so on [1e6]. In recent years, new methods such as high
through-put screening (HTS) of synthetic chemical libraries have
been brought into drug discovery, which has not yet provided the
numbers of high-quality leads as we anticipated [5,7,8]. Therefore,
diversity-oriented synthesis that enables the construction of skel-
etally diverse NP-like libraries can be regarded as a useful supple-
ment to current synthetic chemical libraries [7,9].
matum, has been used as an anti-inflammatory agents, a laxative
and stomach drug for years [14,15]. Recently, just like other
anthraquinone-based compounds, rhein and its analogues have also
been reported to exhibit a low to moderate activity against tumours
[10,16]. There are several anthraquinone-based drugs such as
mitoxantrone, ametantrone and doxorubicin (Fig. 1) used for
treatment of varied cancer in clinic. However, their clinical appli-
cations were limited by their severe cardiac toxicity [16e18].
Therefore, the development of novel anthraquinone-based anti-
cancer drugs by modification of rhein is of high interest and possi-
bility, because they may be well tolerated in humans as NP-like
products and promising as anticancer compounds for the structural
similarity to other anthraquinone drugs.
More recently, a series of NPs, topopyrone A and C isolated from
the culture broths of two fungi, with a fused 1,4-pyrone ring, and
another series of anthraquinone-based compounds benzimidazoles
were reported to have good antitumour activities (Fig. 1) [19,20].
Inspired by these discoveries, we designed two series of novel rhein
analogues bearing a fused thiazole ring to keep the overall planar
Anthraquinones are essential structural motifs in a great number
of NPs and NP-derived compounds such as emodin and aloe-emodin
with anticancer activities probably due to their noncovalent binding
* Corresponding authors.
E-mail addresses: zhmiao@simm.ac.cn (Z.-H. Miao), chyang@simm.ac.cn
(C.-H. Yang).
http://dx.doi.org/10.1016/j.ejmech.2014.07.047
0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.

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Y.-K. Liang et al. / European Journal of Medicinal Chemistry 84 (2014) 505e515
Among them, target products 6j, 6n, and 6p exhibited potent
cytotoxic activities giving IC50 values ranging from 4.3 to 11.8 M.
m
Generally speaking, compounds with more than one heteroatom in
the side aliphatic chain might have better cytotoxic effects as
shown in Table 1. Compounds 6a, 6b, 6d, 6g, and 6h showed weaker
cytotoxicity than other compounds containing more than one
heteroatom in the side chain such as 6e, 6f, 6i, 6j (Table 1). This may
be explained that another nitrogen/oxygen atom in the basic side
chain improved the aqueous solubility of the compounds.
Furthermore, the more lipophilic substituents on the nitrogen atom
of piperazine were not favoured (6l, 6k vs 6m, 6m vs 6n).
Comparing compound 6n with 6m and 6k, we found that the
straight substituent (-Et) on the nitrogen atom of piperazine
showed higher potency than the branched substituent (-iPr) and
the cycloalkyl substituent exhibited the weakest potent among
these compounds. In addition, compounds 6r, 6s with hydrophilic
acyclic aliphatic side chain, and compounds 6c, 6q with seven-
membered ring also showed a moderate improvement in potency
compared with rhein.
Fig. 1. Structure of anthraquinone-based compounds rhein, doxorubicin, benzimid-
azole and topopyrone C.
As described in Table 1, we found that a piperazine ring in the
side chain is very significant for the observed cytotoxicity. Based on
these results, another series of compounds 13aek were designed
with a focus on modification of the substituent on the nitrogen
atom of piperazine in order to increase the solubility of these
compounds. The cytotoxicities of this series of rhein analogues
were evaluated by using the same method as for the first series and
the results were shown in Table 2. Despite most of these com-
pounds in this series had improved potency compared with rhein,
they have weaker potency than the first series, which declared the
substituent on the nitrogen atom of piperazine exerted great effect
on their cytotoxicities. It could be concluded from these results
both in Tables 1 and 2 that two carbon atom aliphatic chain ethyl or
hydroxyethyl group on the nitrogen atom of piperazine ring was
the best among these tested compounds.
structure that is most likely responsible for its cytotoxicity [10], and
the thiazole ring could be further optimized in the purpose of
increasing diversity, water solubility, and potential interactions
with the DNA phosphate backbone.
2. Results and discussion
2.1. Chemistry
The synthesis of anthra[2,1-d]thiazole-6,11-dione derivatives 6
was accomplished according to the synthetic strategy described in
Scheme 1. The intermediate 3 was prepared according to our pre-
vious work in several steps [10]. Iodination of compound 3 selec-
tively at the 4-position with iodine in the presence of silver
sulphate afforded key intermediate 4 [21]. The position of iodin-
ation was further confirmed by 1D NOE, and nuclear overhauser
effect of 1H nuclei of methoxyl group at 1-position was observed by
irradiating the 1H nuclei at 2-position. Compounds 5aes were then
synthesized conveniently in 50e90% yields through one-pot reac-
tion with various commercially available secondary amines and
carbon disulfide in DMF [22]. After that, demethylation of com-
pounds 5aei, 5jes provided the target compounds 6aei, 6jes by
EtSH/AlCl3 or BBr3at ambient temperature, respectively [23,24].
In order to increase the aqueous solubility of target compounds,
another series of compounds 13aek were synthesized according to
the same strategy. The intermediates 11aek were prepared
through nucleophilic substitution of compound 9 by appropriately
secondary amines [25] followed by deprotection (Scheme 2).
To the best of our knowledge, the synthesis of compounds 6 and
13 has never been reported before. All these target synthesized
compounds were novel chemical entities characterized by 1H NMR,
13C NMR, and high resolution mass (EI) spectra. The results are in
detail presented in the experimental part.
Finally, in order to investigate the influence of the hydro-
philicityelipophilicity balance on the activity of the compounds,
we took the calculation of logP into consideration. Generally, in
most of these compounds in Tables 1 and 2, compounds with high
hydrophobicity values (6g, 6h, 13e, 13f and 13h) showed weaker or
even no cytotoxicity.
3. Conclusion
In summary, the 4-position of 3-amino-1,8-dimethoxy-
anthracene-9,10-dione was selectively displaced with iodine in
the presence of silver sulphate, after that two series of benzothia-
zole compounds were synthesized using one-pot method. All target
derivatives were screened against lung cancer A549 cells and cer-
vical cancer HeLa cells, among which sixteen compounds were
found to be more potent than rhein. Especially compound 6n,
giving the IC50 of 5.4 mM and 4.3 mM, respectively, was approxi-
mately 30 times more potent than rhein. This compound could be a
useful lead structure for developing new rhein analogues with
antitumour activity. Furthermore, anthra[2,1-d]thiazole-6,11-dione
offered a novel scaffold to design new anticancer agents.
2.2. Pharmacology
4. Experimental
All of the novel target compounds were evaluated for their
antitumour effects using sulforhodamine B (SRB) assays in lung
cancer cells A549 and cervical cancer cells HeLa. The test results
were shown in the Tables 1 and 2, respectively. And the most active
compounds 6n and 6p were tested three times.
Compared with rhein, most of the first series of tested com-
pounds 6ae6s showed improved cytotoxicity against A549 and
HeLa cell lines at concentrations in the micromolar range (Table 1).
4.1. Chemistry
All the reagents used in the current study were commercial
products and used without purification. Solvents were dried by
standard methods. Reactions were monitored by thin layer chro-
matography (TLC), detected on silica gel glass plates containing
GF254 under UV light. Chemical shifts (d) were reported in parts per

Y.-K. Liang et al. / European Journal of Medicinal Chemistry 84 (2014) 505e515
507
Scheme 1. Synthesis of rhein analogues 6. Reagents and conditions: a) NaH, MeI, DMF, ice bath, overnight; b) NaOH in H2O/EtOH, 50 ꢀC, 1 h; c) Et3N, DPPA, DMF, RT, 1 h; d) dioxane,
reflux, 30 min; e) NaOH in H2O, reflux, 4 h; f) I2, Ag2SO4, ethylene glycol, RT, 3 h; g) amine, CS2, K2CO3, DMF, 115 ꢀC, 6 h; h) EtSH, AlCl3, DCM, RT, 10 h or BBr3, DCM, RT, 10 h.
Scheme 2. Synthesis of rhein analogues 13. Reagents and conditions: a) (Boc)2O, THF; b) MsCl, Et3N, DMAP; c) amines, NaI, MeOH; d) CF3COOH; e) CS2, K2CO3, DMF; f) BBr3, DCM.
million (ppm), and proton coupling patterns are described as
s(singlet), dd (doublet of doublet), d (doublet), t (triplet), q (quartet)
or m (multiplet). 1H NMR spectra were recorded with Varian
Mercury-300 spectrometers using tetramethylsilane (TMS) as an
internal standard. MS and HRMS spectra were recorded on a MAT-
95 spectrometer.
The starting material rhein was purchased from Nanjing Zelang
Medical Technology Co. (P.R. China) and used directly without
further purification.
J ¼ 8.6 Hz, 1H), 6.57 (s, 1H), 3.97 (s, 3H), 3.92 (s, 3H). LC/MS m/z:
410.2 [MþH]þ.
4.3. General procedure for synthesis of compounds 10
A mixture of compound 9 (200 mg, 0.8 mmol), sodium iodine
(289 mg, 1.93 mmol) and substituted amines (1.61 mmol) in meth-
anol (30 mL) was stirred at 40 ꢀC for 5 h. After the reaction was
completed (monitored by TLC), the solutionwas concentrated under
vacuum. Then the crude residue was purified by column chroma-
tography (dichloromethane/methanol), affording pure product 10.
