Novel Sulfonamide Derivatives Carrying a Biologically Active 3,4-Dimethoxyphenyl Moiety as VEGFR-2 Inhibitors
Date
2016
Journal Title
Journal ISSN
Volume Title
Type
Article
Publisher
Chemical and Pharmaceutical Bulletin
Series Info
Chem. Pharm. Bull.;Vol. 64, No. 12, 1747–1754
Doi
Scientific Journal Rankings
Abstract
Novel sulfonamides 3–19 with a biologically active 3,4-dimethoxyphenyl moiety were designed and
synthesized. The structures of the synthesized compounds were established using elemental analyses, IR,
1H-NMR, 13C-NMR spectral data and mass spectroscopy. All the synthesized compounds were evaluated
for their in vitro anticancer activity against four cancer cell lines, namely human hepatocellular carcinoma
(HepG2), human medulloblastoma (Daoy), human cervical cancer (HeLa), and human colon cancer (HT-29),
by using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and dasatinib as
the reference drug. Among the tested derivatives, compounds 4, 10, 16, and 19 showed good activity as cytotoxic
agents. The most active derivatives were evaluated for their ability to inhibit vascular endothelial
growth factor receptor (VEGFR)-2. Compounds Z-4-(3-(3,4-dimethoxyphenyl)-3-oxoprop-1-enylamino)-N-
(5-methyl-1,3,4-thiadiazol-2-yl)-benzenesulfonamide 10 and Z-4-(3-(3,4-dimethoxyphenyl)-3-oxoprop-1-
enylamino)-N-(1H-indazol-6-yl)-benzenesulfonamide 19 were more active as VEGFR-2 inhibitors than dasatinib.
Molecular docking of the most active derivatives on the active site of VEGFR-2 revealed that compound
19 exhibited favorable and promising results.
Description
Keywords
growth factor receptor, benzenesulfonamide, 3,4-dimethoxyphenyl; anticancer
Citation
1) Jemal A., Bray F., Center M. M., Ferlay J., Ward E. F. D., Forman D., Cancer J. Clin., 61, 69–90 (2011). 2) Thun M. J., DeLancey J. O., Center M. M., Jemal A., Ward E. M., Carcinogenesis, 31, 100–110 (2010). 3) Heffeter P., Jakupec M. A., Körner W., Wild S., von Keyserlingk N. G., Elbling L., Zorbas H., Korynevska A., Knasmüller S., Sutterlüty H., Micksche M., Keppler B. K., Berger W., Biochem. Pharmacol., 71, 426–440 (2006). 4) Zwick E., Bange J., Ullrich A., Endocr. Relat. Cancer, 8, 161–173 (2001). 5) Peng F.-W., Xuan J., Wu T.-T., Xue J.-Y., Ren Z.-W., Liu D.-K., Wang X.-Q., Chen X.-H., Zhang J.-W., Xu Y.-G., Shi L., Eur. J. Med. Chem., 109, 1–12 (2016). 6) Sun L., Tran N., Liang C., Tang F., Rice A., Schreck R., Waltz K., Shawver L. K., McMahon G., Tang C., J. Med. Chem., 42, 5120– 5130 (1999). 7) Kubo K., Shimizu T., Ohyama S., Murooka H., Iwai A., Nakamura K., Hasegawa K., Kobayashi Y., Takahashi N., Takahashi K., Kato S., Izawa T., Isoe T., J. Med. Chem., 48, 1359–1366 (2005). 8) Hennequin L. F., Stokes E. S. E., Thomas A. P., Johnstone C., Plé P. A., Ogilvie D. J., Dukes M., Wedge S. R., Kendrew J., Curwen J. O., J. Med. Chem., 45, 1300–1312 (2002). 9) Tripathy R., Reiboldt A., Messina P. A., Iqbal M., Singh J., Bacon E. R., Angeles T. S., Yang S. X., Albom M. S., Robinson C., Chang H., Ruggeri B. A., Mallamo J. P., Bioorg. Med. Chem. Lett., 16, 2158–2162 (2006). 10) Munchhof M. J., Beebe J. S., Casavant J. M., Cooper B. A., Doty J. L., Higdon R. C., Hillerman S. M., Soderstrom C. I., Knauth E. A., Marx M. A., Rossi A. M. K., Sobolov S. B., Sun J., Bioorg. Med. Chem. Lett., 14, 21–24 (2004). 11) Mendel D. B., Laird A. D., Smolich B. D., Blake R. A., Liang C., Hannah A. L., Shaheen R. M., Ellis L. M., Weitman S., Shawver L. K., Cherrington J. M., Anticancer Drug Des., 15, 29–41 (2000). 12) Scott R. W., Neville S. N., Urbina A., Camp D., Stankovic N., Org. Process Res. Dev., 10, 296–303 (2006). 13) Semenza G. L., N. Engl. J. Med., 358, 2066–2067 (2008). 14) Hicklin D. J., Ellis L. M., J. Clin. Oncol., 23, 1011–1027 (2005). 15) Ferrara N., Endocr. Rev., 25, 581–611 (2004). 16) Guo S., Colbert L. S., Fuller M., Zhang Y., Gonzalez-Perez R. R., Biochim. Biophys. Acta, 1806, 108–121 (2010). 17) Partanen T. A., Alitalo K., Miettinen M., Cancer, 86, 2406–2412 (1999). 