Synthesis and evaluation of antiproliferative activity of substituted N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamides

Article abstract of DOI:10.1016/j.tetlet.2013.11.033

Several novel N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide derivatives were prepared as potential antiproliferative agents. The in vitro antiproliferative activity of the synthesized compounds was investigated against a panel of tumor cell lines including breast cancer cell lines (MDA-MB-231, T-47D) and neuroblastoma cell line (SK-N-MC) using MTT colorimetric assay. Etoposide, a well-known anticancer drug, was used as a positive standard drug. Among synthesized compounds, 4-methoxy-N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide (5i) showed the highest antiproliferative activity against MDA-MB-231, T-47D, and SK-N-MC cells. Furthermore, pentafluoro derivatives 5a and 6a exhibited higher antiproliferative activity than doxorubicin against human leukemia cell line (CCRF-CEM) and breast adenocarcinoma (MDA-MB-468) cells. Structure-activity relationship studies revealed that xanthone benzenesulfonamide hybrid compounds can be used for the development of new lead anticancer agents.

Full text of DOI:10.1016/j.tetlet.2013.11.033

Tetrahedron Letters 55 (2014) 373–375
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and evaluation of antiproliferative activity of substituted
N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamides
Somayeh Motavallizadeh a, Asal Fallah-Tafti a, Saeedeh Maleki a, Amir Nasrolahi Shirazi c,
Mahboobeh Pordeli b, Maliheh Safavi b, Sussan Kabudanian Ardestani b, Shaaban Asd c, Rakesh Tiwari c,d
,
Donghoon Oh c, Abbas Shafiee a, Alireza Foroumadi a, Keykavous Parang c,d, , Tahmineh Akbarzadeh
a,
⇑
⇑
a Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design & Development Research Center, Tehran University of Medical Sciences, Tehran, Iran
b Institute of Biochemistry and Biophysics, Department of Biochemistry, University of Tehran, Tehran, Iran
c Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA
d School of Pharmacy, Chapman University, Orange, CA 92866, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Several novel N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide derivatives were prepared as potential
antiproliferative agents. The in vitro antiproliferative activity of the synthesized compounds was inves-
tigated against a panel of tumor cell lines including breast cancer cell lines (MDA-MB-231, T-47D) and
neuroblastoma cell line (SK-N-MC) using MTT colorimetric assay. Etoposide, a well-known anticancer
drug, was used as a positive standard drug. Among synthesized compounds, 4-methoxy-N-(9-oxo-9H-
xanthen-4-yl)benzenesulfonamide (5i) showed the highest antiproliferative activity against MDA-MB-
231, T-47D, and SK-N-MC cells. Furthermore, pentafluoro derivatives 5a and 6a exhibited higher
antiproliferative activity than doxorubicin against human leukemia cell line (CCRF-CEM) and breast
adenocarcinoma (MDA-MB-468) cells. Structure–activity relationship studies revealed that xanthone
benzenesulfonamide hybrid compounds can be used for the development of new lead anticancer agents.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 5 October 2013
Revised 5 November 2013
Accepted 10 November 2013
Available online 19 November 2013
Keywords:
Antiproliferative activity
Benzenesulfonamides
Cancer
Xanthone
Cancer is known as one of the leading causes of mortality
throughout the world, a disease characterized by uncontrolled cell
growth, metastasis, and invasion. Inhibition of cancer cell prolifer-
ation is one of the most important principles in the treatment of
cancer using anticancer compounds. The difficulty to diagnose
the disease at the earlier stages, narrow therapeutic indices of
chemotherapeutic agents, and the development of multidrug
resistance are some of the major obstacles, which has made
cancer treatment challenging and caused high mortality rate
worldwide.1,2
Among different classes of chemotherapeutic agents, com-
pounds that act by DNA intercalation, such as the 9-anilinoacridine
amsacrine and the xanthone derivative dimethylxanthenone-4-
acetic acid (DMXAA) have attracted particular attention, due to
their high therapeutic potential. The data for xanthone binding
studies with DNA indicate that the planar tricycle moiety serves
as an important feature for designing new DNA intercalators.3–6
In addition, sulfonamide derivatives have been found to possess
potent anticancer activities through a variety of mechanisms such
as cell cycle perturbation in the G1 phase, disruption of
microtubule assembly, angiogenesis inhibition, and functional
suppression of the transcriptional activator NF-Y.7–9 Based on the
diverse biological activities of the xanthones and aryl sulfona-
mides, we designed and synthesized a series of novel hybrid com-
pounds containing both xanthone and sulfonamide entities in one
molecule and evaluated them for their antiproliferative activity.