4.2. 2-Amino-1-iodo-4,5-dimethoxyanthracene-9,10-dione (4)
4.3.1. Tert-Butyl 4-(2-(pyrrolidin-1-yl)ethyl)piperazine-1-
The compound 3 [21] (300 mg, 1.06 mmol) was added to a
mixture of iodine (156 mg, 0.61 mmol) and silver sulphate (330 mg,
1.06 mmol) in ethylene glycol (30 mL) at 35 ꢀC.The mixture was
stirred at this temperature for 2.5 h. After the reaction was
completed (monitored by TLC), 50 mL water was added to the re-
action mixture and then extracted with dichloromethane. The
organic layer was filtrated to get the clean organic layer and washed
with aqueous Na2S2O3, dried over anhydrous Na2SO4 and evapo-
rated to dryness. The residue was purified by column chromatog-
raphy on silica gel (ethyl acetate/hexane 3:1) to give the desired
product as a deep red solid (335 mg, 77%). 1H NMR (300 MHz,
carboxylate(10a)
Yield 49%; 1H NMR (300 MHz, CDCl3)
d 3.56e3.37 (m, 8H), 3.27
(t, J ¼ 5.9 Hz, 2H), 2.90 (t, J ¼ 5.9 Hz, 2H), 2.52e2.45 (m, 4H),
2.22e2.14 (m, 4H), 1.43 (s, 9H). LC/MS m/z: 284.3 [MþH]þ.
4.3.2. Tert-Butyl 4-(2-(4-methylpiperidin-1-yl)ethyl)piperazine-1-
carboxylate(10c)
Yield 52%; 1H NMR (300 MHz, CDCl3)
d
3.67 (d, J ¼ 12.1 Hz, 2H),
3.48e3.37 (m, 4H), 3.16 (t, J ¼ 5.9 Hz, 2H), 3.03e2.87 (m, 4H),
2.54e2.43 (m, 4H), 2.05e1.67 (m, 5H), 1.44 (s, 9H), 1.03 (d,
J ¼ 6.4 Hz, 3H). LC/MS m/z: 312.3[MþH]þ.
CDCl3)
d
7.69 (dd, J ¼ 7.7, 1.0 Hz, 1H), 7.60e7.54 (m, 1H), 7.22 (d,

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Y.-K. Liang et al. / European Journal of Medicinal Chemistry 84 (2014) 505e515
Table 1
Antitumour activities of compounds 6aes.
Compounds
CLogPa
IC50(mM)
A549 cell
HeLa cell
Rhein
6a
3.53
5.67
115.1
>100
123.2
55.8
6b
6c
6d
5.11
6.56
6.52
148.3
39.4
66.0
44.8
41.0
60.4
6e
6f
5.55
4.67
19.6
21.1
16.7
26.9
6g
6h
7.00
6.39
>100
117.9
86.7
108.1
6i
4.29
33.4
30.3
6j
4.70
5.22
5.88
6.3
11.8
58.1
68.4
6k
6l
65.7
54.8
6m
6nb
6o
6.02
5.71
5.18
15.0
14.8
5.4 0.61
20.2
4.3 0.05
27.4
6pb
6q
4.61
3.89
6.5 0.42
15.2
4.5 0.12
19.7
6r
6s
4.32
4.59
30.4
45.9
23.2
30.6
a
Calculated using ChemBioDraw Ultra 13.0.
The data represent the mean and standard deviation of the compounds from three independent experiments.
b

Y.-K. Liang et al. / European Journal of Medicinal Chemistry 84 (2014) 505e515
509
Table 2
Antitumour activities of compounds 13aek.
Compounds
CLogPa
4.86
IC50 (mM)
A549 cell
HeLa cell
81.1
13a
13b
13c
13d
13e
70.3
5.42
6.22
4.20
8.73
46.4
86.9
38.2
82.1
>100.0
57.1
>100.0
>100.0
13f
6.61
5.56
7.23
>100.0
32.8
>100.0
>100.0
>100.0
13g
13h
>100.0
13i
13j
4.25
3.72
23.4
24.2
71.3
80.1
13k
4.56
3.53
54
>100.0
Rhein
95.8
92.2
a
Calculated using ChemBioDraw Ultra 13.0.
4.3.3. Tert-Butyl 4-(2-(dibutylamino)ethyl)piperazine-1-
4.3.4. Tert-Butyl 4-(2-(diethylamino)ethyl)piperazine-1-
carboxylate(10e)
carboxylate(10f)
Yield 42%; 1H NMR (400 MHz, CDCl3)
d
3.32e3.19 (m, 4H),
Yield 47%; 1H NMR (400 MHz, CDCl3)
d 3.41e3.35 (m, 4H), 3.28 (q,
2.81e2.74 (m, 6H), 2.72e2.64 (m, 2H), 2.39e2.27 (m, 4H), 1.27e1.19
J ¼ 7.2Hz, 4H), 3.20(t, J ¼ 5.9 Hz, 2H), 2.79(t, J ¼ 5.9 Hz, 2H), 2.46e2.39
(m, 17H), 0.76 (t, J ¼ 5.8 Hz, 6H). LC/MS m/z: 341.5 [MþH]þ.
(m, 4H),1.36 (t, J ¼ 7.4 Hz, 6H),1.33 (s, 9H). LC/MS m/z: 286.3 [MþH]þ.

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Y.-K. Liang et al. / European Journal of Medicinal Chemistry 84 (2014) 505e515
4.3.5. Tert-Butyl 4-(2-(4-ethylpiperazin-1-yl)ethyl)piperazine-1-
1H), 4.01 (s, 3H), 3.99 (s, 3H), 3.80e3.66 (m, 4H), 2.81e2.69 (m, 4H),
2.67e2.53 (m, 1H), 0.48 (d, J ¼ 12.4 Hz, 3H). 13C NMR (126 MHz,
carboxylate(10i)
Yield 53%; 1H NMR (400 MHz, CDCl3)
d
3.61e3.54 (m, 4H),
CDCl3) d 183.97, 181.70, 175.13, 160.12, 159.75, 159.04, 134.02,
3.38e3.29 (m, 6H), 3.15e2.95 (m, 8H), 2.45 (q, J ¼ 7.1 Hz, 4H), 1.43
133.49, 126.92, 124.23, 122.11, 118.98, 118.64, 117.59, 107.29, 57.60,
(s, 9H), 1.11 (t, J ¼ 7.2 Hz, 3H). LC/MS m/z: 327.3 [MþH]þ.
56.70, 56.60, 33.60, 30.80, 21.70. LC/MS m/z: 423.2 [MþH]þ.
4.3.6. Tert-Butyl 4-(2-(4-methylpiperazin-1-yl)ethyl)piperazine-1-
4.4.5. 2-(2-(2-Hydroxyethyl)piperidin-1-yl)-5,7-dimethoxyanthra
carboxylate(10j)
[2,1-d]thiazole-6,11-dione (5e)
Yield 32%; 1H NMR (300 MHz, CDCl3)
d
3.56e3.49 (m, 2H),
Yield 75%; red powder.1H NMR (300 MHz, CDCl3)
d
7.86 (d, J ¼ 7.7
3.34e3.25 (m, 6H), 3.20 (m, 2H), 3.05 (m, 2H), 2.93e2.84 (m, 6H),
2.82e2.76 (m, 2H), 2.41 (s, 3H), 1.42 (s, 9H). LC/MS m/z: 313.3
[MþH]þ.
Hz,1H), 7.66e7.59 (m,1H), 7.33 (d, J ¼ 7.2 Hz,1H), 7.32 (s,1H), 4.02 (s,
3H), 4.01 (s, 3H), 3.83e3.61 (m, 2H), 3.48e3.30 (m, 2H), 2.22e2.05
(m, 1H), 1.98e1.81 (m, 2H), 1.81e1.66 (m, 6H). 13C NMR (126 MHz,
DMSO-d6)
d 183.49, 180.31, 174.60, 159.65, 159.37, 158.93, 134.32,
4.3.7. Tert-Butyl 4-(2-(4-isopropylpiperazin-1-yl)ethyl)piperazine-
133.70, 126.71, 124.02, 121.33, 119.81, 118.64, 117.35, 107.65, 58.30,
1-carboxylate(10k)
56.85, 56.75, 32.51, 28.09, 25.50, 18.99. LC/MS m/z: 453.2 [MþH]þ.
Yield 43%; 1H NMR (400 MHz, CDCl3)
d 3.53e3.38 (m, 5H),
3.36e2.98 (m, 8H), 2.78e2.70 (m, 2H), 2.69e2.60 (m, 2H),
4.4.6. 2-(3-Hydroxypiperidin-1-yl)-5,7-dimethoxyanthra[2,1-d]
2.55e2.45 (m, 4H), 1.55e1.35 (m, 15H). LC/MS m/z: 341.4 [MþH]þ.
thiazole-6,11-dione (5f)
Yield 79%; red powder. 1H NMR (400 MHz, CDCl3)
d 7.86 (d,
4.4. General procedure for synthesis of 2-substituted 5,7-
dimethoxyanthra[2,1-d]thiazole-6,11-dione 5aes and 12aek
J ¼ 7.8 Hz, 1H), 7.62 (t, J ¼ 8.1 Hz, 1H), 7.38 (s, 1H), 7.32 (d, J ¼ 8.4 Hz,
1H), 4.03 (s, 3H), 4.01 (s, 3H), 3.82 (d, J ¼ 11.8 Hz, 1H), 3.60 (dd,
J ¼ 12.5, 6.9 Hz, 2H), 2.07e1.93 (m, 3H), 1.79e1.65 (m, 4H). 13C NMR
A mixture of the compound 4 (205 mg, 0.5 mmol), carbon di-
sulfide (44 mg, 0.6 mmol), amine (0.75 mmol), copper tri-
fluoromethanesulfonate (90 mg, 0.25 mmol), and potassium
carbonate (208 mg, 1.5 mmol) in dimethyl formamide (20 mL) was
stirred at 115 ꢀC for 6 h. The cooled solution was partitioned be-
tween dichloromethane and water, and the organic layer was
washed with water and brine, and then dried over anhydrous
MgSO4. After removal of the solvent in vacuo, the residue was pu-
rified by silica-gel chromatography to give the desired 2-
substituted 5,7-dimethoxyanthra[2,1-d]thiazole-6,11-dione.
(126 MHz, CD3OD) d 183.79, 182.17, 175.69, 160.16, 159.73, 158.64,
133.91, 133.80, 126.84, 123.69, 121.89, 118.98, 118.77, 117.41, 106.95,
65.31, 56.38, 56.27, 56.19, 55.79, 32.09, 22.35. LC/MS m/z: 425.1
[MþH]þ.
