Synthesis of New Chromen-5-one Derivatives from Dimedone and their Antiproliferative Evaluations against Selected Cancer Cell Lines Together with Hepatocellular Carcinoma and Cervical Carcinoma


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Abstract

Background:The coumarin nuclei, which exist in many heterocyclic compounds, has gained a lot of attention over the past decade due to their wide range of biological activities such as antibacterial, anticoagulant, antiviral, antifungal, anticancer, and anti-inflammatory properties.

Objective:The multi-component reactions of 5,5-dimethylcyclohexane-1,3-dione with acetophenone derivatives and triethoxymethane produced biologically active target chromene molecules and their fused derivatives.

Methods:The reaction of 5,5-dimethylcyclohexane-1,3-dione and each of triethoxymethane and acetophenone derivatives 3a-g in absolute ethanol containing triethylamine gave the 4,6,7,8-tetrahydro-5H-chromen-5-one derivatives 4a-g. Compounds 4a-d were used for further heterocyclization reactions to produce biologically active fused pyrazole, thiophene, and thiazole derivative corporate with the chromenes caffold.

Results:The cytotoxicity of the synthesized compounds were evaluated using six cancer cell lines together with c-Met kinase and PC-3 cell line inhibitions. In addition, cytotoxicity toward hepatocellular carcinoma HepG2 and cervical carcinoma HeLa was carried out as well as the in-vitro cytotoxic potential for all compounds against peripheral blood lymphocytes (PBL) extracted from healthy donors. Morphological changes of the A549 cell line by the two most active compounds were also studied.

Conclusion:The synthesized heterocyclic compounds were originally obtained from 5,5-dimethylcyclohexane- 1,3-dione. Several of the produced compounds exhibited high inhibitions toward several cancer cell lines proving high inhibitions, therefore, encouraging further studies to synthesize heterocyclic compounds based on chromene scaffold.