18) Folkman J., N. Engl. J. Med., 285, 1182–1186 (1971). 19) Jain R. K., Duda D. G., Willett C. G., Sahani D. V., Zhu A. X., Loeffler J. S., Batchelor T. T., Sorensen A. G., Nat. Rev. Clin. Oncol., 6, 327–338 (2009). 20) Baka S., Clamp A. R., Jayson G. C., Expert Opin. Ther. Targets, 10, 867–876 (2006). 21) Gupta K., Zhang J., Postgrad. Med. J., 81, 236–242 (2005). 22) Sternberg C. N., Davis I. D., Mardiak J., Szczylik C., Lee E., Wagstaff J., Barrios C. H., Salman P., Gladkov O. A., Kavina A., Zarbá J. J., Chen M., McCann L., Pandite L., Roychowdhury D. F., Hawkins R. E., J. Clin. Oncol., 28, 1061–1068 (2010). 23) van der Graaf W. T., Blay J.-Y., Chawla S. P., Kim D.-W., Bui- Nguyen B., Casali P. G., Schöffski P., Aglietta M., Staddon A. P., Beppu Y., Le Cesne A., Gelderblom H., Judson I. R., Araki N., Ouali M., Marreaud S., Hodge R., Dewji M. R., Coens C., Demetri G. D., Fletcher C. D., Dei Tos A. P., Hohenberger P.; EORTC Soft Tissue and Bone Sarcoma Group, PALETTE study group, Lancet, 379, 1879–1886 (2012). 24) Bukowski R. M., Yasothan U., Kirkpatrick P., Nat. Rev. Drug Discov., 9, 17–18 (2010). 25) Fukuoka K., Usuda J., Iwamoto Y., Fukumoto H., Nakamura T., Yoneda T., Narita N., Saijo N., Nishio K., Invest. New Drugs, 19, 219–227 (2001). 26) Supuran C. T., Scozzafava A., Expert Opin. Ther. Pat., 10, 575–600 (2000). 27) Payne J. E., Bonnefous C., Hassig C. A., Symons K. T., Guo X., Nguyen P.-M., Annable T., Wash P. L., Hoffman T. Z., Rao T. S., Shiau A. K., Malecha J. W., Noble S. A., Hager J. H., Smith N. D., Bioorg. Med. Chem. Lett., 18, 6093–6096 (2008). 28) Kawai M., BaMaung N. Y., Fidanze S. D., Erickson S. A., Tedrow J. S., Sanders W. J., Vasudevan A., Park C., Hutchins C., Comess K. M., Kalvin D., Wang J., Zhang Q., Lou P., Tucker-Garcia L., Bouska J., Bell R. L., Lesniewski R., Henkin J., Sheppard G. S., Bioorg. Med. Chem. Lett., 16, 3574–3577 (2006). 29) Supuran C. T., Scozzafava A., Expert Opin. Ther. Pat., 12, 217–242 (2002). 30) Villar R., Encio I., Migliaccio M., Gil M. J., Martinez-Merino V., Bioorg. Med. Chem., 12, 963–968 (2004). 31) Huang S., Connolly P. J., Lin R., Emanuel S., Middleton S. A., Bioorg. Med. Chem. Lett., 16, 3639–3641 (2006). 32) Hande K. R., Hagey A., Berlin J., Cai Y., Meek K., Kobayashi H., Lockhart A. C., Medina D., Sosman J., Gordon G. B., Rothenberg M. L., Clin. Cancer Res., 12, 2834–2840 (2006). 33) Nakamura K., Yamamoto A., Kamishohara M., Takahashi K., Taguchi E., Miura T., Kubo K., Shibuya M., Isoe T., Mol. Cancer Ther., 3, 1639–1649 (2004). 34) Al-Dosari M. S., Ghorab M. M., Al-Said M. S., Nissan Y. M., Chem. Pharm. Bull., 61, 50–58 (2013). 35) Al-Said M. S., Ghorab M. M., Nissan Y. M., Chem. Cent. J., 6, 64 (2012). 36) Ghorab M. M., Ragab F. A., Heiba H. I., Agha H. M., Nissan Y. M., Arch. Pharm. Res., 35, 59–68 (2012). 37) Al-Dosari M. S., Ghorab M. M., Alsaid M. S., Nissan Y. M., Ahmed A. B., Eur. J. Med. Chem., 69, 373–383 (2013). 38) Ghorab M. M., Ceruso M., Alsaid M. S., Nissan Y. M., Arafa R. K., Supuran C. T., Eur. J. Med. Chem., 87, 186–196 (2014). 39) Ghorab M. M., Alsaid M. S., Ceruso M., Nissan Y. M., Supuran C. T., Bioorg. Med. Chem., 22, 3684–3695 (2014). 40) Ghorab M. M., Alsaisd M. S., Nissan Y. M., Acta Pol. Pharm., 72, 65–78 (2015). 41) Ghorab M. M., Alsaid M. S., Al-Dosari M. S., Nissan Y. M., Al- Mishari A. A., Chem. Cent. J., 10, 18 (2016). 42) Wan J.-P., Cao S., Liu Y., J. Org. Chem., 80, 9028–9033 (2015). 43) Al-Salahi M. M. R., Ashour A. E., Alswaidan I., Asian J. Chem., 26, 2173–2176 (2014). 44) Lombardo L. J., Lee F. Y., Chen P., Norris D., Barrish J. C., Behnia K., Castaneda S., Cornelius L. A. M., Das J., Doweyko A. M., Fairchild C., Hunt J. T., Inigo I., Johnston K., Kamath A., Kan D., Klei H., Marathe P., Pang S., Peterson R., Pitt S., Schieven G. L., Schmidt R. J., Tokarski J., Wen M.-L., Wityak J., Borzilleri R. M., J. Med. Chem., 47, 6658–6661 (2004). 45) Biovendor kit. Human VEGF-R2/KDR ELISA. Cat. No.: RBMS2019R