Anticancer Activity of Aminoacid Linked Novel 4-Methylumbelliferone Derivatives

Author(s): Manish Sinha*, Baljeet Kaur, Amandeep Kaur, Shruti Kuletha, Karanveer Singh, Rohit Bhatia

Journal Name: Current Bioactive Compounds

Volume 15 , Issue 1 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: Cancer is a disease of high mortality. The therapeutic agents currently available are insufficient to cure it and are associated with serious side effects. 4-methylumbelliferone is a natural product containing benzo-α-pyrones as a central nucleus. Benzo-α-pyrone is a privileged moiety having multifarious biological activities including anticancer activity. A series of compounds were synthesized taking 4-methylumbelliferone as a core nucleus and screened for their anticancer activity against HeLa cancer cell line.

Methods: The 4-methylumbelliferone was linked with aminoacids using chloroacetyl chloride or ethyl chloroacetate as linker. The N-methylmorpholine and isobutylchloroformate protocol was used for amidic coupling. The final compounds were tested against the HeLa cancer cell lines using SRB assay protocol.

Results: Three compounds have shown significant anticancer activity viz 9a, 12f and 15l having GI50 (µg/ml) value of, 56.1, 30.9 and 50.9, respectively. Other compound 9f and 13 showed weak anticancer activity having GI50 (µg/ml) value of 97.2 and 71.1, respectively.

Conclusion: It has been found that the synthesized derivatives have inhibitory effect on the growth of cancer cell line. Compound 12f has been found as the most active compound of the synthesized series.

Keywords: Umbelliferone, coumarin, anticancer, benzo-α-pyrone, aminoacid, aminobenzoic acids.