About the authors

Rafat Mohareb

Department of chemistry, Faculty of Science, Cairo University

Author for correspondence.
Email: info@benthamscience.net

Mahmoud Abdelaziz

Department of Chemistry, Faculty of Science, University of Tabuk

Email: info@benthamscience.net

Rasha Jame

Department of Chemistry, Faculty of Science, University of Tabuk

Email: info@benthamscience.net

Noha Omer

Department of Chemistry, Faculty of Science, University of Tabuk

Email: info@benthamscience.net

Hanan Labib

Department of chemistry, Faculty of Science, Cairo University

Email: info@benthamscience.net

References

  1. Noureen, S.; Ali, S.; Iqbal, J.; Zia, M.A.; Hussain, T. Synthesis, comparative theoretical and experimental characterization of some new 1,3,5 triazine based heterocyclic compounds and in vitro evaluation as promising biologically active agents. J. Mol. Struct., 2022, 1268, 133622. doi: 10.1016/j.molstruc.2022.133622
  2. Fetouh, H.A.; Ismail, A.M.; Hamid, H.A.; Bashier, M.O. Synthesis of promising nanocomposites from an antitumer and biologically active heterocyclic compound uploaded by clay and chitosan polymers. Int. J. Biol. Macromol., 2019, 137, 1211-1220. doi: 10.1016/j.ijbiomac.2019.06.187 PMID: 31254576
  3. Nguyen, H.D.; Kim, M.S. Identification of promising inhibitory heterocyclic compounds against acetylcholinesterase using QSAR, ADMET, biological activity, and molecular docking. Comput. Biol. Chem., 2023, 104, 107872. doi: 10.1016/j.compbiolchem.2023.107872 PMID: 37119698
  4. Sallam, E.R.; Aboulnaga, S.F.; Samy, A.M.; Beltagy, D.M.; El Desouky, J.M.; Abdel-Hamid, H.; Fetouh, H.A. Synthesis, characterization of new heterocyclic compound: pyrazolyl hydrazino quinoxaline derivative: 3-5-(hydroxy1methyl)-1-phenylpyrazol-3-yl-2-2, 4, 5-trimethoxybenzylidine hydrazonyl-quinoxaline of potent antimicrobial, antioxidant, antiviral, and antitumor activity. J. Mol. Struct., 2023, 1271, 133983. doi: 10.1016/j.molstruc.2022.133983
  5. Negi, M.; Chawla, P.A.; Faruk, A.; Chawla, V. Role of heterocyclic compounds in SARS and SARS CoV-2 pandemic. Bioorg. Chem., 2020, 104, 104315. doi: 10.1016/j.bioorg.2020.104315 PMID: 33007742
  6. Raza, M.A.; Farwa, U.; Ishaque, F.; Al-Sehemi, A.G. Designing of thiazolidinones against chicken pox, monkey pox, and hepatitis viruses: A computational approach. Comput. Biol. Chem., 2023, 103, 107827. doi: 10.1016/j.compbiolchem PMID: 36805155
  7. Deng, X.; Luo, T.; Zhang, X.; Li, Y.; Xie, L.; Jiang, W.; Liu, L.; Wang, Z. Design, synthesis and biological evaluation of 3-arylisoquinoline derivatives as topoisomerase I and II dual inhibitors for the therapy of liver cancer. Eur. J. Med. Chem., 2022, 237, 114376. doi: 10.1016/j.ejmech.2022.114376 PMID: 35462164
  8. Mahurkar, N.D.; Gawhale, N.; Lokhande, M.N.; Uke, S.J.; Kodape, M.M. Benzimidazole: A versatile scaffold for drug discovery and beyond – A comprehensive review of synthetic approaches and recent advancements in medicinal chemistry. Results Chem., 2023, 6, 101139. doi: 10.1016/j.rechem.2023.101139
  9. Talele, T.T.; Arora, P.; Kulkarni, S.S.; Patel, M.R.; Singh, S.; Chudayeu, M.; Kaushik-Basu, N. Structure-based virtual screening, synthesis and SAR of novel inhibitors of hepatitis C virus NS5B polymerase. Bioorg. Med. Chem., 2010, 18(13), 4630-4638. doi: 10.1016/j.bmc.2010.05.030 PMID: 20627595
  10. Smith, H.M. Sir William Henry Perkin. Torchbearers Chem., 1949, 196, 1838-1907. doi: 10.1016/B978-1-4831-9805-7.50192-4