4.4.7. 2-(Diisopropylamino)-5,7-dimethoxyanthra[2,1-d]thiazole-
6,11-dione (5g)
Yield 64%; red powder. 1H NMR (400 MHz, CDCl3)
d 7.87 (d,
J ¼ 7.7 Hz, 1H), 7.62 (t, J ¼ 8.0 Hz, 1H), 7.38 (s, 1H), 7.31 (d, J ¼ 8.4 Hz,
1H), 4.14 (dt, J ¼ 13.9, 6.8 Hz, 2H), 4.05 (s, 3H), 4.01 (s, 3H), 1.49 (s,
6H), 1.47 (s, 6H). 13C NMR (126 MHz, CDCl3)
d 184.11, 181.79, 172.80,
4.4.1. 5,7-Dimethoxy-2-(piperidin-1-yl)anthra[2,1-d]thiazole-6,11-
160.05, 159.75, 159.27, 134.11, 133.40, 126.70, 124.33, 121.60, 118.97,
118.59, 117.11, 107.24, 56.69, 56.58, 56.54, 20.31. LC/MS m/z: 426.2.0
[MþH]þ.
dione (5a)
Yield 70%; red powder. 1H NMR (300 MHz, CDCl3)
d 7.86 (d,
J ¼ 7.7 Hz, 1H), 7.62 (t, J ¼ 8.1 Hz, 1H), 7.38 (s, 1H), 7.31 (d, J ¼ 8.2 Hz,
1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.83e3.62 (m, 4H), 1.78e1.70 (m, 6H).
4.4.8. 2-(Diethylamino)-5,7-dimethoxyanthra[2,1-d]thiazole-6,11-
13C NMR (126 MHz, CDCl3)
d
183.93, 181.69, 175.11, 160.12, 159.74,
dione (5h)
158.86, 134.00, 133.49, 126.89, 124.20, 121.96, 118.97, 118.63, 117.56,
Yield 80%; red powder. 1H NMR (300 MHz, CDCl3)
d 7.87 (d,
107.23, 56.69, 56.58, 49.73, 25.49, 24.15. LC/MS m/z: 409.2 [MþH]þ.
J ¼ 7.6 Hz, 1H), 7.62 (t, J ¼ 8.0 Hz, 1H), 7.41 (s, 1H), 7.32 (d, J ¼ 8.7 Hz,
1H), 4.04 (s, 3H), 4.01 (s, 3H), 3.68 (q, J ¼ 7.1, 6.4 Hz, 4H), 1.35 (t,
4.4.2. 5,7-Dimethoxy-2-(pyrrolidin-1-yl)anthra[2,1-d]thiazole-
J ¼ 7.0 Hz, 6H).13C NMR (126 MHz, CDCl3)
d 184.03, 181.75, 174.28,
6,11-dione (5b)
160.12, 159.76, 159.20, 134.03, 133.56, 126.87, 124.22, 122.18, 119.00,
118.70, 117.33, 107.22, 56.76, 56.67, 45.85, 13.03. LC/MS m/z: 397.2
[MþH]þ.
Yield66%;redpowder.1HNMR (400 MHz, CDCl3)
d
7.88 (dd, J ¼ 7.7,
1.1 Hz,1H), 7.63 (dd, J ¼ 8.3, 7.7 Hz,1H), 7.46 (s,1H), 7.32 (d, J ¼ 8.4,1H),
4.03 (s, 3H), 4.02 (s, 3H), 3.84e3.55 (m, 4H), 2.15 (d, J ¼ 6.2 Hz, 4H).13
C
NMR (126 MHz, CDCl3)
d
183.94,181.67,172.05,160.14,159.75,159.01,
4.4.9. 5,7-Dimethoxy-2-morpholinoanthra[2,1-d]thiazole-6,11-
134.03, 133.46, 126.92, 124.19, 122.07, 118.96, 118.62, 117.32, 107.28,
dione (5i)
56.67, 56.57, 49.63, 25.65. LC/MS m/z: 395.2 [MþH]þ.
Yield 76%; red powder. 1H NMR (300 MHz, CDCl3)
d 7.87 (d,
J ¼ 7.7 Hz, 1H), 7.63 (t, J ¼ 8.0 Hz, 1H), 7.42 (s, 1H), 7.32 (d, J ¼ 8.4 Hz,
4.4.3. 2-(Azepan-1-yl)-5,7-dimethoxyanthra[2,1-d]thiazole-6,11-
1H), 4.04 (s, 3H), 4.02 (s, 3H), 3.90e3.83 (m, 4H), 3.81e3.74 (m,
dione (5c)
4H).13C NMR (126 MHz, CDCl3)
d 183.76, 181.64, 175.53, 160.06,
Yield 68%; red powder. 1H NMR (300 MHz, CDCl3)
d
7.87 (dd,
159.76, 158.29, 133.91, 133.60, 127.04, 124.07, 121.55, 118.97, 118.68,
J ¼ 7.7, 1.1 Hz, 1H), 7.65e7.59 (m, 1H), 7.41 (s, 1H), 7.32 (dd, J ¼ 8.5,
1.0 Hz, 1H), 4.03 (s, 3H), 4.01 (s, 3H), 3.93e3.62 (m, 4H), 1.99e1.84
(m, 4H), 1.65 (dt, J ¼ 5.6, 2.6 Hz, 4H). 13C NMR (126 MHz, CDCl3)
118.10, 107.83, 66.22, 56.71, 56.58, 48.32. LC/MS m/z: 411.2 [MþH]þ.
4.4.10. 2-(4-(Dimethylamino)piperidin-1-yl)-5,7-dimethoxyanthra
d
184.03, 181.65, 174.93, 160.10, 159.72, 159.12, 134.01, 133.40,
[2,1-d]thiazole-6,11-dione (5j)
126.86, 124.22, 122.08, 118.92, 118.60, 117.30, 107.17, 56.65, 56.53,
Yield 45%; red powder. 1H NMR (300 MHz, CDCl3)
d 7.86 (d,
29.65, 27.73, 27.35. LC/MS m/z: 423.2 [MþH]þ.
J ¼ 7.7 Hz, 1H), 7.62 (t, J ¼ 8.1 Hz, 1H), 7.39 (s, 1H), 7.31 (d, J ¼ 8.3 Hz,
1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.31e3.21 (m, 2H), 3.03e3.00 (m, 1H),
2.58e2.44 (m, 2H), 2.32 (s, 6H), 1.76e1.50 (m, 4H). 13C NMR
4.4.4. 5,7-Dimethoxy-2-(4-methylpiperidin-1-yl)anthra[2,1-d]
thiazole-6,11-dione (5d)
(126 MHz, CD3OD) d 179.88, 178.11, 171.05, 156.17, 155.76, 154.68,
Yield 70%; red powder. 1H NMR (300 MHz, CDCl3)
d
7.83 (d,
129.87, 123.01, 119.85, 118.03, 115.05, 114.78, 113.74, 109.95, 103.40,
J ¼ 7.7 Hz, 1H), 7.59 (t, J ¼ 8.0 Hz, 1H), 7.37 (s, 1H), 7.29 (d, J ¼ 8.4 Hz,
57.75, 52.55, 52.41, 43.66, 36.89, 23.20. LC/MS m/z: 452.2 [MþH]þ.

Y.-K. Liang et al. / European Journal of Medicinal Chemistry 84 (2014) 505e515
511
4.4.11. 2-(4-Cyclopropylpiperazin-1-yl)-5,7-dimethoxyanthra[2,1-
(m, 2H), 3.76e3.65 (m, 2H), 3.66e3.55 (m, 2H), 3.55e3.43 (m, 2H),
2.18e2.07 (m, 2H). 13C NMR (126 MHz, CDCl3)
188.39, 186.17,
178.71, 167.17, 164.63, 164.37, 163.43, 138.54, 131.74, 131.69, 128.70,
126.59, 123.61, 122.60, 122.49, 112.51, 61.45, 61.32, 58.49, 51.58,
47.31, 46.55, 27.36. LC/MS m/z: 452.2 [MþH]þ.
d]thiazole-6,11-dione (5k)
d
Yield 52%; red powder. 1H NMR (400 MHz, CDCl3)
d
7.86 (d,
J ¼ 7.7 Hz, 1H), 7.62 (t, J ¼ 8.0 Hz, 1H), 7.40 (s, 1H), 7.32 (d, J ¼ 8.4 Hz,
1H), 4.03 (s, 3H), 4.01 (s, 3H), 3.78e3.71 (m, 4H), 2.82e2.74 (m, 4H),
1.74e1.70 (m, 1H), 0.54e0.46 (m, 4H). 13C NMR (126 MHz, CDCl3)
d
183.87, 181.64, 175.25, 160.09, 159.75, 158.69, 133.97, 133.53,
4.4.18. 2-((2,3-Dihydroxypropyl)(methyl)amino)-5,7-
126.98, 124.17, 121.90, 118.97, 118.66, 117.84, 107.55, 56.71, 56.59,
dimethoxyanthra[2,1-d]thiazole-6,11-dione (5r)
52.55, 48.35, 38.38, 6.09. LC/MS m/z: 450.2 [MþH]þ.