The general procedure for the synthesis of substituted
N-(9-oxo-9H-xanthen-4-yl) benzenesulfonamides 5a–i and 6a–g
is depicted in Scheme 1. 2-(2-Nitrophenoxy)benzoic acid (1) was
prepared according to the previously reported method.10,11 Com-
pound 1 underwent cyclization in the presence of sulfuric acid
(H2SO4) under reflux conditions to afford nitro-9H-xanthen-9-one
2.12 Subsequent reaction of 2 with stannous chloride dehydrates
in concentrated hydrochloric acid afforded corresponding amino-
9H-xanthen-9-one 3. Finally, the reaction of 3 with the substituted
benzenesulfonyl chloride 4 in the presence of triethylamine in
chloroform afforded N-(9-oxo-9H-xanthen-4-yl)benzenesulfona-
mides 5a–i and 6a–g.13 The chemical structures of final products
were confirmed with 1H NMR, 13C NMR, and mass spectroscopy.
The antiproliferative activities of compounds 5a–i and 6a–g
were evaluated by MTT reduction assay against two different
breast cancer cell lines (MDA-MB-231 and T-47D) and a neuroblas-
toma cell line (SK-N-MC) (Table 1). Compound 5i containing a
4-methoxy group on the phenyl ring was the most potent
⇑
Corresponding authors.
E-mail addresses: kparang@uri.edu (K. Parang), akbarzad@tums.ac.ir
(T. Akbarzadeh).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.033

374
S. Motavallizadeh et al. / Tetrahedron Letters 55 (2014) 373–375
O
CO2H
O
O
O
b
a
X
X
O
X
NO2
NO2
NH2
3a X = H
3b
X = Cl
1a X = H
2a X = H
1b
2b
X = Cl
X = Cl
O
O
a: Y = penta F
b: Y = 3-Cl
O
O
S
c: Y = 4-Cl
c
3
+
Cl
d: Y = 2,5-di Cl
e: Y = 2,4,5-tri Cl
f: Y = 3-Cl, 2-Me
g: Y = 4-Br
h: Y = 4-NO2
i: Y = 4-OMe
Y
X
O
O
HN
S
4
5a-i X = H
6a-g
X = Cl
Y
Scheme 1. Reagents and conditions: (a) H2SO4, reflux, 30 min; (b) SnCl2, concd HCl, 100 °C, 4 h then NaOH 10%, rt, 30 min; (c) Et3N, CHCl3, rt.
Table 1
Among the compounds without a substituted chlorine on the
Antiproliferative activity (IC50, in
lM) of compounds against different cancer cell
xanthone ring, compound 5i with a 4-methoxy group on the ben-
zenesulfonamide ring was the most potent compound, suggesting
that the presence of an electron donor group on the benzenesul-
fonamide ring increases the antiproliferative activity in this series
of compounds. Introducing a methyl group in the position 2 of the
benzenesulfonamide ring in compound 5f led to a significant in-
creased antiproliferative activity compared to compound 5b. Sim-
ilarly, compound 6d with 2-methyl substitution showed enhanced
antiproliferative activity compared to 6b suggesting that methyl
substitution in position 2 of the benzenesulfonamide ring could re-
sult in increased antiproliferative activity in both substituted
xanthone series of compounds with or without the chlorine group.
