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 (MDAMB- 468) cells. Structure-activity relationship studies revealed that xanthone benzenesulfonamide hybrid compounds can be used for development of new lead anticancer agents

Akbarzadeh, Tahmineh

Ardestani, Sussan Kabudanian

Asd, Shaaban

Fallah-Tafti, Asal

Foroumadi, Alireza

Maleki, Saeedeh

Motavallizadeh, Somayeh

Oh, Donghoon

Parang, Keykavous

Pordeli, Mahboobeh

Safavi, Maliheh

Shafiee, Abbas

Shirazi, Amir Nasrolahi

Tiwari, Rakesh

English

Chapman University Digital Commons

Chapman UniversityChapman University Digital CommonsPharmacy Faculty Articles and Research School of Pharmacy2014Synthesis and Evaluation of AntiproliferativeActivity of Substituted N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamidesSomayeh MotavallizadehUniversity of TehranAsal Fallah-TaftiUniveristy of TehranSaeedeh MalekiUniversity of TehranAmir Nasrolahi ShiraziChapman University, shirazi@chapman.eduMahboobeh PordeliTehran University of Medical SciencesSee next page for additional authorsFollow this and additional works at: http://digitalcommons.chapman.edu/pharmacy_articlesPart of the Cancer Biology Commons, Medical Biochemistry Commons, and the Pharmaceuticsand Drug Design CommonsThis Article is brought to you for free and open access by the School of Pharmacy at Chapman University Digital Commons. It has been accepted forinclusion in Pharmacy Faculty Articles and Research by an authorized administrator of Chapman University Digital Commons. For more information,please contact laughtin@chapman.edu.Recommended CitationSomayeh Motavallizadeh, Asal Fallah-Tafti, Saeedeh Maleki, Amir Nasrolahi Shirazi, Mahboobeh Pordeli, Maliheh Safavi, SussanKabudanian Ardestani, Shaaban Asd, Rakesh Tiwari, Donghoon Oh, Abbas Shafiee, Alireza Foroumadi, Keykavous Parang, TahminehAkbarzadeh. Synthesis and evaluation of antiproliferative activity of substituted N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamides.Tetrahedron Letters, 55.2 (2008): 373-375.DOI: 10.1016/j.tetlet.2013.11.033Synthesis and Evaluation of Antiproliferative Activity of Substituted N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamidesCommentsNOTICE: this is the author’s version of a work that was accepted for publication in Tetrahedron Letters.Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting,and other quality control mechanisms may not be reflected in this document. Changes may have been made tothis work since it was submitted for publication. A definitive version was subsequently published inTetrahedron Letters, volume 55, issue 2, in 2008. DOI: 10.1016/j.tetlet.2013.11.033The Creative Commons license below applies only to this version of the article.Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0License.CopyrightElsevierAuthorsSomayeh Motavallizadeh, Asal Fallah-Tafti, Saeedeh Maleki, Amir Nasrolahi Shirazi, Mahboobeh Pordeli,Maliheh Safavi, Sussan Kabudanian Ardestani, Shaaban Asd, Rakesh Tiwari, Donghoon Oh, Abbas Shafiee,Alireza Foroumadi, Keykavous Parang, and Tahmineh AkbarzadehThis article is available at Chapman University Digital Commons: http://digitalcommons.chapman.edu/pharmacy_articles/86Synthesis and evaluation of antiproliferative activity ofsubstituted N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamidesSomayeh Motavallizadeha, Asal Fallah-Taftia, Saeedeh Malekia, Amir Nasrolahi Shirazic,Mahboobeh Pordelib, Maliheh Safavib, Sussan Kabudanian Ardestanib, Shaaban Asdc,Rakesh Tiwaric,d, Donghoon Ohc, Abbas Shafieea, Alireza Foroumadia, KeykavousParangc,d, and Tahmineh AkbarzadehaaDepartment of Medicinal Chemistry, Faculty of Pharmacy and Drug Design & DevelopmentResearch Center, Tehran University of Medical Sciences, Tehran, IranbInstitute of Biochemistry and Biophysics, Department of Biochemistry, University of Tehran,Tehran, IrancDepartment of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University ofRhode Island, Kingston, Rhode Island, 02881, USAdSchool of Pharmacy, Chapman University, Orange, CA, 92866, USAAbstractSeveral novel N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamides derivatives were prepared aspotential antiproliferative agents. The in vitro antiproliferative activity of the synthesizedcompounds 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. Amongsynthesized compounds, 4-methoxy-N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide (5i) showedthe highest antiproliferative activity against MDA-MB-231, T-47D, and SK-N-MC cells.Furthermore, pentafluoro derivatives 5a and 6a exhibited higher antiproliferative activity thandoxorubicin against human leukemia cell line (CCRF-CEM) and breast adenocarcinoma (MDA-MB-468) cells. Structure-activity relationship studies revealed that xanthone benzenesulfonamidehybrid compounds can be used for development of new lead anticancer agents.KeywordsAntiproliferative Activity; Benzenesulfonamides; Cancer; XanthoneCancer is known as one of the leading causes of mortality throughout the world, a diseasecharacterized by uncontrolled cell growth, metastasis, and invasion. Inhibition of cancer cellproliferation is one of the most important principles in the treatment of cancer usinganticancer compounds. The difficulty to diagnose the disease at the earlier stages, narrow© 2013 Elsevier Ltd. All rights reserved.Correspondence to: Keykavous Parang; Tahmineh Akbarzadeh.Supplementary MaterialSupplementary data associated with this article can be found, in the online version.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to ourcustomers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review ofthe resulting proof before it is published in its final citable form. Please note that during the production process errors may bediscovered which could affect the content, and all legal disclaimers that apply to the journal pertain.NIH Public AccessAuthor ManuscriptTetrahedron Lett. Author manuscript; available in PMC 2015 January 08.Published in final edited form as:Tetrahedron Lett. 2014 January 8; 55(2): 373–375. doi:10.1016/j.tetlet.2013.11.033.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscripttherapeutic indices of chemotherapeutic agents, and the development of multidrug resistanceare some of the major obstacles, which has made cancer treatment challenging and causedhigh mortality rate worldwide.1,2Among different classes of chemotherapeutic agents, compounds that act by DNAintercalation, such as the 9-anilinoacridine amsacrine and the xanthone derivativedimethylxanthenone-4-acetic acid (DMXAA) have attracted particular attention, due to theirhigh therapeutic potential. The data for xanthone binding studies with DNA indicate that theplanar tricycle moiety serves as an important feature for designing new DNAintercalators.3–6In addition, sulfonamide derivatives have been found to possess potent anticancer activitiesthrough a variety of mechanisms such as cell cycle perturbation in the G1 phase, disruptionof microtubule assembly, angiogenesis inhibition, and functional suppression of thetranscriptional activator NF-Y.7–9 Based on the diverse biological activities of the xanthonesand aryl sulfonamides, we designed and synthesized a series of novel hybrid compoundscontaining both xanthone and sulfonamide entities in one molecule and evaluated them fortheir 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)benzoicacid (1) was prepared according to the previously reported method.10,11 Compound 1underwent cyclization in the presence of sulfuric acid (H2SO4) under reflux conditions toafford nitro-9H-xanthen-9-one 2.12 Subsequent reaction of 2 with stannous chloridedehydrates 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 oftriethylamine in chloroform afforded N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamides 5a–iand 6a–g. The chemical structures of final products were confirmed with 1H NMR, 13CNMR, and mass spectroscopy.The antiproliferative activities of compounds 5a–i and 6a–g were evaluated by MTTreduction 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-methoxygroup on the phenyl ring was the most potent compound in this series against these three celllines. 