  11. Mariappan, P.; Kiran, K.R.; Swathy, P.S.; Kaniyassery, A.; Thorat, S.A.; Bhagyashree, P.; Thiruvengadam, M.; Muthusamy, A. Sacred groves and nakshatravan trees - A comparative analysis for their medicinal properties and volatile compounds for human health. S. Afr. J. Bot., 2022, 151, 623-638. doi: 10.1016/j.sajb.2022.08.029
  12. Santos, Jr C.M.; Silva, S.M.C.; Sales, E.M.; Velozo, E.D.S.; Dos Santos, E.K.P.; Canuto, G.A.B.; Azeredo, F.J.; Barros, T.F.; Biegelmeyer, R. Coumarins from Rutaceae: Chemical diversity and biological activities. Fitoterapia, 2023, 168, 105489. doi: 10.1016/j.fitote.2023.105489 PMID: 36990289
  13. Vuai, S.A.H.; Khalfan, M.S.; Babu, N.S. DFT and TD-DFT studies for optoelectronic properties of coumarin based donor-π-acceptor (D-π-A) dyes: Applications in dye-sensitized solar cells (DSSCS). Heliyon, 2021, 7(11), e08339. doi: 10.1016/j.heliyon.2021.e08339 PMID: 34816038
  14. Mavazzan, A.; Kamble, R.R.; Mendhe, A.; Sankapal, B.R.; Bayannavar, P.K.; Madar, S.F.; Metre, T.V.; Pasha, K.M.M.; Kodasi, B.; Nadoni, V.B. Synthesis of phenothiazine dyes featuring coumarin unit and CdS NWs as photoanodes for efficient dye-sensitized solar cells. Physica B, 2023, 668, 415253. doi: 10.1016/j.physb.2023.415253
  15. Mandal, S.; Kandregula, G.R. A computational finding on the effect of π-conjugated acceptors in thiophene-linked coumarin dyes for potential suitability in DSSC application. J. Photochem. Photobiol. Chem., 2023, 435-, 1232, 114300. doi: 10.1016/j.jphotochem.2022.114300
  16. Ramasamy, A.K.; Rajamanickam, G.; Bangaru, S.; Perumalsamy, R. The significance of methoxy substitution and π-spacer arrangements on carbazole donor and furofuran π-spacer based promising sensitizers for dye sensitized solar cells. Comput. Theor. Chem., 2024, 114468. doi: 10.1016/j.comptc.2024.114468
  17. Yahya, M.; Bouziani, A.; Ocak, C.; Seferoğlu, Z.; Sillanpää, M. Organic/metal-organic photosensitizers for dye-sensitized solar cells (DSSC): Recent developments, new trends, and future perceptions. Dyes Pigments, 2021, 192, 109227. doi: 10.1016/j.dyepig.2021.109227
  18. Souilah, M.; Hachi, M.; Fitri, A.; Benjelloun, A.T.; Benzakour, M.; Mcharfi, M.; Zgou, H. Efficient tuning of various coumarin based donor dyes with diketopyrrolopyrrole by forming D-A′-π-A structure for high-efficiency solar cells: A DFT/TD-DFT study. Chem. Data Collect., 2023, 45, 101017. doi: 10.1016/j.cdc.2023.101017
  19. Torres, E.; Sequeira, S.; Parreira, P.; Mendes, P.; Silva, T.; Lobato, K.; Brites, M.J. Coumarin dye with ethynyl group as π-spacer unit for dye sensitized solar cells. J. Photochem. Photobiol. Chem., 2015, 310, 1-8. doi: 10.1016/j.jphotochem.2015.05.017
  20. Martins, S.; Avó, J.; Lima, J.; Nogueira, J.; Andrade, L.; Mendes, A.; Pereira, A.; Branco, P.S. Styryl and phenylethynyl based coumarin chromophores for dye sensitized solar cells. J. Photochem. Phtobiol. A: Chemistry, 2018, 353, 564-569. doi: 10.1016/j.jphotochem.2017.12.018
  21. Maikhuri, V.K.; Verma, V.; Mathur, D.; Prasad, A.K.; Khatri, V. Synthesis of substituted 2H-Chromenes via Pd-catalyzed C-H activation and thermal cyclization. Carbohydr. Res., 2024, 536, 109018. doi: 10.1016/j.carres.2023.109018 PMID: 38185030
  22. Dash, A.K.; Mukherjee, D.; Dhulap, A.; Haider, S.; Kumar, D. Green chemistry appended synthesis, metabolic stability and pharmacokinetic assessment of medicinally important chromene dihydropyrimidinones. Bioorg. Med. Chem. Lett., 2019, 29(24), 126750. doi: 10.1016/j.bmcl.2019.126750 PMID: 31699608
