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. Author manuscript; available in PMC: 2015 Jan 8.
Published in final edited form as: Tetrahedron Lett. 2013 Nov 19;55(2):373–375. doi: 10.1016/j.tetlet.2013.11.033

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,✉
PMCID: PMC3895536  NIHMSID: NIHMS542578  PMID: 24453382

Abstract

Several novel N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamides 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 development of new lead anticancer agents.

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 proliferation 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, compounds 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 sulfonamides, we designed and synthesized a series of novel hybrid compounds 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) benzenesulfonamide 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 Compound 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 benzenesulfonamide 4 in the presence of triethylamine in chloroform afforded N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamides 5a–i and 6a–g. The chemical structures of final products were confirmed with 1H NMR, 13C NMR, and mass spectroscopy.

Scheme 1.

Scheme 1

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Reagents and conditions: (a) H2SO4, reflux, 30 min; (b) SnCl2, conc. HCl, 100 °C, 4 h then NaOH 10%, RT, 30 min; (c) Et3N, CHCl3, RT.

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 neuroblastoma cell line (SK-N-MC) (Table 1). Compound 5i containing a 4-methoxy group on the phenyl ring was the most potent compound in this series against these three cell lines. This compound exhibited higher antiproliferative activity against SK-N-MC (IC50 = 25.2 μM) and T-47D (IC50 = 19.7 μM) 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 μM).

Table 1.

Antiproliferative activity (IC50, in μM) of compounds against different cancer cell lines, neuroblastoma cell line (SK-N-MC) and breast cancer cell line (MDA-MB-231, T-47D).

Compounds X Y SK-N-MC
IC50 (μM)		 MDA-MB-231
IC50 (μM)		 T-47D
IC50 (μM)
5a H Penta F 58.7±30.8 85±15.9 53.9±4.7
5b H 3-Cl >100 >100 58.6±1.8
5c H 4-Cl >100 83.3±26.9 33.8±9.3
5d H 2,5-di-Cl 95.8±28 >100 53.3±4.5
5e H 2,4,5-tri Cl 78.5±6.4 60.4±17.2 36.3±9.2
5f H 3-Cl,2-CH3 38.3±4.7 67.5±8.3 56.5±28.7
5g H 4-Br 47.9±20.7 85.4±24.7 63.4±9.8
5h H 4-NO2 90.9±16.4 96.3±49.2 52.7±22.4
5i H 4-OCH3 25.2±26.5 54.4±21 19.7±0.18
6a Cl Penta F 40.8±8.2 40.2±4.6 39±18
6b Cl 3-Cl 40.5±28.3 59.5±37 83.±513
6c Cl 2,4,5-tri-Cl 24.9±16.1 66.7±9.7 67.9±6.7
6d Cl 3-Cl,2-CH3 41.3±23.5 30.4±5.9 49.3±26.7
6e Cl 4-Br 37.1±12.7 45.3±3.8 46.9±17
6f Cl 4-NO2 >100 63.1±20.7 76.1±1.6
6g Cl 4-OCH3 >100 62.3±0.2 45±11.3
Etoposide - - 33.4±11.7 36.6±5.9 32.7±5.5
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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 μM) against SK-N-MC cell line in comparison with etoposide (IC50 = 33.4 μM). 3-Chloro-2-methylbenzene sulfonamide analog 6d with IC50 value of 30.4 μM showed higher antiproliferative 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 6 position of xanthone ring showed generally more antiproliferative activity compared with the corresponding compounds without the chlorine moiety (6a, 6b, 6c, 6e versus 5a, 5b, 5c, 5d, 5e, 5g, respectively).

Among the compounds without a substituted chlorine on the xanthone ring, compound 5i with a 4-methoxy group on benzenesulfonamide ring was the most potent compound, suggesting that the presence of an electron donor group on benzenesulfonamide 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 significant increased antiproliferative activity compared to compound 5b. Similarly, 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 result to increased antiproliferative activity in both substituted xanthone series of compounds with or without chlorine group.

Alternatively, antiproliferative activity of substituted benzenesulfonamides derivatives were evaluated against human leukemia (CCRF-CEM), breast adenocarcinoma (MDA-MB-468), and colorectal carcinoma (HCT-116) cell lines at the concentration of 50 μM (Figure 1) to determine whether the compounds are consistently cytotoxic against other cancer cell lines and to compare their activity with doxorubicin (Dox). Compounds 5a, 5c, 6a, and 6d exhibited 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 antiproliferative 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.

Figure 1.

Figure 1

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Inhibition of HCT-116, CCRF-CEM, and MDA-MB-468 cells by compounds 5a–i and 6a–g (50 μM) 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).

Compounds 5e, 5g, 5h, 5f, and 6g demonstrated modest antiproliferative activities (40–74%) against all three cell lines. Furthermore, nine compounds 5b, 5d, 5h, 6b, 6c, 6e, and 6f exhibited significantly higher antiproliferative activity against HCT-116 and MDA-MB-468 cell lines that CCRF-CEM cells. For example, 6c, 6e, and 6f inhibited HCT-116 by 68, 63, 68% and MDA-MB-468 cells by 66, 60, and 71%, respectively. The presence of either chlorine or bromine groups on both rings decreased the antiproliferative activity as shown in compounds 6b–c, 6e, 6f.

In conclusion, a series of 18 novel xanthone sulphonamide derivatives 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 prototypes and development of new lead compounds as antiproliferative agents.

Supplementary Material

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Acknowledgments

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 Number 8 P20 GM103430-12 for sponsoring the core facility.

Footnotes

Supplementary Material

Supplementary data associated with this article can be found, in the online version.

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