Yield 67%; red powder. 1H NMR (300 MHz, CDCl3)
d 7.80e7.75
(dd, J ¼ 7.7, 1.0 Hz, 1H), 7.61e7.54 (m, 1H), 7.30e7.27 (m, 1H), 7.25 (s,
1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.78e3.69 (m, 2H), 3.52 (d, J ¼ 4.4 Hz,
2H), 3.32e3.30 (m, 1H), 3.28 (s, 3H). 13C NMR (126 MHz, CD3OD)
4.4.12. Ethyl 4-(5,7-dimethoxy-6,11-dioxo-6,11-dihydroanthra[2,1-
d]thiazol-2-yl)piperazine-1-carboxylate (5l)
Yield 89%; red powder. 1H NMR (300 MHz, CDCl3)
d
7.83 (d,
d 179.80, 177.95, 172.42, 156.21, 155.80, 153.85, 129.89, 129.83,
J ¼ 7.7 Hz, 1H), 7.61 (t, J ¼ 8.0 Hz, 1H), 7.35 (s, 1H), 7.33 (d, 1H), 4.21
(q, J ¼ 7.1 Hz, 2H), 4.03 (s, 3H), 4.01 (s, 3H), 3.79e3.70 (m, 4H),
3.70e3.62 (m, 4H),1.31 (t, J ¼ 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3)
123.03, 119.77, 117.72, 115.05, 114.81, 113.59, 103.05, 66.22, 59.04,
52.57, 52.43, 25.69. LC/MS m/z: 429.2 [MþH]þ.
d
183.65, 181.53, 175.18, 160.01, 159.73, 158.23, 155.29, 133.86,
4.4.19. 2-((2-Hydroxyethyl)(methyl)amino)-5,7-dimethoxyanthra
133.58, 126.97, 124.01, 121.57, 118.93, 118.66, 118.03, 107.78, 61.91,
[2,1-d]thiazole-6,11-dione (5s)
56.67, 56.54, 47.97, 45.39, 14.67. LC/MS m/z: 482.2 [MþH]þ.
Yield 64%; red powder. 1H NMR (400 MHz, CDCl3)
d 7.86 (dd,
J ¼ 7.7, 1.0 Hz, 1H), 7.72e7.65 (m, 1H), 7.47 (s, 1H), 7.40 (dd, J ¼ 8.3,
1.0 Hz, 1H), 4.04 (s, 3H), 4.02 (s, 3H), 3.92 (t, J ¼ 5.4 Hz, 2H), 3.81 (d,
J ¼ 5.2 Hz, 1H), 3.38 (s, 3H), 3.36 (dt, J ¼ 3.2, 1.6 Hz, 2H). 13C NMR
4.4.13. 2-(4-Isopropylpiperazin-1-yl)-5,7-dimethoxyanthra[2,1-d]
thiazole-6,11-dione (5m)
Yield 82%; red powder. 1H NMR (300 MHz, CDCl3)
d
7.87 (dd,
(126 MHz, CDCl3) d 187.74, 186.23, 179.82, 164.10, 163.68, 162.60,
J ¼ 7.7, 1.0 Hz,1H), 7.66e7.60 (m, 1H), 7.40 (s, 1H), 7.34e7.29 (m, 1H),
4.03 (s, 3H), 4.01 (s, 3H), 3.84e3.77 (m, 4H), 2.81 (dt, J ¼ 13.4, 6.5 Hz,
1H), 2.73e2.66 (m, 4H), 1.10 (s, 3H), 1.08 (s, 3H). 13C NMR (126 MHz,
137.91, 137.76, 130.80, 127.59, 126.04, 122.95, 122.75, 121.16, 110.83,
63.46, 63.42, 63.40, 60.27, 60.16. LC/MS m/z: 399.2 [MþH]þ.
CD3OD)
d
183.82, 182.15, 175.33, 160.14, 159.73, 158.58, 133.82,
4.4.20. 5,7-Dimethoxy-2-(4-(2-(pyrrolidin-1-yl)ethyl)piperazin-1-
126.94, 123.76, 121.85, 119.01, 118.76, 117.63, 107.34, 56.46, 56.32,
yl)anthra[2,1-d]thiazole-6,11-dione (12a)
54.76, 47.91, 18.06. LC/MS m/z: 452.2 [MþH]þ.
Yield 50%; deep red powder. 1H NMR (300 MHz, CDCl3)
d 7.85 (d,
J ¼ 7.5 Hz, 1H), 7.62 (t, J ¼ 7.8 Hz, 1H), 7.38 (s, 1H), 7.31 (d, J ¼ 8.7 Hz,
4.4.14. 2-(4-Ethylpiperazin-1-yl)-5,7-dimethoxyanthra[2,1-d]
1H), 4.03 (s, 3H), 4.01 (s, 3H), 3.86e3.75 (m, 4H), 2.73e2.61 (m,
thiazole-6,11-dione (5n)
12H), 1.87e1.80 (m, 4H). 13C NMR (126 MHz, CDCl3)
d 183.81, 181.61,
Yield 68%; red powder. 1H NMR (300 MHz, CDCl3)
d
7.86 (dd,
175.16, 160.06, 159.74, 158.61, 133.94, 133.54, 126.97, 124.13, 121.85,
118.96, 118.67, 117.86, 107.59, 56.71, 56.60, 54.66, 53.42, 52.82,
48.22, 23.38. LC/MS m/z: 507.3 [MþH]þ.
J ¼ 7.7, 1.0 Hz, 1H), 7.66e7.58 (m, 1H), 7.40 (s, 1H), 7.31 (dd, J ¼ 8.4,
0.9 Hz, 1H), 4.03 (s, 3H), 4.01 (s, 3H), 3.85e3.76 (m, 4H), 2.66e2.57
(m, 4H), 2.51 (q, J ¼ 7.2 Hz, 2H), 1.14 (t, J ¼ 7.2 Hz, 3H). 13C NMR
(126 MHz, CDCl3)
d
183.87, 181.64, 175.22, 160.09, 159.76, 158.65,
4.4.21. 5,7-Dimethoxy-2-(4-(2-(piperidin-1-yl)ethyl)piperazin-1-
133.97, 133.51, 127.00, 124.17, 121.87, 118.96, 118.65, 117.89, 107.60,
yl)anthra[2,1-d]thiazole-6,11-dione (12b)
56.70, 56.58, 52.29, 52.05, 48.28, 11.97. LC/MS m/z: 438.2 [MþH]þ.
Yield 39%; deep red powder. 1H NMR (300 MHz, CDCl3)
d 7.82 (d,
J ¼ 7.6 Hz, 1H), 7.58 (t, J ¼ 8.0 Hz, 1H), 7.35 (s, 1H), 7.28 (d, J ¼ 9.0 Hz,
1H), 4.00 (s, 3H), 3.98 (s, 3H), 3.80e3.70 (m, 4H), 2.65e2.60 (m, 4H),
2.55e2.51 (m, 4H), 2.47e2.42 (m, 4H), 1.62e1.54 (m, 6H). 13C NMR
4.4.15. 5,7-Dimethoxy-2-(4-methylpiperazin-1-yl)anthra[2,1-d]
thiazole-6,11-dione (5o)
Yield 89%; red powder. 1H NMR (300 MHz, CDCl3)
d
7.83 (dd,
(126 MHz, CDCl3) d 183.84, 181.61, 175.18, 160.07, 159.74, 158.63,
J ¼ 7.7, 1.0 Hz, 1H), 7.64e7.56 (m, 1H), 7.37 (s, 1H), 7.29 (dd, J ¼ 8.5,
133.95, 133.51, 126.97, 124.15, 121.85, 118.95, 118.65, 117.86, 107.58,
56.69, 56.61, 56.58, 55.85, 55.38, 55.08, 55.05, 52.92, 52.87, 25.86,
24.24. LC/MS m/z: 521.3 [MþH]þ.
1.0 Hz, 1H), 4.01 (s, 3H), 3.99 (s, 3H), 3.81e3.74 (m, 4H), 2.59e2.52
(m, 4H), 2.47 (s, 3H). 13C NMR (126 MHz, CDCl3)
d 183.84, 181.63,
175.25, 160.08, 159.75, 158.61, 133.96, 133.53, 127.00, 124.16, 121.85,
118.97, 118.66, 117.92, 107.62, 56.71, 56.59, 54.34, 54.26, 46.14. LC/
MS m/z: 424.2 [MþH]þ.
4.4.22. 5,7-Dimethoxy-2-(4-(2-(4-methylpiperidin-1-yl)ethyl)
piperazin-1-yl)anthra[2,1-d]thiazole-6,11-dione (12c)
Yield 40%; deep red powder. 1H NMR (300 MHz, CDCl3)
d 7.83 (d,
4.4.16. 2-(4-(2-Hydroxyethyl)piperazin-1-yl)-5,7-dimethoxyanthra
J ¼ 6.5 Hz, 1H), 7.69e7.54 (m, 1H), 7.36 (s, 1H), 7.30 (d, J ¼ 7.7 Hz,
1H), 4.01 (s, 3H), 3.99 (s, 3H), 3.86e3.72 (m, 4H), 3.24e2.98 (m, 4H),
2.78e2.56 (m, 12H), 1.26e1.17 (m, 1H), 0.95e0.91 (m, 3H). 13C NMR
[2,1-d]thiazole-6,11-dione (5p)
Yield 75%; red powder. 1H NMR (300 MHz, CDCl3)
d 7.87 (d,
J ¼ 7.7 Hz, 1H), 7.63 (t, J ¼ 8.0 Hz, 1H), 7.41 (s, 1H), 7.33 (d, J ¼ 8.5 Hz,
1H), 4.42e4.26 (m, 1H), 4.04 (s, 3H), 4.02 (s, 3H), 3.85e3.78 (m, 4H),
3.68 (dt, J ¼ 10.9, 5.4 Hz, 4H), 2.74e2.68 (m, 4H). 13C NMR (126 MHz,
(126 MHz, CDCl3) d 183.84, 181.63, 175.18, 160.07, 159.76, 158.59,
133.96, 133.59, 127.01, 124.15, 121.86, 119.01, 118.71, 117.91, 107.64,
56.76, 56.66, 55.58, 55.00, 54.39, 52.84, 48.28, 33.14, 30.22, 21.61.
LC/MS m/z: 535.3 [MþH]þ.
CDCl3) d 183.91,181.69,175.24,160.12,159.79,158.56,133.97,133.59,
127.08, 124.17, 121.81, 119.00, 118.71, 118.05, 107.73, 59.38, 59.00,
57.92, 57.87, 56.74, 56.61, 52.28, 52.23. LC/MS m/z: 454.2 [MþH]þ.
