Searching for new cytotoxic agents based on chromen-4-one and chromane-2,4-dione scaffolds

Alexandra Gaspar , Maryam Mohabbati, Fernando Cagide, Nima Razzaghi-Asl, Ramin Miri, Omidreza Firuzi , Fernanda Borges

Abstract


Cancer is a major cause of death worldwide and novel anticancer agents for its better management are much needed. Benzopyrone-based compounds, such as chromones, possess several distinctive chemical and biological properties, of which the cytotoxicity against cancer cells seems to be prominent. In this study, two series of compounds based on chromen-4-one (3-10) and chromane-2,4-dione (11-18) scaffolds were synthesized in moderate/high yields and evaluated for cytotoxicity against HL-60, MOLT-4, and MCF-7 cancer cells using MTT assay. In general, the compounds exhibited moderate cytotoxic effects against the cancer cell lines, among which, a superior potency could be observed against MOLT-4 cells. Chroman-2,4-dione (11-18) derivatives had overall higher potencies compared to their chromen-4-one (3-10) counterparts. Compound 13 displayed the lowest IC50 values against HL-60 (IC50, 42.0 ± 2.7 µM) and MOLT-4 cell lines (IC50, 24.4 ± 2.6 µM), while derivative 11 showed the highest activity against MCF-7 cells (IC50, 68.4 ± 3.9 µM). In conclusion, this study provides important information on the cytotoxic effects of chromone derivatives. Benzochroman-2,4-dione has been identified as a promising scaffold, which its potency can be modulated by tailored synthesis with the aim of finding novel and dissimilar anticancer compounds.

 


Keywords


Antineoplastic agents; Cancer; Chromones; Drug screening.

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Borges F, Roleira F, Milhazes N, Santana L, Uriarte E. Simple coumarins and analogues in medicinal chemistry: occurrence, synthesis and biological activity. Curr Med Chem. 2005;12(8):887-916.

Lee T, Gong YD. Solid-phase parallel synthesis of drug-like artificial 2H-benzopyran libraries. Molecules. 2012;17(5):5467-5496.

Gaspar A, Matos MJ, Garrido J, Uriarte E, Borges F. Chromone: a valid scaffold in medicinal chemistry. Chem Rev. 2014;114(9):4960-4992.

Gomes LR, Low JN, Cagide F, Gaspar A, Reis J, Borges F. Structural characterization of some N-phenyl-4-oxo-4H-2-chromone carboxamides. Acta Crystallogr B Struct Sci Cryst Eng Mater. 2013;69(Pt 3):294-309.

Kim MK, Yoon H, Barnard DL, Chong Y. Design, synthesis and antiviral activity of 2-(3-amino-4-piperazinylphenyl) chromone derivatives. Chem Pharm Bull. 2013;61(4):486-488.

Raj T, Bhatia RK, Sharma RK, Gupta V, Sharma D, Ishar MP. Mechanism of unusual formation of 3-(5-phenyl-3H-[1,2,4]dithiazol-3-yl)chromen-4-ones and 4-oxo-4Hchromene-3-carbothioic acid N-phenylamides and their antimicrobial evaluation. Eur J Med Chem. 2009;44(8):3209-3216.

Ishar MP, Singh G, Singh S, Sreenivasan KK, Singh G. Design, synthesis, and evaluation of novel 6-chloro-/fluorochromone derivatives as potential topoisomerase inhibitor anticancer agents. Bioorg Med Chem Lett. 2006;16(5):1366-1370.

Nam DH, Lee KY, Moon CS, Lee YS. Synthesis and anticancer activity of chromone-based analogs of lavendustin A. Eur J Med Chem. 2010;45(9): 4288-4292.

Kim SH, Lee YH, Jung SY, Kim HJ, Jin C, Lee YS. Synthesis of chromone carboxamide derivatives with antioxidative and calpain inhibitory properties. Eur J Med Chem. 2011;46(5):1721-1728.

Shaveta, Singh A, Kaur M, Sharma S, Bhatti R, Singh P. Rational design, synthesis and evaluation of chromone-indole and chromone-pyrazole based conjugates: Identification of a lead for antiinflammatory drug. Eur J Med Chem. 2014;77:185-192.

Alcaro S, Gaspar A, Ortuso F, Milhazes N, Orallo F, Uriarte E, et al. Chromone-2- and -3-carboxylic acids inhibit differently monoamine oxidases A and B. Bioorg Med Chem Lett. 2010;20(9): 2709-2712.

Gaspar A, Reis J, Fonseca A, Milhazes N, Viña D, Uriarte E, et al. Chromone 3-phenylcarboxamides as potent and selective MAO-B inhibitors. Bioorg Med Chem Lett. 2011;21(2):707-709.

Cagide F, Silva T, Reis J, Gaspar A, Borges F, Gomes LR, et al. Discovery of two new classes of potent monoamine oxidase-B inhibitors by tricky chemistry. Chem. Commun. 2015;51(14): 2832-2835.

Cagide F, Gaspar A, Reis J, Chavarria D, Vilar S, Hripcsak G, et al. Navigating in chromone chemical space: discovery of novel and distinct A3 adenosine receptor ligands. RSC Advances. 2015;5:78572-78585.

Gaspar A, Reis J, Kachler S, Paoletta S, Uriarte E, Klotz KN, et al. Discovery of novel A3 adenosine receptor ligands based on chromone scaffold. Biochem Pharmacol. 2012;84(1):21-29.

Stankovic´ N, Mladenovic´ M, Matic´ S, Stanic´ S, Stankovic´ V, Mihailovic´ M, et al. Serum albumin binding analysis and toxicological screening of novel chroman-2,4-diones as oral anticoagulants. Chem Biol Interact. 2015;227:18-31.