Alternatively, antiproliferative activity of substituted benzene-
sulfonamide derivatives was evaluated against human leukemia
(CCRF-CEM), breast adenocarcinoma (MDA-MB-468), and colorec-
lines, neuroblastoma cell line (SK-N-MC) and breast cancer cell line (MDA-MB-231,
T-47D)
Compounds
X
Y
SK-N-MC
IC50 M)
MDA-MB-231
IC50 M)
T-47D
IC50 (lM)
(
l
(
l
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
6d
6e
6f
6g
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
—
Penta F
3-Cl
4-Cl
2,5-Di-Cl
2,4,5-Tri Cl
3-Cl,2-CH3
4-Br
58.7 30.8
>100
>100
85 15.9
>100
83.3 26.9
>100
53.9 4.7
58.6 1.8
33.8 9.3
53.3 4.5
36.3 9.2
56.5 28.7
63.4 9.8
52.7 22.4
19.7 0.18
39 18
95.8 28
78.5 6.4
38.3 4.7
47.9 20.7
90.9 16.4
25.2 26.5
40.8 8.2
40.5 28.3
24.9 16.1
41.3 23.5
37.1 12.7
>100
60.4 17.2
67.5 8.3
85.4 24.7
96.3 49.2
54.4 21
40.2 4.6
59.5 37
66.7 9.7
30.4 5.9
45.3 3.8
63.1 20.7
62.3 0.2
36.6 5.9
4-NO2
4-OCH3
Penta F
3-Cl
2,4,5-Tri-Cl
3-Cl,2-CH3
4-Br
4-NO2
4-OCH3
—
83 513
67.9 6.7
49.3 26.7
46.9 17
76.1 1.6
45 11.3
32.7 5.5
tal carcinoma (HCT-116) cell lines at the concentration of 50 lM
(Fig. 1) to determine whether the compounds are consistently
cytotoxic against other cancer cell lines and to compare their activ-
ity with doxorubicin (Dox). Compounds 5a, 5c, 6a, and 6d exhib-
ited consistent antiproliferative activity against all three cell
lines. Among all the compounds, compounds 5a and 6a exhibited
the highest antiproliferative activity against all the cell lines. For
example, compound 6a inhibited the cell proliferation of HCT-
116 (86%), CCRF-CEM (75%), and MDA-MB-468 (65%). Structure–
activity relationship (SAR) revealed that the presence of five
fluorine on the second ring improved the antiproliferative activity
significantly (5a and 6a) against these three cell lines. Compounds
5a (79% and 79%) and 6a (86% and 75%) showed higher antiprolif-
erative activity than Dox (63% and 73%) against HCT-116 and CCRF-
CEM cells, respectively. Furthermore, compound 6d (86%) was
more active than Dox against HCT-116 cells and was consistently
active against CCRF-CEM and MDA-MB-468 cells. Compound 5i
that showed high antiproliferative activity against SK-N-MC and
T-47D in the previous assay was consistently cytotoxic against
HCT-116 (71%) and CCRF-CEM (77%) cells.
>100
33.4 11.7
Etoposide
compound in this series against these three cell lines. This com-
pound exhibited higher antiproliferative activity against SK-N-
MC (IC50 = 25.2 lM) and T-47D (IC50 = 19.7 lM) cell lines when
compared with etoposide. Compound 5i showed 1.7-fold higher
antiproliferative activity against T-47D cell line when compared
with control drug etoposide (IC50 = 32.7 lM).
In general, the compounds were more potent against SK-N-MC
cell line when compared with other tested cell lines. Compounds 5i
and 6c exhibited higher antiproliferative activity (IC50 = 24.9–
25.2
(IC50 = 33.4
6d with IC50 value of 30.4
l
M) against SK-N-MC cell line in comparison with etoposide
M). 3-Chloro-2-methylbenzene sulfonamide analog
M showed higher antiproliferative
l
l
activity than etoposide against MDA-MB-231 cell line.
Structure–activity relationship studies revealed that the
antiproliferative activity of synthesized compounds was partly
influenced by the type of substituents positioned on the phenyl
ring. Most of the compounds bearing chlorine substitution in the
6th position of the xanthone ring showed generally more antipro-
liferative activity compared with the corresponding compounds
without the chlorine moiety (6a, 6b, 6c, 6e vs 5a, 5b, 5c, 5d, 5e,
5g, respectively).
Compounds 5e, 5g, 5h, 5f, and 6g demonstrated modest anti-
proliferative activities (40–74%) against all three cell lines. Further-
more, seven compounds 5b, 5d, 5h, 6b, 6c, 6e, and 6f exhibited
significantly higher antiproliferative activity against HCT-116 and
MDA-MB-468 cell lines than CCRF-CEM cells. For example, 6c, 6e,
and 6f inhibited HCT-116 by 68%, 63%, and 68% and MDA-MB-
468 cells by 66%, 60%, and 71%, respectively. The presence of either

S. Motavallizadeh et al. / Tetrahedron Letters 55 (2014) 373–375
375
160
140
120
100
80
HCT-116
CCRF-CEM
MDA-MB-468
60
40
20
0
DMSO Dox
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
6d
6e
6f
6g
Figure 1. Inhibition of HCT-116, CCRF-CEM, and MDA-MB-468 cells by compounds 5a–i and 6a–g (50
l
M) after 24 h incubation. The results are shown as the percentage of
the control DMSO that has no compound (set at 100%). All the experiments were performed in triplicate ( SD).
chlorine or bromine groups on both rings decreased the antiprolif-
erative activity as shown in compounds 6b, 6c, 6e, and 6f.