4.4.23. 5,7-Dimethoxy-2-(4-(2-morpholinoethyl)piperazin-1-yl)
anthra[2,1-d]thiazole-6,11-dione (12d)
4.4.17. 4-(5,7-Dimethoxy-6,11-dioxo-6,11-dihydroanthra[2,1-d]
Yield 64%; deep red powder. 1H NMR (300 MHz, CDCl3)
d 7.85
thiazol-2-yl)-1,4-diazepane-1-carbaldehyde (5q)
(dd, J ¼ 7.7, 1.1 Hz, 1H), 7.66e7.57 (m, 1H), 7.39 (s, 1H), 7.31 (dd,
J ¼ 8.5, 1.0 Hz, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.85e3.75 (m, 4H),
3.75e3.68 (m, 4H), 2.73e2.62 (m, 4H), 2.59 (dd, J ¼ 5.8, 3.2 Hz, 4H),
Yield 52%; red powder. 1H NMR (300 MHz, CDCl3)
d 8.10 (d,
J ¼ 23.9 Hz, 1H), 7.86 (d, J ¼ 7.6 Hz, 1H), 7.63 (t, J ¼ 8.0 Hz, 1H), 7.41
(s, 1H), 7.33 (d, J ¼ 8.3 Hz, 1H), 4.04 (s, 3H), 4.02 (s, 3H), 3.87e3.76
2.55e2.45 (m, 4H). 13C NMR (126 MHz, CDCl3)
d 183.77, 181.52,

512
Y.-K. Liang et al. / European Journal of Medicinal Chemistry 84 (2014) 505e515
175.08, 159.99, 159.67, 158.50, 133.86, 133.43, 126.91, 124.06, 121.73,
118.86, 118.58, 117.84, 107.54, 66.69, 56.60, 56.48, 56.16, 55.29,
54.02, 52.77, 48.11. LC/MS m/z: 523.2 [MþH]þ.
4.4.30. 2-(4-(2-(4-Isopropylpiperazin-1-yl)ethyl)piperazin-1-yl)-
5,7-dimethoxyanthra[2,1-d]thiazole-6,11-dione (12k)
Yield 45%; deep red powder. 1H NMR (300 MHz, CDCl3)
d 7.83 (d,
J ¼ 7.7 Hz, 1H), 7.60 (t, J ¼ 7.2 Hz, 1H), 7.37 (s, 1H), 7.29 (d, J ¼ 8.6 Hz,
4.4.24. 2-(4-(2-(Dibutylamino)ethyl)piperazin-1-yl)-5,7-
1H), 4.01 (s, 3H), 3.99 (s, 3H), 3.82e3.70 (m, 4H), 2.68e2.51 (m,
dimethoxyanthra[2,1-d]thiazole-6,11-dione (12e)
17H), 1.07 (d, J ¼ 6.3 Hz, 6H). 13C NMR (126 MHz, CDCl3)
d 183.88,
Yield 25%; deep red powder. 1H NMR (300 MHz, CDCl3)
d
7.86 (d,
181.65, 175.19, 160.09, 159.76, 158.63, 133.96, 133.54, 127.01, 124.17,
121.85, 118.98, 118.68, 117.92, 107.62, 56.72, 56.60, 55.77, 55.68,
54.94, 53.49, 53.37, 52.88, 48.46, 48.26, 18.39. LC/MS m/z: 564.3
[MþH]þ.
J ¼ 7.1 Hz, 1H), 7.63 (t, J ¼ 8.7 Hz, 1H), 7.40 (s, 1H), 7.32 (d, J ¼ 8.1 Hz,
1H), 4.03 (s, 3H), 4.02 (s, 3H), 3.86e3.74 (m, 4H), 2.76e2.64 (m, 8H),
1.64e1.48 (m, 4H), 1.41e1.23 (m, 8H), 0.98e0.91 (m, 6H). 13C NMR
(126 MHz, CDCl3)
d 183.86, 181.67, 175.20, 160.09, 159.77, 158.56,
133.96, 133.59, 127.04, 124.16, 121.84, 119.00, 118.70, 117.99, 107.69,
56.75, 56.63, 53.66, 52.80, 50.61, 48.22, 29.71, 20.49, 13.95. LC/MS
m/z: 565.3 [MþH]þ.
4.5. General procedure for the preparation of compounds 6aei
A mixture of compound 5a (30 mg, 0.073 mmol), ethyl
mercaptan (55 mL, 0.73 mmol), anhydrous aluminium trichloride
(98 mg, 0.73 mmol) in dichloromethane was stirred at 35 ꢀC for
10 h. After reaction was completed (monitored by TLC), the mixture
was quenched with sodium carbonate saturated solution and
extracted with dichloromethane. Then the organic phase was
acidified with HCl (1 M) and dried over anhydrous sodium sulphate,
After the organic solution was concentrated under vacuum, the
crude residue was purified by column chromatography (dichloro-
methane/methanol ¼ 100:1).
4.4.25. 2-(4-(2-(Diethylamino)ethyl)piperazin-1-yl)-5,7-
dimethoxyanthra[2,1-d]thiazole-6,11-dione (12f)
Yield 64%; deep red powder. 1H NMR (300 MHz, CDCl3)
d 7.84 (d,
J ¼ 7.2 Hz, 1H), 7.60 (t, J ¼ 7.7 Hz, 1H), 7.37 (s, 1H), 7.30 (d, J ¼ 8.1 Hz,
1H), 4.01 (s, 3H), 4.00 (s, 3H), 3.86e3.68 (m, 4H), 2.66e2.51 (m,
12H), 1.05 (t, J ¼ 6.9 Hz, 6H). 13C NMR (126 MHz, CDCl3)
d 183.88,
181.66, 175.22, 160.09, 159.77, 158.63, 133.98, 133.58, 127.02, 124.18,
121.88, 118.70, 117.92, 107.63, 77.02, 56.76, 56.65, 56.22, 52.94,
50.08, 48.30, 47.47, 11.40. LC/MS m/z: 509.3 [MþH]þ.
4.5.1. 5,7-Dihydroxy-2-(piperidin-1-yl)anthra[2,1-d]thiazole-6,11-
4.4.26. 2-(4-(2-(Dimethylamino)ethyl)piperazin-1-yl)-5,7-
dione (6a)
dimethoxyanthra[2,1-d]thiazole-6,11-dione (12g)
Yield 40%; red powder. 1H NMR (300 MHz, CDCl3)
d 12.42 (s, 1H),
Yield 55%; deep red powder. 1H NMR (300 MHz, CDCl3)
d 7.85 (d,
12.39 (s, 1H), 7.82 (d, 1H), 7.64 (t, J ¼ 7.9 Hz, 1H), 7.29 (d, J ¼ 0.7 Hz,
J ¼ 7.0 Hz, 1H), 7.68e7.55 (m, 1H), 7.39 (s, 1H), 7.31 (d, J ¼ 8.5 Hz,
1H), 7.18 (s, 1H), 3.87e3.68 (m, 4H), 1.81e1.72 (m, 6H). 13C NMR
1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.88e3.72 (m, 4H), 2.71e2.60 (m, 4H),
(126 MHz, CDCl3)
d 189.94, 181.78, 175.48, 163.43, 162.75, 162.32,
2.59e2.48 (m, 4H), 2.30 (s, 6H). 13C NMR (126 MHz, CDCl3)
d 183.86,
136.17, 132.76, 126.34, 124.95, 124.75, 119.67, 116.28, 110.67, 109.74,
29.72, 25.63, 24.12. HRMS (EI) m/z [M]þcalcd for C20H16N2O4S:
380.0831, found: 380.0829.
181.63, 175.20, 160.08, 159.76, 158.65, 133.97, 133.56, 126.99, 124.17,
121.88, 118.99, 118.69, 117.88, 107.60, 58.33, 56.75, 56.64, 56.48,
52.89, 48.24, 45.94. LC/MS m/z: 481.3 [MþH]þ.
4.5.2. 5,7-Dihydroxy-2-(pyrrolidin-1-yl)anthra[2,1-d]thiazole-6,11-
4.4.27. 2-(4-(2-(Diisopropylamino)ethyl)piperazin-1-yl)-5,7-
dione (6b)
dimethoxyanthra[2,1-d]thiazole-6,11-dione (12h)
Yield 35%; red powder. 1H NMR (300 MHz, CDCl3)
d 12.42 (s, 1H),
Yield 20%; deep red powder. 1H NMR (300 MHz, CDCl3)
d 7.84 (d,
12.37 (s, 1H), 7.82 (d, J ¼ 7.8 Hz, 1H), 7.64 (t, J ¼ 7.8 Hz, 1H), 7.31 (d,
J ¼ 7.7 Hz, 1H), 7.60 (t, J ¼ 8.0 Hz, 1H), 7.38 (s, 1H), 7.30 (d, J ¼ 8.4 Hz,
1H), 4.01 (s, 3H), 4.00 (s, 3H), 3.84e3.68 (m, 4H), 3.23e2.92 (m, 2H),
2.74e2.32 (m, 8H), 1.27e0.84 (m, 12H). 13C NMR (126 MHz, CDCl3)
J ¼ 9.3 Hz,1H), 7.17 (s,1H), 3.89e3.55 (m, 4H), 2.19e2.15 (m, 4H). 13
C
NMR (126 MHz, CDCl3)
d 190.13, 181.93, 172.68, 163.44, 162.66,
162.39, 136.23, 132.85, 126.47, 125.17, 124.86, 119.73, 116.32, 110.86,
109.71, 49.91, 25.55. HRMS (EI) m/z [M]þcalcd for C19H14N2O4S:
366.0674, found: 366.0667.
d
183.88, 181.66, 175.23, 160.09, 159.76, 158.62, 133.97, 133.54,
127.01, 124.17, 121.87, 118.98, 118.67, 117.92, 107.63, 56.71, 56.59,
52.94, 48.25, 20.67. LC/MS m/z: 537.3 [MþH]þ.