  23. Ostadzadeh, H.; Kiyani, H. Multicomponent synthesis of tetrahydrobenzobpyrans, pyrano2,3-dpyrimidines, and dihydropyrano3,2-cchromenes catalyzed by sodium benzoate. Polycycl. Aromat. Compd., 2023. Available online. doi: 10.1080/10406638.2022.2162091
  24. Elinson, M.N.; Vereshchagin, A.N.; Ryzhkova, Y.E.; Karpenko, K.A.; Ryzhkov, F.V.; Egorov, M.P. Electrocatalytic cascade selective approach to 3-aryl-2‘H,3H,4H-spiro{Furo2,3-cchromene-2,5’-pyrimidine}-2′,4,4′,6‘(1’H,3'H)tetraones and its automatic screening docking studies. Polycycl. Aromat. Compd., 2022, 8356-8370. doi: 10.1080/10406638.2022.2149568
  25. Li, Y.; Luo, Z.; Zhou, A.; Liu, W.; Fan, J.; Miao, J.; Guo, B.; Tang, L.; Fan, L. Design and synthesis of novel benzoxazole/chromene-phthalide scaffolds hybrids as potential natural products-based fungicide. Nat. Prod. Res., 2024, 38(14), 2441-2446. doi: 10.1080/14786419.2023.2177993 PMID: 36762769
  26. Huang, J.H.; Lv, J.M.; Xie, Y.F.; Zhao, H.; Xiao, L.Y.; Dai, P.; Qin, S.Y.; Hu, D.; Gao, H.; Yao, X.S. Isolation of new compounds related to xyloketals biosynthesis implies an alternative pathway for furan-fused-chromene formation. Org. Biomol. Chem., 2023, 21(20), 4309-4318. PMID: 37171256
  27. Mohareb, R.M.; Mostafa, B.M. Uses of ethyl benzoylacetate for the synthesis of thiophene, thiazole, pyridine, and pyran derivatives with antitumor activities. J. Heterocycl. Chem., 2020, 57, 1275-1290. doi: 10.1002/jhet.3865
  28. Abdel-Galil, E.; Moawad, E.B.; El-Mekabaty, A.; Said, G.E. Synthesis, characterization and antibacterial activity of some new thiazole and thiazolidinone derivatives containing phenyl benzoate moiety. Synth. Commun., 2018, 48, 2083-2092. doi: 10.1080/00397911.2018.1482349
  29. Mohareb, R.M.; Al-Omran, F.; Azzam, R.A. Heterocyclic ring extension of estrone: synthesis and cytotoxicity of fused pyran, pyrimidine and thiazole derivatives. Steroids, 2014, 84, 46-56. doi: 10.1016/j.steroids.2014.03.012 PMID: 24686206
  30. Mohareb, R.M.; Zaki, M.Y.; Abbas, N.S. Synthesis, anti-inflammatory and anti-ulcer evaluations of thiazole, thiophene, pyridine and pyran derivatives derived from androstenedione. Steroids, 2015, 98, 80-91. doi: 10.1016/j.steroids.2015.03.001 PMID: 25759119
  31. Peach, M.L.; Tan, N.; Choyke, S.J.; Giubellino, A.; Athauda, G.; Burke, T.R., Jr; Nicklaus, M.C.; Bottaro, D.P.; Bottaro, D.P. Directed discovery of agents targeting the Met tyrosine kinase domain by virtual screening. J. Med. Chem., 2009, 52(4), 943-951. doi: 10.1021/jm800791f PMID: 19199650
  32. Bacco, F.D.; Luraghi, P.; Medico, E.; Reato, G.; Girolami, F.; Perera, T.; Gabriele, P.; Comoglio, P.M.; Boccaccio, C. J. Natl. Cancer Inst., 2011, 103, 645-661. PMID: 21464397
  33. Rubin, J.S.; Bottaro, D.P.; Aaronson, S.A. Hepatocyte growth factor/scatter factor and its receptor, the c-met proto-oncogene product. Biochim. Biophys. Acta, 1993, 1155(3), 357-371. doi: 10.1016/0304-419x(93)90015-5 PMID: 8268192
  34. Organ, S.L.; Tsao, M.S. An overview of the c-MET signaling pathway. Ther. Adv. Med. Oncol., 2011, 3(1)(Suppl.), S7-S19. doi: 10.1177/1758834011422556 PMID: 22128289
  35. Jeffers, M.; Rong, S.; Vande Woude, G.F. Hepatocyte growth factor/scatter factor-Met signaling in tumorigenicity and invasion/metastasis. J. Mol. Med. (Berl.), 1996, 74(9), 505-513. doi: 10.1007/BF00204976 PMID: 8892055
  36. Knudsen, B.S.; Gmyrek, G.A.; Inra, J.; Scherr, D.S.; Vaughan, E.D.; Nanus, D.M.; Kattan, M.W.; Gerald, W.L.; Vande, W.G.F. High expression of the Met receptor in prostate cancer metastasis to bone. Urology, 2002, 60(6), 1113-1117. doi: 10.1016/S0090-4295(02)01954-4 PMID: 12475693