Ravichandran S, SubramanI K, Arunkumar R. Synthesis of some chromene derivatives. Int J ChemTech Res. 2009;1(2):329-331.

Keri RS, Budagumpi S, Pai RK, Balakrishna RG. Chromones as a privileged scaffold in drug discovery: a review. Eur J Med Chem. 2014; 78:340-374.

Narang AS, Desai D. Anticancer Drug Development. In: Lu Y, Mahato RI, editors. Pharmaceutical Perspectives of Cancer Therapeutics. New York: Springer; 2009. pp. 49-50.

Noushini S, Alipour E, Emami S, Safavi M, Kabudanian Ardestani S, Gohari AR, et al. Synthesis and cytotoxic properties of novel (E)-3-benzylidene-7-methoxychroman-4-one derivatives. DARU J Pharm Sci. 2013;21:31-40.

Kawase M, Tanaka T, Kan H, Tani S, Nakashima H, Sakagami H. Biological activity of 3-formylchromones and related compounds. In Vivo. 2007;21(5):829-834.

Kanagalakshmi K, Premanathan M, Priyanka R, Hemalatha B, Vanangamudi A. Synthesis, anticancer and antioxidant activities of 7-methoxyisoflavanone and 2,3-diarylchromanones. Eur J Med Chem. 2010;45(6):2447-2452.

Lee J, Park T, Jeong S, Kimb KH, Hong C. 3-Hydroxychromones as cyclindependent kinase inhibitors: synthesis and biological evaluation. Bioorg Med Chem Lett. 2007;17(5):1284-1287.

Raju BC, Rao RN, Suman P, Yogeeswari P, Sriram D, Shaik TB, et al. Synthesis, structure-activity relationship of novel substituted 4H-chromen-1,2,3,4-tetrahydropyrimidine-5-carboxylates as potential anti-mycobacterial and anticancer agents. Bioorg Med Chem Lett. 2011;21(10):2855-2859.

Zwergel C, Valente S, Salvato A, Xu Z, Talhi O, Mai A, et al. Novel benzofuran-chromone and -coumarin derivatives: synthesis and biological activity in K562 human leukemia cells. Medchemcommun. 2013;4(12):1571-1579.

Ili DR, Jevti VV, Radi GP, Arsikin K, Risti B, Harhaji-Trajkovi L, et al. Synthesis, characterization and cytotoxicity of a new palladium(II) complex with a coumarine-derived ligand. Eur J Med Chem. 2014;74:502-508.

Dolatkhah Z, Javanshir S, Sadr AS, Hosseini J, Sardari S. Synthesis, molecular docking, molecular dynamics studies, and biological evaluation of 4H-chromone-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives as potential antileukemic agents. J Chem Inf Model. 2017;57(6):1246-1257.

Amin KM, Syam YM, Anwar MM, Ali HI, Abdel-Ghani TM, Serry AM. Synthesis and molecular docking study of new benzofuran and furo[3,2-g]chromone-based cytotoxic agents against breast cancer and p38alpha MAP kinase inhibitors. Bioorg Chem. 2018;76:487-500.

Awadallah FM, El-Waei TA, Hanna MM, Abbas SE, Ceruso M, Oz BE, et al. Synthesis, carbonic anhydrase inhibition and cytotoxic activity of novel chromone-based sulfonamide derivatives. Eur J Med Chem. 2015;96:425-435.

Miri R, Firuzi O, Peymani P, Nazarian Z, Shafiee A. Synthesis and cytotoxicity study of new cyclopenta [b]quinoline-1,8-dione derivatives. Iran J Pharm Res. 2011;10(3):489-496.

Sarkarzadeh H, Miri R, Firuzi O, Amini M, Razzaghi-Asl N, Edraki N, et al. Synthesis and antiproliferative activity evaluation of imidazole-based indeno[1,2-b]quinoline-9,11-dione derivatives. Arch Pharm Res. 2013;36(4):436-447.

Mohammadi MK, Firuzi O, Khoshneviszadeh M, Razzaghi-Asl N, Sepehri S, Miri R. Novel 9-(alkylthio)-Acenaphtho[1,2-e]-1,2,4-triazine derivatives: synthesis, cytotoxic activity and molecular docking studies on B-cell lymphoma 2 (Bcl-2). DARU. 2014;22(1):2-11.

Ranjbar S, Edraki N, Khoshneviszadeh M, Foroumadi A, Miri R, Khoshneviszadeh M. Design, synthesis, cytotoxicity evaluation and docking studies of 1,2,4-triazine derivatives bearing different arylidene-hydrazinyl moieties as potential mTOR inhibitors. Res Pharm Sci. 2018;13(1):1-11.

Haghighijoo Z, Rezaei Z, Jaberipoor M, Taheri S, Jani M, Khabnadideh S. Structure based design and anti-breast cancer evaluation of some novel 4-anilinoquinazoline derivatives as potential epidermal growth factor receptor inhibitors. Res Pharm Sci. 2018;13(4):360-367.

Rusiecki V, Warne S. Synthesis of Nα-Fmoc-Nε-Nvoc-Lysine and use in the preparation of selectively functionalized peptides. Bioorganic Med Chem Lett. 1993;3(4):707-710.

Gaspar A, Silva T, Yáñez M, Vina D, Orallo F, Ortuso F, et al. Chromone, a privileged scaffold for the development of monoamine oxidase inhibitors. J Med Chem. 2011;54(14): 5165-5173.

Cagide F, Borges F, Gomes L, Low J. Synthesis and characterisation of new 4-oxo-N-(substituted-thiazol-2-yl)-4H-chromene-2-carboxamides as potential adenosine receptor ligands. J Mol Struct. 2015;1089:206-215.


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