4.5.3. 2-(Azepan-1-yl)-5,7-dihydroxyanthra[2,1-d]thiazole-6,11-
4.4.28. 2-(4-(2-(4-Ethylpiperazin-1-yl)ethyl)piperazin-1-yl)-5,7-
dione (6c)
dimethoxyanthra[2,1-d]thiazole-6,11-dione (12i)
Yield 42%; red powder. 1H NMR (300 MHz, CDCl3)
d 12.40 (s,
Yield 32%; deep red powder. 1H NMR (300 MHz, CDCl3)
d 7.84 (d,
1H), 12.34 (s, 1H), 7.78 (dd, J ¼ 7.5, 1.0 Hz, 1H), 7.61 (t, J ¼ 7.9 Hz,
J ¼ 7.7 Hz, 1H), 7.60 (t, J ¼ 8.0 Hz, 1H), 7.38 (s, 1H), 7.30 (d, J ¼ 8.5 Hz,
1H), 7.25e7.21 (m, 1H), 7.15 (s, 1H), 4.04e3.80 (m, 4H), 1.94e1.88
1H), 4.01 (s, 3H), 4.00 (s, 3H), 3.81e3.70 (m, 4H), 2.68e2.61 (m, 6H),
(m, 4H), 1.67e1.62 (m, 4H). 13C NMR (126 MHz, CDCl3)
d 189.92,
2.61e2.52 (m, 8H), 2.46 (q, J ¼ 7.1 Hz, 4H), 1.10 (t, J ¼ 7.2 Hz, 3H). 13
C
181.83, 175.59, 163.40, 162.72, 162.32, 136.14, 132.78, 126.48,
124.96, 124.75, 119.65, 116.30, 110.62, 109.60, 52.51, 29.72, 27.30.
HRMS (EI) m/z [M]þcalcd for C21H18N2O4S: 394.0987, found:
394.0981.
NMR (126 MHz, CDCl3)
d 183.88, 181.66, 175.19, 160.09, 159.76,
158.62, 133.96, 133.54, 127.01, 124.17, 121.85, 118.97, 118.67, 117.92,
107.62, 56.71, 56.59, 55.69, 55.65, 53.06, 52.84, 52.45, 52.27, 48.26,
11.55. LC/MS m/z: 550.3 [MþH]þ.
4.4.29. 5,7-Dimethoxy-2-(4-(2-(4-methylpiperazin-1-yl)ethyl)
4.5.4. 7-Dihydroxy-2-(4-methylpiperidin-1-yl)anthra[2,1-d]
piperazin-1-yl)anthra[2,1-d]thiazole-6,11-dione (12j)
thiazole-6,11-dione (6d)
Yield 31%; deep red powder. 1H NMR (300 MHz, CDCl3)
d
7.83 (d,
Yield 33%; red powder. 1H NMR (300 MHz, CDCl3)
d 12.42 (s, 1H),
J ¼ 7.6 Hz, 1H), 7.60 (t, J ¼ 8.0 Hz, 1H), 7.36 (s, 1H), 7.29 (d, J ¼ 8.3 Hz,
1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.81e3.71 (m, 4H), 2.66e2.61 (m, 4H),
2.60e2.51 (m, 10H), 2.29 (s, 3H). 13C NMR (126 MHz, CDCl3)
12.39 (s, 1H), 7.81 (d, J ¼ 7.8 Hz, 1H), 7.67e7.60 (m, 1H), 7.29 (d,
J ¼ 1.2 Hz, 1H), 7.18 (s, 1H), 3.39e3.09 (m, 4H), 1.92e1.70 (m, 5H),
1.02 (d, J ¼ 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d 190.00, 181.84,
d
183.85, 181.63, 175.18, 160.08, 159.75, 158.60, 133.95, 133.54,
175.46,163.44,162.78,162.35, 136.19,132.78, 126.39, 124.99,124.78,
119.69, 116.30, 110.72, 109.79, 33.70, 30.78, 29.72, 21.63. HRMS (EI)
m/z [M]þcalcd for C21H18N2O4S: 394.0987, found: 394.0981.
126.99, 124.15, 121.84, 118.96, 118.67, 117.90, 107.61, 56.70, 56.58,
55.67, 54.81, 53.20, 52.87, 45.73. LC/MS m/z: 536.3 [MþH]þ.

Y.-K. Liang et al. / European Journal of Medicinal Chemistry 84 (2014) 505e515
513
4.5.5. 5,7-Dihydroxy-2-(2-(2-hydroxyethyl)piperidin-1-yl)anthra
4.6.1. 2-(4-(Dimethylamino)piperidin-1-yl)-5,7-dihydroxyanthra
[2,1-d]thiazole-6,11-dione (6e)
[2,1-d]thiazole-6,11-dione (6j)
Yield 30%; red powder. 1H NMR (300 MHz, DMSO-d6)
d
12.10 (s,
Yield 40%; red powder. 1H NMR (300 MHz, CDCl3)
d
12.34 (s, 1H),
1H), 12.09 (s, 1H), 7.68 (t, J ¼ 7.9 Hz, 1H), 7.53 (d, J ¼ 7.3 Hz, 1H), 7.25
12.28 (s, 1H),7.86 (d, J ¼ 7.7 Hz, 1H), 7.62 (t, J ¼ 8.1 Hz, 1H), 7.37 (s,
1H), 7.29 (d, J ¼ 8.3 Hz, 1H), 3.29e3.19 (m, 2H), 2.93e2.87 (m, 1H),
2.53e2.41 (m, 2H), 2.29 (s, 6H), 1.73e1.49 (m, 4H). 13C NMR
(d, J ¼ 8.0 Hz,1H), 6.87 (s, 1H), 4.73e4.51 (m, 2H), 3.48 (q, J ¼ 6.4 Hz,
3H), 2.04e1.68 (m, 8H). 13C NMR (126 MHz, DMSO-d6)
d 189.28,
181.02, 175.34, 162.80, 162.52, 161.71, 137.02, 132.47, 125.87, 124.85,
124.75, 119.52, 116.09, 109.62, 109.33, 58.26, 58.18, 55.40, 35.58,
32.61, 25.58, 24.21. HRMS (EI) m/z [M]þcalcd for C22H20N2O5S:
424.1039, found: 424.1101.
(126 MHz, CD3OD) d 189.67, 181.16, 174.99, 162.63, 162.05, 161.74,
137.29, 132.58, 125.61, 125.15, 119.72, 116.17, 115.67, 110.41, 109.94,
61.87, 36.29, 29.49, 25.98. HRMS (EI): m/z [M]þcalcd for
C22H21N3O4S: 423.1253, found: 423.1250.
4.5.6. 5,7-Dihydroxy-2-(3-hydroxypiperidin-1-yl)anthra[2,1-d]
4.6.2. 2-(4-Cyclopropylpiperazin-1-yl)-5,7-dihydroxyanthra[2,1-d]
thiazole-6,11-dione (6f)
thiazole-6,11-dione (6k)
Yield 28%; red powder. 1H NMR (300 MHz, CDCl3)
d 12.34 (s, 1H),
Yield 30%; red powder. 1H NMR (300 MHz, CDCl3)
d 12.38 (s, 1H),
12.31 (s,1H), 7.78 (d, J ¼ 7.3 Hz,1H), 7.62 (t, J ¼ 7.8 Hz,1H), 7.25e7.22
12.35 (s, 1H), 7.79 (dd, J ¼ 7.5, 1.1 Hz, 1H), 7.68e7.59 (m, 1H), 7.29 (d,
J ¼ 1.2 Hz, 1H), 7.19 (s, 1H), 3.92e3.71 (m, 4H), 2.84e2.73 (m, 4H),
1.77e1.66 (m, 1H), 0.59e0.42 (m, 4H). 13C NMR (126 MHz, CDCl3)
(m, 1H), 7.14 (s, 1H), 4.06e4.00 (m, 1H), 3.87e3.58 (m, 4H),
2.13e1.93 (m, 4H). 13C NMR (126 MHz, DMSO-d6)
d 189.35, 180.96,
175.28, 162.78, 162.46, 161.71, 137.07, 132.47, 125.73, 124.92, 124.77,
119.59, 116.10, 109.76, 109.43, 65.10, 35.57, 31.75, 25.57, 22.57. HRMS
(EI) m/z [M]þcalcd for C20H16N2O5S: 396.0780, found: 396.0773.
d
190.03, 181.60, 175.58, 163.30, 162.35, 162.33, 136.23, 132.67,
126.04, 125.00, 124.80, 119.70, 116.19, 111.06, 109.92, 52.57, 38.34,
6.12. HRMS (EI) m/z [M]þcalcd for C22H19N3O4S: 421.1096, found:
421.1089.
4.5.7. 2-(Diisopropylamino)-5,7-dihydroxyanthra[2,1-d]thiazole-
6,11-dione (6g)
4.6.3. Ethyl 4-(5,7-dihydroxy-6,11-dioxo-6,11-dihydroanthra[2,1-d]
Yield 40%; red powder. 1H NMR (400 MHz, CDCl3)
d 12.46 (s, 1H),
thiazol-2-yl)piperazine-1-carboxylate (6l)
12.40 (s, 1H), 7.80 (dd, J ¼ 7.5, 1.0 Hz, 1H), 7.62 (t, J ¼ 7.9 Hz, 1H), 7.26
Yield 35%; red powder. 1H NMR (400 MHz, CDCl3)
d 12.32 (s, 1H),
(dd, J ¼ 8.3, 0.9 Hz, 1H), 7.17 (s, 1H), 4.20e4.05 (m, 2H), 1.50 (d,
12.29 (s, 1H), 7.78 (dd, J ¼ 7.5, 1.0 Hz, 1H), 7.66e7.60 (m, 1H), 7.28 (d,
J ¼ 1.0 Hz, 1H), 7.18 (s, 1H), 4.21 (q, J ¼ 7.1 Hz, 2H), 3.84e3.76 (m,
4H), 3.70e3.65 (m, 4H), 1.31 (t, J ¼ 7.1 Hz, 3H). 13C NMR (126 MHz,
J ¼ 6.7 Hz, 1H). 13C NMR (101 MHz, CDCl3)
d 189.81, 181.92, 173.40,
163.38, 162.86, 162.26, 136.02, 132.80, 125.85, 124.71, 124.63, 119.56,
116.36, 110.52, 109.39, 29.70, 20.35. HRMS (EI) m/z [M]þcalcd for
CDCl3)
d 190.24, 181.56, 175.67, 163.22, 162.39, 161.89, 155.27,
C
21H20N2O4S: 396.1144, found: 396.1142.