  37. Humphrey, P.A.; Zhu, X.; Zarnegar, R.; Swanson, P.E.; Ratliff, T.L.; Vollmer, R.T.; Day, M.L. Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. Am. J. Pathol., 1995, 147(2), 386-396. PMID: 7639332
  38. Verras, M.; Lee, J.; Xue, H.; Li, T.H.; Wang, Y.; Sun, Z. The androgen receptor negatively regulates the expression of c-Met: implications for a novel mechanism of prostate cancer progression. Cancer Res., 2007, 67(3), 967-975. doi: 10.1158/0008-5472.CAN-06-3552 PMID: 17283128
  39. De Bacco, F.; Luraghi, P.; Medico, E.; Reato, G.; Girolami, F.; Perera, T.; Gabriele, P.; Comoglio, P.M.; Boccaccio, C. Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer. J. Natl. Cancer Inst., 2011, 103(8), 645-661. doi: 10.1093/jnci/djr093 PMID: 21464397
  40. Li, S.; Zhao, Y.; Wang, K.; Gao, Y.; Han, J.; Cui, B.; Gong, P. Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors. Bioorg. Med. Chem., 2013, 21(11), 2843-2855. doi: 10.1016/j.bmc.2013.04.013 PMID: 23628470
  41. Karagülle, O.O.; Yurttaş, A.G. Synergistic effects of ozone with doxorubicin on the proliferation, apoptosis and metastatic profile of luminal-B type human breast cancer cell line. Tissue Cell, 2023, 85, 102233. doi: 10.1016/j.tice.2023.102233 PMID: 37866151
  42. Saharkhiz, S.; Zarepour, A.; Nasri, N.; Cordani, M.; Zarrabi, A. A comparison study between doxorubicin and curcumin co-administration and co-loading in a smart niosomal formulation for MCF-7 breast cancer therapy. Eur. J. Pharm. Sci., 2023, 191, 106600. doi: 10.1016/j.ejps.2023.106600 PMID: 37802230
  43. Saharkhiz, S.; Zarepour, A.; Zarrabi, A. A new theranostic pH-responsive niosome formulation for doxorubicin delivery and bio-imaging against breast cancer. Int. J. Pharm., 2023, 637, 122845. doi: 10.1016/j.ijpharm.2023.122845 PMID: 36958608
  44. Han, X.; Alu, A.; Liu, H.; Shi, Y.; Wei, X.; Cai, L.; Wei, Y. Biomaterial-assisted biotherapy: A brief review of biomaterials used in drug delivery, vaccine development, gene therapy, and stem cell therapy. Bioact. Mater., 2022, 17, 29-48. doi: 10.1016/j.bioactmat.2022.01.011 PMID: 35386442
  45. Mendieta, I.; Rodríguez-Nieto, M.; Nuñez-Anita, R.E.; Menchaca-Arredondo, J.L.; García-Alcocer, G.; Berumen, L.C.; Berumen, L.C. Ultrastructural changes associated to the neuroendocrine transdifferentiation of the lung adenocarcinoma cell line A549. Acta Histochem., 2021, 123(8), 151797. doi: 10.1016/j.acthis.2021.151797 PMID: 34688180
  46. Gao, J.; Zhao, Y.; Wang, C.; Ji, H.; Yu, J.; Liu, C.; Liu, A. A novel synthetic chitosan selenate (CS) induces apoptosis in A549 lung cancer cells via the Fas/FasL pathway. Int. J. Biol. Macromol., 2020, 158, 689-697. doi: 10.1016/j.ijbiomac.2020.05.016 PMID: 32387597
  47. Nunhart, P.; Konkoľová, E.; Janovec, L.; Jendželovský, R.; Vargová, J.; Ševc, J.; Matejová, M.; Miltáková, B.; Fedoročko, P.; Kozurkova, M. Fluorinated 3,6,9-trisubstituted acridine derivatives as DNA interacting agents and topoisomerase inhibitors with A549 antiproliferative activity. Bioorg. Chem., 2020, 94, 103393. doi: 10.1016/j.bioorg.2019.103393 PMID: 31679839
  48. Mohareb, R.M.; Mukhtar, S.; Parveen, H.; Abdelaziz, M.A.; Alwan, E.S. Anti-proliferative, Morphological and Molecular docking studies of new thiophene derivatives and their strategy in ionic liquid immobilized reactions. Anticancer. Agents Med. Chem., 2024, 24(9), 691-708. doi: 10.2174/0118715206262307231122104748 PMID: 38321904

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