In conclusion, a series of 18 novel xanthone sulfonamide deriv-
atives were synthesized and evaluated for their anticancer activity
against a panel of cancer cell lines. Compound 5i containing a 4-
methoxy group was more antiproliferative than etoposide against
SK-N-MC and T-47D cells. Furthermore, the assay results showed
that pentafluoro derivatives 5a and 6a had higher antiproliferative
activity against HCT-116 and CCRF-CEM cells than Dox. Structure–
activity relationship studies provided insights for designing the
next generation of xanthone benzenesulfonamide hybrid proto-
types and development of new lead compounds as antiproliferative
agents.
References and notes
1. Teodori, E.; Dei, D.; Scapecchi, S.; Gualtieri, F. Farmaco 2002, 57, 385–415.
2. Krishna, R.; Mayer, D. Eur. J. Pharm. Sci. 2000, 11, 265–283.
3. Denny, W. A. Curr. Med. Chem. 2006, 9, 1655–1665.
4. Sousa, E.; Paiva, A.; Nazareth, N.; Gales, L.; Damas, A. M.; Nascimento, M. S. J.;
Pinto, M. Eur. J. Med. Chem. 2009, 44, 3830–3835.
5. (a) Saraiva, L.; Fresco, P.; Pinto, E.; Sousa, E.; Pinto, M.; Goncalves, J. Bioorg. Med.
Chem. 2003, 11, 1215–1225; (b) Madalena, P.; Cerqueira, F.; Sousa, M. E.;
Nascimento, M. S. J.; Pinto, M. Bioorg. Med. Chem. 2002, 10, 3725–3730.
6. Mosmann, T. J. Immunol. Methods 1983, 65, 55–63.
7. Reddy, N. S.; Mallireddigari, M. R.; Cosenza, S.; Gumireddy, K.; Bell, S. C.; Reddy,
P.; Reddy, M. V. R. Bioorg. Med. Chem. Lett. 2004, 14, 4093–4097.
8. Medina, J. C.; Shan, B.; Beckmann, H.; Farrell, R. P.; Clark, D. L.; Learned, R. M.;
Roche, D.; Li, A.; Baichwal, V.; Case, C.; Baeuerle, P. A.; Rosen, T.; Jaen, J. C.
Bioorg. Med. Chem. Lett. 1998, 8, 2653–2656.
9. Luo, Y.; Qiu, K.; Lu, X.; Liu, K.; Fu, J.; Zhu, H. Bioorg. Med. Chem. 2011, 19, 4730–
4738.
Acknowledgments
10. Akbarzadeh, T.; Tabatabai, S. A.; Khoshnoud, M. J.; Shafaghi, B.; Shafiee, A.
Bioorg. Med. Chem. 2003, 11, 769–773.
11. Kostakis, I. K.; Pouli, N.; Marakos, P.; Skaltsounis, A.; Pratsinis, H.; Kletsas, D.
Bioorg. Med. Chem. 2006, 14, 2910–2934.
12. Okabayashi, I.; Iwata, N. Chem. Pharm. Bull. 1980, 28, 2831–2835.
13. General procedure for the synthesis of substituted N-(9-oxo-9H-xanthen-4-yl)
This work was supported by grants from the Research Council
of Tehran University of Medical Sciences. We also acknowledge
the financial support from the American Cancer Society Grant #
RSG-07-290-01-CDD. We thank National Center for Research
Resources, NIH, and Grant No. 8 P20 GM103430-12 for sponsoring
the core facility.
benzenesulfonamide (5). Triethylamine (15 mmol) was added to
a stirring
solution of 3 (12 mmol) and appropriate benzenesulfonyl chloride (13 mmol)
in chloroform (50 mL). The reaction mixture was stirred at room temperature.
The progress of the reaction was monitored by TLC using CH2Cl2 as a mobile
phase. When compound 3 was consumed, the precipitate was filtered and
purified by column chromatography (silica gel) using CH2Cl2 as the eluent.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.11.033.