136.40, 132.62, 125.63, 125.19, 124.94, 119.80, 116.12, 111.56, 110.24,
62.03, 48.19, 43.20, 14.69. HRMS (EI) m/z [M]þcalcd for
4.5.8. 2-(Diethylamino)-5,7-dihydroxyanthra[2,1-d]thiazole-6,11-
C22H19N3O6S: 453.0995, found: 453.0988.
dione (6h)
Yield 38%; red powder. 1H NMR (300 MHz, CDCl3)
d 12.39 (s, 1H),
4.6.4. 5,7-Dihydroxy-2-(4-isopropylpiperazin-1-yl)anthra[2,1-d]
12.34 (s, 1H), 7.77 (d, J ¼ 7.4 Hz, 1H), 7.61 (t, J ¼ 8.0 Hz, 1H), 7.24 (d,
thiazole-6,11-dione (6m)
J ¼ 1.0 Hz, 1H), 7.16 (s, 1H), 3.69 (m, 4H), 1.36 (t, J ¼ 7.2 Hz, 6H). 13
C
Yield 41%; red powder. 1H NMR (300 MHz, CDCl3)
d 12.33 (s, 1H),
NMR (126 MHz, CDCl3)
d 189.89, 181.80, 174.89, 163.37, 162.77,
12.27 (s, 1H), 7.74 (d, J ¼ 7.5 Hz, 1H), 7.59 (t, J ¼ 7.9 Hz, 1H), 7.23 (d,
J ¼ 8.4 Hz, 1H), 7.10 (s, 1H), 3.91e3.69 (m, 4H), 2.81 (hept, J ¼ 6.7 Hz,
1H), 2.73e2.63 (m, 4H), 1.08 (d, J ¼ 12.8, 6.4 Hz, 6H). 13C NMR
162.31, 136.14, 132.74, 126.50, 124.91, 124.75, 119.63, 116.27, 110.63,
109.59, 29.72, 13.08. HRMS (EI) m/z [M]þcalcd for C19H16N2O4S:
368.0831, found: 368.0825.
(126 MHz, DMSO-d6)
d 189.13, 180.66, 174.61, 162.15, 161.67, 161.20,
136.67, 132.07, 129.51, 124.94, 124.50, 119.14, 115.67, 109.71, 109.27,
4.5.9. 5,7-Dihydroxy-2-morpholinoanthra[2,1-d]thiazole-6,11-
53.92, 47.53, 47.34, 17.88, 17.85. HRMS (EI) m/z [M]þcalcd for
dione (6i)
C22H21N3O4S: 423.1253, found: 423.1256.
Yield 47%; red powder. 1H NMR (300 MHz, CDCl3)
d 12.37 (s, 1H),
12.34 (s, 1H), 7.82 (dd, J ¼ 7.5, 1.1 Hz, 1H), 7.68e7.62 (m, 1H), 7.30
4.6.5. 2-(4-Ethylpiperazin-1-yl)-5,7-dihydroxyanthra[2,1-d]
(dd, J ¼ 8.5, 1.1 Hz, 1H), 7.24 (s, 1H), 3.76e3.71 (m, 4H), 3.65e3.56
(m, 4H). 13C NMR (126 MHz, CDCl3)
d 186.81, 182.27, 175.38, 163.31,
thiazole-6,11-dione (6n)
Yield 36%; red powder. 1H NMR (300 MHz, CDCl3)
d 12.34 (s, 1H),
163.12, 162.97, 135.25, 134.77, 124.54, 123.83, 121.02, 120.06, 118.52,
112.25, 111.68, 66.43, 52.02. HRMS (EI): m/z [M]þcalcd for
12.29 (s, 1H), 7.76 (d, J ¼ 7.4 Hz, 1H), 7.60 (t, J ¼ 7.8 Hz, 1H), 7.23 (d,
1H), 7.13 (s, 1H), 4.34e3.70 (m, 4H), 2.65e2.56 (m, 4H), 2.46 (q,
J ¼ 7.0 Hz, 2H), 1.14 (t, J ¼ 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3)
C
19H14N2O5S: 382.0623, found: 382.0616.
d
190.02, 181.56, 175.53, 163.27, 162.31, 136.23, 132.65, 126.00,
4.6. General procedure for the preparation of compounds 6jes and
13aek
124.99, 124.80, 119.69, 116.16, 111.08, 109.92, 52.26, 52.07, 51.90,
11.99. HRMS (EI) m/z [M]þcalcd for C21H19N3O4S: 409.1096, found:
409.1087.
The intermediate 5 or 12 (0.11 mmol) was dissolved in anhy-
drous dichloromethane (20 mL) and cooled to ꢁ10ꢀCunder nitro-
gen, then treated with 4 M solution of boron tribromide in diethyl
ether (0.41 mL, 1.65 mmol). After stirred for 3 h, the solution was
shifted to room temperature overnight. After the reaction was
completed (monitored by TLC), the solution was cooled in an ice
bath and treated dropwise sodium bicarbonate saturated solution
while stirring. The mixture was extracted with dichloromethane.
The organic phase was dried over sodium sulphate and concen-
trated under vacuum. The crude residue was purified by column
chromatography (dichloromethane/methanol ¼ 100:1).
4.6.6. 5,7-Dihydroxy-2-(4-methylpiperazin-1-yl)anthra[2,1-d]
thiazole-6,11-dione (6o)
Yield 33%; red powder. 1H NMR (300 MHz, CDCl3)
d 12.35 (s, 1H),
12.31 (s, 1H), 7.77 (dd, J ¼ 7.5, 1.1 Hz, 1H), 7.65e7.58 (m, 1H), 7.26
(dd, J ¼ 8.4, 1.2 Hz, 1H), 7.16 (s, 1H), 3.89e3.75 (m, 4H), 2.62e2.53
(m, 4H), 2.37 (s, 3H). 13C NMR (126 MHz, CDCl3)
d 190.14, 181.67,
175.62, 163.31, 162.37, 162.31, 136.28, 132.70, 126.00, 125.09, 124.86,
119.74, 116.20, 111.19, 110.02, 54.28, 46.08. HRMS (EI) m/z [M]þcalcd
for C20H17N3O4S: 395.0940, found: 395.0942.

514
Y.-K. Liang et al. / European Journal of Medicinal Chemistry 84 (2014) 505e515
4.6.7. 5,7-Dihydroxy-2-(4-(2-hydroxyethyl)piperazin-1-yl)anthra
4.6.13. 5,7-Dihydroxy-2-(4-(2-(4-methylpiperidin-1-yl)ethyl)
piperazin-1-yl)anthra[2,1-d]thiazole-6,11-dione (13c)
Yield 34%; deep red powder. 1H NMR (500 MHz, CDCl3)
d 12.34
[2,1-d]thiazole-6,11-dione (6p)
Yield 37%; red powder. 1H NMR (300 MHz, CDCl3)
d
12.38 (s, 1H),
12.35 (s, 1H), 7.82 (d, J ¼ 7.5 Hz, 1H), 7.69e7.60 (m, 1H), 7.30 (d,
J ¼ 1.6 Hz, 1H), 7.22 (s, 1H), 3.90e3.78 (m, 4H), 3.73e3.66 (m, 2H),
2.74e2.67 (m, 4H), 2.67e2.62 (m, 2H). 13C NMR (126 MHz, DMSO-
(s, 2H), 7.79 (d, J ¼ 7.3 Hz, 1H), 7.63 (t, J ¼ 7.9 Hz, 1H), 7.28 (d,
J ¼ 8.7 Hz, 1H), 7.16 (s, 1H), 3.92e3.75 (m, 4H), 3.15e2.88 (m, 4H),
2.71e2.65 (m, 6H), 2.63e2.59 (m, 2H), 2.13e1.92 (m, 4H), 1.63e1.55
d6)
d
189.48, 180.92, 175.18, 162.65, 162.12, 161.71, 137.13, 132.45,
(m, 1H), 0.96 (d, J ¼ 6.2 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d 190.07,
125.48, 124.97, 124.89, 119.63, 116.06, 110.19, 109.65, 60.23, 58.87,
52.69. HRMS (EI) m/z [M]þcalcd for C21H19N3O5S: 425.1045, found:
425.1039.
181.61, 175.53, 163.29, 162.34, 162.30, 136.25, 132.67, 126.00, 125.03,
124.82, 119.71, 116.18, 111.10, 109.96, 55.98, 55.63, 54.46, 52.85,
33.89, 30.55, 21.79. HRMS (EI): m/z [M]þcalcd for C27H30N4O4S:
506.1988, found: 506.1987.
4.6.8. 4-(5,7-Dihydroxy-6,11-dioxo-6,11-dihydroanthra[2,1-d]
4.6.14. 5,7-Dihydroxy-2-(4-(2-morpholinoethyl)piperazin-1-yl)
thiazol-2-yl)-1,4-diazepane-1-carbaldehyde (6q)
Yield 44%; red powder. 1H NMR (300 MHz, DMSO-d6)
d 12.19 (s,
anthra[2,1-d]thiazole-6,11-dione (13d)
Yield 20%; deep red powder. 1H NMR (300 MHz, CDCl3)
d 12.35
1H),12.18 (s,1H), 8.06 (s,1H), 7.78 (t, J ¼ 7.9 Hz,1H), 7.69 (dd, J ¼ 7.4,
1.2 Hz, 1H), 7.37 (dd, J ¼ 8.3, 1.0 Hz, 1H), 7.14 (s, 1H), 4.11e3.85 (m,
4H), 3.82e3.63 (m, 4H), 2.04e1.95 (m, 2H). 13C NMR (126 MHz,
(s, 2H), 7.79 (d, J ¼ 7.5 Hz, 1H), 7.62 (t, J ¼ 7.9 Hz, 1H), 7.27 (d,
J ¼ 5.9 Hz, 1H), 7.17 (s, 1H), 3.88e3.78 (m, 4H), 3.76e3.70 (m, 4H),
2.71e2.64 (m, 4H), 2.62e2.55 (m, 4H), 2.54e2.48 (m, 4H). 13C NMR
CD3OD)
d 190.39, 181.75, 177.86, 163.31, 163.26, 163.22, 162.92,
(126 MHz, CDCl3)
d 190.12, 181.68, 175.52, 163.30, 162.36, 162.29,
136.46, 131.82, 129.80, 128.39, 124.87, 119.75, 115.07, 111.10, 110.17,
42.01, 38.94, 35.51, 31.79, 29.55. HRMS (EI): m/z [M]þcalcd for
136.27, 132.68, 125.97, 125.08, 124.85, 119.72, 116.19, 111.15, 110.00,
66.88, 56.32, 55.38, 54.11, 52.87. HRMS (EI): m/z [M]þcalcd for
C
21H17N3O5S: 423.0889, found: 423.0876.