Bedoya, L.M.; Beltrán, M.; Sancho, R.; Olmedo, D.A.; Sánchez-Palomino, S.; del Olmo, E.; López-Pérez, J.L.; Muñoz, E.; San Feliciano, A.; Alcamí, J. 4-Phenylcoumarins as HIV transcription inhibitors. Bioorg. Med. Chem. Lett., 2005, 15(20), 4447-4450.
Lee, K.H. Current developments in the discovery and design of new drug candidates from plant natural product leads. J. Nat. Prod., 2004, 67(2), 273-283.
Thaisrivongs, S.; Tomich, P.K.; Watenpaugh, K.D.; Chong, K.T.; Howe, W.J.; Yang, C.P.; Strohbach, J.W.; Turner, S.R.; McGrath, J.P.; Bohanon, M.J. Structure-based design of HIV protease inhibitors: 4-hydroxycoumarins and 4-hydroxy-2-pyrones as non-peptidic inhibitors. J. Med. Chem., 1994, 37(20), 3200-3204.
Kirkiacharian, S.; Thuy, D.T.; Sicsic, S.; Bakhchinian, R.; Kurkjian, R.; Tonnaire, T. Structure-activity relationships of some 3-substituted-4-hydroxycoumarins as HIV-1 protease inhibitors. Farmaco, 2002, 57(9), 703-708.
Kidane, A.G.; Salacinski, H.; Tiwari, A.; Bruckdorfer, K.R.; Seifalian, A.M. Anticoagulant and antiplatelet agents: their clinical and device application(s) together with usages to engineer surfaces. Biomacromolecules, 2004, 5(3), 798-813.
Appendino, G.; Mercalli, E.; Fuzzati, N.; Arnoldi, L.; Stavri, M.; Gibbons, S.; Ballero, M.; Maxia, A. Antimycobacterial coumarins from the sardinian giant fennel (Ferula communis). J. Nat. Prod., 2004, 67(12), 2108-2110.
Khan, K.M.; Saify, Z.S.; Khan, M.Z. Zia-Ullah; Choudhary, I.M.; Atta-Ur-Rahman; Perveen, S.; Chohan, Z.H.; Supuran, C.T. Synthesis of coumarin derivatives with cytotoxic, antibacterial and antifungal activity. J. Enzyme Inhib. Med. Chem., 2004, 19(4), 373-379.
Ito, C.; Itoigawa, M.; Mishina, Y.; Filho, V.C.; Enjo, F.; Tokuda, H.; Nishino, H.; Furukawa, H. Chemical constituents of Calophyllum brasiliense. 2. Structure of three new coumarins and cancer chemopreventive activity of 4-substituted coumarins. J. Nat. Prod., 2003, 66(3), 368-371.
Lee, B.H.; Clothier, M.F.; Dutton, F.E.; Conder, G.A.; Johnson, S.S. Anthelmintic beta-hydroxyketoamides (BKAs). Bioorg. Med. Chem. Lett., 1998, 8(23), 3317-3320.
Kontogiorgis, C.A.; Hadjipavlou-Litina, D.J. Synthesis and antiinflammatory activity of coumarin derivatives. J. Med. Chem., 2005, 48(20), 6400-6408.
Ghate, M.; Manohar, D.; Kulkarni, V.; Shobha, R.; Kattimani, S.Y. Synthesis of vanillin ethers from 4-(bromomethyl) coumarins as anti-inflammatory agents. Eur. J. Med. Chem., 2003, 38(3), 297-302.
Silván, A.M.; Abad, M.J.; Bermejo, P.; Sollhuber, M.; Villar, A. Antiinflammatory activity of coumarins from santolina oblongifolia. J. Nat. Prod., 1996, 59(12), 1183-1185.
Nicolaides, D.N.; Fylaktakidou, K.C.; Litinas, K.E.; Hadjipavlou-Litina, D. Fluorine in heterocyclic chemistry. Eur. J. Med. Chem., 1998, 33(9), 715-724.
Raj, H.G.; Parmar, V.S.; Jain, S.C.; Goel, S. Poonam; Himanshu; Malhotra, S.; Singh, A.; Olsen, C.E.; Wengel, J. Mechanism of biochemical action of substituted 4-methylbenzopyran-2-ones. Part I: Dioxygenated 4-methyl coumarins as superb antioxidant and radical scavenging agents. Bioorg. Med. Chem., 1998, 6(6), 833-839.
Kontogiorgis, C.A.; Hadjipavlou-Litina, D.J. Synthesis and biological evaluation of novel coumarin derivatives with a 7-azomethine linkage. Bioorg. Med. Chem. Lett., 2004, 14(3), 611-614.
Barrett, G.C.; Elmore, D.T. Amino Acids and Peptides; Cambridge University Press: Cambridge, 2004.
Tiwari, D.; Haque, S.; Misra, S.; Chandra, R. Synthesis and pharmacological screening of N-substituted anthranilic acid derivatives. Int J. Drug Dev. Res., 2011, 3(2), 265-271.
Akberova, S.I.; Ershov, F.I.; Musaev Galbinur, P.I.; Tazulakhova, E.B.; Mamedova, V.M. Time course of interferon status of patients with herpetic keratitis during treatment with actipol, a new inteferon inducer. Vestn. Oftalmol., 2001, 117(1), 33-36.
Akberova, S.I. New biological properties of p-aminobenzoic acid. Izv. Akad. Nauk Ser. Biol., 2002, 4(4), 477-481.
Gichner, T.; Véleminský, J.; Rapoport, I.A.; Vasilieva, S.V. Antimutagenic effect of p-aminobenzoic acid on the mutagenicity of N-methyl-N'-nitro-N-nitrosoguanidine in Salmonella typhimurium. Mutat. Res., 1987, 192(2), 95-98.
Gichner, T.; Velemínský, J. Inhibitors of N-nitroso compounds-induced mutagenicity. Mutat. Res., 1988, 195(1), 21-43.
Ramaĭia, L.K.; Pomerantseva, M.D.; Malashenko, A.M. Effects of para-aminobenzoic acid on radiosensitivity of mice of different strains. Radiats. Biol. Radioecol., 2002, 42(2), 169-172.
Esposito, M.; Vannozzi, M.O.; Viale, M.; Fulco, R.A.; Collecchi, P.; Merlo, F.; De Cian, F.; Zicca, A.; Cadoni, A.; Poirier, M.C. Para-aminobenzoic acid suppression of cis-diamminedichloro-platinum(II) nephrotoxicity. Carcinogenesis, 1993, 14(12), 2595-2599.
Esposito, M.; Vannozzi, M.; Viale, M.; Pellecchia, C.; Civalleri, D.; Gogioso, L. Effect of para-aminobenzoic acid on the pharmacokinetics and urinary-excreation of cis-diamminedichloro- platinum(II) in rats. Anticancer Res., 1995, 15, 2541-2547.
Drozd, N.N.; Makarov, V.A.; Miftakhova, N.T.; Kalugin, S.A.; Stroeva, O.G.; Akberova, S.I. Antithrombotic activity of para-aminobenzoic acid. Eksp. Klin. Farmakol., 2000, 63(3), 40-44.
Richards, R.M.; Xing, D.K. Investigation of synergism between combinations of ciprofloxacin, polymyxin, sulphadiazine and p-aminobenzoic acid. J. Pharm. Pharmacol., 1993, 45(3), 171-175.
Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J.T.; Bokesch, H.; Kenney, S.; Boyd, M.R. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst., 1990, 82(13), 1107-1112.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 06 February, 2019
Page: [51 - 62]
Pages: 12
DOI: 10.2174/1573407213666170210143503
Price: $65

Article Metrics

PDF: 25