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. Compound5i showed 1.7-fold higher antiproliferative activity against T-47D cell line when comparedwith control drug etoposide (IC50 = 32.7 μM).In general, the compounds were more potent against SK-N-MC cell line when comparedwith 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 μMshowed higher antiproliferative activity than etoposide against MDA-MB-231 cell line.Structure-activity relationship studies revealed that the antiproliferative activity ofsynthesized compounds was partly influenced by the type of substituents positioned on thephenyl ring. Most of the compounds bearing chlorine substitution in the 6 position ofxanthone ring showed generally more antiproliferative activity compared with thecorresponding compounds without the chlorine moiety (6a, 6b, 6c, 6e versus 5a, 5b, 5c, 5d,5e, 5g, respectively).Motavallizadeh et al. Page 2Tetrahedron Lett. Author manuscript; available in PMC 2015 January 08.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptAmong the compounds without a substituted chlorine on the xanthone ring, compound 5iwith a 4-methoxy group on benzenesulfonamide ring was the most potent compound,suggesting that the presence of an electron donor group on benzenesulfonamide ringincreases the antiproliferative activity in this series of compounds. Introducing a methylgroup in the position 2 of the benzenesulfonamide ring in compound 5f led to significantincreased antiproliferative activity compared to compound 5b. Similarly, compound 6d with2-methyl substitution showed enhanced antiproliferative activity compared to 6b suggestingthat methyl substitution in position 2 of the benzenesulfonamide ring could result toincreased antiproliferative activity in both substituted xanthone series of compounds with orwithout chlorine group.Alternatively, antiproliferative activity of substituted benzenesulfonamides derivatives wereevaluated 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) todetermine whether the compounds are consistently cytotoxic against other cancer cell linesand to compare their activity with doxorubicin (Dox). Compounds 5a, 5c, 6a, and 6dexhibited consistent antiproliferative activity against all three cell lines. Among all thecompounds, compounds 5a and 6a exhibited the highest antiproliferative activity against allthe 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 antiproliferativeactivity 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%) againstHCT-116 and CCRF-CEM cells, respectively. Furthermore, compound 6d (86%) was moreactive than Dox against HCT-116 cells and was consistently active against CCRF-CEM andMDA-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%) andCCRF-CEM (77%) cells.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 6fexhibited significantly higher antiproliferative activity against HCT-116 and MDA-MB-468cell 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 eitherchlorine or bromine groups on both rings decreased the antiproliferative activity as shown incompounds 6b–c, 6e, 6f.In conclusion, a series of 18 novel xanthone sulphonamide derivatives were synthesized andevaluated for their anticancer activity against a panel of cancer cell lines. Compound 5icontaining a 4-methoxy group was more antiproliferative than etoposide against SK-N-MCand T-47D cells. Furthermore, the assay results showed that pentafluoro derivatives 5a and6a had higher antiproliferative activity against HCT-116 and CCRF-CEM cells than Dox.Structure-activity relationship studies provided insights for designing the next generation ofxanthone benzenesulfonamide hybrid prototypes and development of new lead compoundsas antiproliferative agents.Supplementary MaterialRefer to Web version on PubMed Central for supplementary material.Motavallizadeh et al. Page 3Tetrahedron Lett. Author manuscript; available in PMC 2015 January 08.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptAcknowledgmentsThis work was supported by grants from the Research Council of Tehran University of Medical Sciences. We alsoacknowledge the financial support from the American Cancer Society Grant # RSG-07-290-01-CDD. We thankNational Center for Research Resources, NIH, and Grant Number 8 P20 GM103430-12 for sponsoring the corefacility.References and notes1. Teodori E, Dei D, Scapecchi S, Gualtieri F. Farmaco. 