C25H26N4O5S: 494.1624, found: 494.1625.
4.6.9. 2-((2,3-Dihydroxypropyl)(methyl)amino)-5,7-
dihydroxyanthra[2,1-d]thiazole-6,11-dione (6r)
Yield 45%; red powder. 1H NMR (300 MHz, CDCl3)
4.6.15. 2-(4-(2-(Dibutylamino)ethyl)piperazin-1-yl)-5,7-
dihydroxyanthra[2,1-d]thiazole-6,11-dione (13e)
d
12.29 (s, 1H),
Yield 57%; deep red powder. 1H NMR (300 MHz, CDCl3)
d 12.36
12.25 (s, 1H), 7.78 (d, J ¼ 7.4 Hz, 1H), 7.64 (t, J ¼ 7.8 Hz, 1H),
(s, 2H), 7.80 (dd, J ¼ 7.5, 1.1 Hz, 1H), 7.63 (dd, J ¼ 8.3, 7.6 Hz, 1H),
7.29e7.26 (dd, J ¼ 7.2, 1.1 Hz, 1H), 7.18 (s, 1H), 3.89e3.77 (m, 4H),
2.69e2.64 (m, 6H), 2.63e2.58 (m, 2H), 2.56e2.49 (m, 4H),1.51e1.36
7.34e7.27 (m, 1H), 7.16 (s, 1H), 4.10e3.91 (m, 2H), 3.72e3.52 (m,
3H), 2.01 (s, 3H). 13C NMR (126 MHz, DMSO-d6)
d 189.43, 181.07,
175.94, 162.73, 162.07, 161.72, 137.07, 131.86, 124.91, 119.58, 117.10,
116.16, 113.13, 109.72, 109.38, 69.75, 64.23, 49.05. HRMS (EI) m/z
[M]þcalcd for C19H16N2O6S: 400.0729, found: 400.0674.
(m, 8H), 0.87 (t, J ¼ 5.9 Hz, 6H). 13C NMR (126 MHz, CDCl3)
d 190.17,
181.73, 175.58, 163.33, 162.39, 162.33, 136.31, 132.73, 126.02, 125.13,
124.88, 119.75, 116.22, 111.18, 110.05, 54.15, 54.09, 54.07, 52.89,
33.85, 20.63, 14.04. HRMS (ESI): m/z [Mþ1]þcalcd for C29H36N4O4S:
536.2457, found: 537.2546.
4.6.10. 5,7-Dihydroxy-2-((2-hydroxyethyl)(methyl)amino)anthra
[2,1-d]thiazole-6,11-dione (6s)
Yield 36%; red powder. 1H NMR (300 MHz, DMSO-d6)
d 12.13 (s,
4.6.16. 2-(4-(2-(Diethylamino)ethyl)piperazin-1-yl)-5,7-
2H), 7.71 (t, J ¼ 7.9 Hz, 1H), 7.59 (d, J ¼ 7.4 Hz, 1H), 7.29 (d, J ¼ 8.2 Hz,
dihydroxyanthra[2,1-d]thiazole-6,11-dione (13f)
1H), 6.97 (s,1H), 3.80e3.63 (m, 4H), 3.25 (s, 3H). 13C NMR (101 MHz,
Yield 17%; deep red powder. 1H NMR (300 MHz, CDCl3)
d 12.34
DMSO-d6)
d 189.38, 180.93, 175.76, 162.73, 162.40, 161.72, 137.04,
(s, 2H), 7.80 (dd, J ¼ 7.4, 1.0 Hz, 1H), 7.63 (dd, J ¼ 8.4, 7.7 Hz, 1H),
7.30e7.26 (dd, J ¼ 7.5, 1.1 Hz, 1H), 7.19 (s, 1H), 3.89e3.79 (m, 4H),
2.72e2.68 (m, 4H), 2.05e1.96 (m, 8H), 0.90e0.88 (m, 6H). 13C NMR
132.51, 124.89, 124.76, 119.56, 119.92, 116.10, 109.73, 109.33, 58.58,
58.49, 14.41. HRMS (EI) m/z [M]þcalcd for C18H14N2O5S: 370.0623,
found: 370.0611.
(126 MHz, CDCl3)
d 190.21, 181.71, 175.58, 163.31, 162.40, 162.22,
136.35, 132.71, 125.95, 125.17, 124.91, 119.78, 116.20, 111.28, 110.11,
52.72, 49.14, 47.22, 14.15. HRMS (EI): m/z [M]þcalcd for
C25H28N4O4S: 480.1831, found: 480.1840.
4.6.11. 5,7-Dihydroxy-2-(4-(2-(pyrrolidin-1-yl)ethyl)piperazin-1-
yl)anthra[2,1-d]thiazole-6,11-dione (13a)
Yield 26%; deep red powder. 1H NMR (300 MHz, CDCl3)
d 12.34
(s, 2H), 7.78 (dd, J ¼ 7.5, 1.1 Hz, 1H), 7.66e7.58 (dd, J ¼ 8.3, 7.5 Hz,
1H), 7.29e7.26 (dd, J ¼ 7.5, 1.2 Hz, 1H), 7.16 (s, 1H), 3.89e3.76 (m,
4H), 2.73e2.63 (m, 12H), 1.90e1.80 (m, 4H). 13C NMR (126 MHz,
4.6.17. 2-(4-(2-(Dimethylamino)ethyl)piperazin-1-yl)-5,7-
dihydroxyanthra[2,1-d]thiazole-6,11-dione (13g)
Yield 35%; deep red powder. 1H NMR (300 MHz, CDCl3)
d 12.36
CDCl3)
d 190.13, 181.66, 175.55, 163.31, 162.36, 162.29, 136.29,
(s, 2H), 7.80 (dd, J ¼ 8.7, 1.5 Hz, 1H), 7.63 (dd, J ¼ 8.3, 7.6 Hz, 1H), 7.27
(dd, J ¼ 6.7, 1.1 Hz, 1H), 7.18 (s, 1H), 3.92e3.73 (m, 4H), 2.70e2.62
(m, 4H), 2.61e2.55 (m, 2H), 2.55e2.49 (m, 2H), 2.31 (s, 6H). 13C
132.69, 126.00, 125.09, 124.86, 119.74, 116.19, 111.16, 110.01, 54.59,
53.25, 52.77, 23.38. HRMS (EI): m/z [M]þcalcd for C25H26N4O4S:
478.1675, found: 478.1675.
NMR (126 MHz, CDCl3)
d 190.15, 181.74, 175.55, 163.34, 162.38,
162.36, 136.29, 132.73, 126.05, 125.12, 124.87, 119.75, 116.23, 111.15,
4.6.12. 5,7-Dihydroxy-2-(4-(2-(piperidin-1-yl)ethyl)piperazin-1-yl)
110.02, 56.58, 56.12, 52.86, 45.74. HRMS (EI): m/z [M]þcalcd for
anthra[2,1-d]thiazole-6,11-dione (13b)
C23H24N4O4S: 452.1518, found: 452.1510.
Yield 31%; deep red powder. 1H NMR (300 MHz, CDCl3)
d 12.35
(s, 2H), 7.79 (dd, J ¼ 7.5, 1.1 Hz, 1H), 7.63 (dd, J ¼ 8.3, 7.6 Hz, 1H), 7.28
(dd, J ¼ 4.6, 1.0 Hz, 1H), 7.18 (s, 1H), 3.89e3.75 (m, 4H), 2.68e2.65
(m, 4H), 2.62e2.53 (m, 4H), 2.53e2.40 (m, 4H), 1.66e1.59 (m, 4H),
4.6.18. 2-(4-(2-(Diisopropylamino)ethyl)piperazin-1-yl)-5,7-
dihydroxyanthra[2,1-d]thiazole-6,11-dione (13h)
Yield 61%; deep red powder, mp. 1H NMR (300 MHz, CDCl3)
1.52e1.44 (m, 2H). 13C NMR (126 MHz, CDCl3)
d
190.15, 181.72,
d
12.34 (s, 2H), 7.81e7.76 (d, J ¼ 7.4 Hz, 1H), 7.62 (t, J ¼ 7.9 Hz, 1H),
7.27 (d, J ¼ 7.5 Hz,1H), 7.17 (s, 1H), 3.88e3.74 (m, 4H), 2.71e2.66 (m,
4H), 2.08e1.88 (m, 4H), 1.63e1.48 (m, 2H), 1.29e1.26 (m, 12H). 13
NMR (126 MHz, CDCl3) 190.14, 181.68, 175.59, 163.31, 162.37,
162.28, 136.29, 132.71, 126.00, 125.11, 124.86, 119.74, 116.20, 111.18,
175.56, 163.34, 162.38, 162.35, 136.29, 132.73, 126.04, 125.11, 124.86,
119.74, 116.22, 111.15, 110.02, 56.37, 55.53, 55.03, 52.87, 25.61, 24.09.
HRMS (EI): m/z [M]þcalcd for C26H28N4O4S: 492.1831, found:
492.1832.
C
d

Y.-K. Liang et al. / European Journal of Medicinal Chemistry 84 (2014) 505e515
515
110.03, 52.92, 48.22, 33.85, 14.15. HRMS (EI): m/z [M]þcalcd for
27H32N4O4S: 508.2144, found: 508.2146.
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C
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d 12.37
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(IC50) values were determined with the Logit method.
Acknowledgements
This work was financially supported by the Chinese Academy of
Sciences (“Interdisciplinary Cooperation Team” Program for Science
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Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.07.047.