2002; 57:385–415. [PubMed: 12058813]2. Krishna R, Mayer D. Eur J Pharm Sci. 2000; 11:265–283. [PubMed: 11033070]3. Denny WA. Current Med Chem. 2006; 9:1655–1665.4. Sousa E, Paiva A, Nazareth N, Gales L, Damas AM, Nascimento MSJ, Pinto M. Eur J Med Chem.2009; 44:3830–3835. [PubMed: 19428155]5. Saraiva L, Fresco P, Pinto E, Sousa E, Pinto M, Goncalves J. Bioorg Med Chem. 2003; 11:1215–1225. [PubMed: 12628649]6. Mosmann T. J Immun Methods. 1983; 65:55–63.7. Reddy NS, Mallireddigari MR, Cosenza S, Gumireddy K, Bell SC, Reddy P, Reddy MVR. BioorgMed Chem Lett. 2004; 14:4093–4097. [PubMed: 15225733]8. Medina JC, Shan B, Beckmann H, Farrell RP, Clark DL, Learned RM, Roche D, Li A, Baichwal V,Case C, Baeuerle PA, Rosen T, Jaen JC. Bioorg Med Chem Lett. 1998; 8:2653–2656. [PubMed:9873597]9. Luo Y, Qiu K, Lu X, liu K, Fu J, Zhu H. Bioorg Med Chem. 2011; 19:4730–4738. [PubMed:21783370]10. Akbarzadeh T, Tabatabai SA, Khoshnoud MJ, Shafaghi B, Shafiee A. Bioorg Med Chem. 2003;11:769–773. [PubMed: 12538007]11. Kostakis IK, Pouli N, Marakos P, Skaltsounis A, Pratsinis H, Kletsas D. Bioorg Med Chem. 2006;14:2910–2934. [PubMed: 16376546]12. Okabayashi I, Iwata N. Chem Pharm Bull. 1980; 28:2831–2835.13. Anuchapreeda S, Thanarattanakorn P, Sittipreechacharn S, Tima S, Chanarat P, Limtrakul P. ArchPharm Res. 2006; 29:866–873. [PubMed: 17121181]14. Ling R, Yoshida M, Mariano PS. J Org Chem. 1996; 61:4439–4449. [PubMed: 11667350]15. Madalena P, Cerqueira F, Sousa ME, Nascimento MSJ, Pinto M. Bioorg Med Chem. 2002;10:3725–3730. [PubMed: 12413829]16. General procedure for the synthesis of substituted N-(9-oxo-9H-xanthen-4-yl)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 mixturewas stirred at room temperature. The progress of the reaction was monitored by TLC usingCH2Cl2 as a mobile phase. When compound 3 was consumed, the precipitate was filtered andpurified by column chromatography (silica gel) using CH2Cl2 as the eluent.Motavallizadeh et al. Page 4Tetrahedron Lett. Author manuscript; available in PMC 2015 January 08.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptFigure 1.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 DMSOthat has no compound (set at 100%). All the experiments were performed in triplicate (±SD).Motavallizadeh et al. Page 5Tetrahedron Lett. Author manuscript; available in PMC 2015 January 08.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 1.Reagents and conditions: (a) H2SO4, reflux, 30 min; (b) SnCl2, conc. HCl, 100 °C, 4 h thenNaOH 10%, RT, 30 min; (c) Et3N, CHCl3, RT.Motavallizadeh et al. Page 6Tetrahedron Lett. Author manuscript; available in PMC 2015 January 08.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptMotavallizadeh et al. Page 7Table 1Antiproliferative activity (IC 50, 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).CompoundsXYSK-N-MCIC50 (μM)MDA-MB-231IC50 (μM)T-47DIC50 (μM)5aHPenta F58.7±30.885±15.953.9±4.75bH3-Cl>100>10058.6±1.85cH4-Cl>10083.3±26.933.8±9.35dH2,5-di-Cl95.8±28>10053.3±4.55eH2,4,5-tri Cl78.5±6.460.4±17.236.3±9.25fH3-Cl,2-CH338.3±4.767.5±8.356.5±28.75gH4-Br47.9±20.785.4±24.763.4±9.85hH4-NO290.9±16.496.3±49.252.7±22.45iH4-OCH325.2±26.554.4±2119.7±0.186aClPenta F40.8±8.240.2±4.639±186bCl3-Cl40.5±28.359.5±3783.±5136cCl2,4,5-tri-Cl24.9±16.166.7±9.767.9±6.76dCl3-Cl,2-CH341.3±23.530.4±5.949.3±26.76eCl4-Br37.1±12.745.3±3.846.9±176fCl4-NO2>10063.1±20.776.1±1.66gCl4-OCH3>10062.3±0.245±11.3Etoposide--33.4±11.736.6±5.932.7±5.5Tetrahedron Lett. Author manuscript; available in PMC 2015 January 08.

Synthesis and Evaluation of Antiproliferative Activity of Substituted N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamides

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Synthesis and Evaluation of Antiproliferative Activity of Substituted N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamides

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