Curcuminoid Chalcones: Synthesis and Biological Activity against the Human Colon Carcinoma (Caco-2) Cell Line


Cite item

Full Text

Abstract

Background:There are many current scientific reports on the synthesis of various derivatives modelled on the structure of known small-molecular and natural bioactive compounds. Curcuminoid chalcones are an innovative class of compounds with significant therapeutic potential against various diseases and they perfectly fit into the current trends in the search for new biologically active substances.

Aims:The aim of this study was to design and synthesise a series of curcuminoid chalcones.

Objective:The objective of this scientific paper was to synthesise twelve curcuminoid chalcones and confirm their structures using spectral methods. Additionally, the biological activity of three of the synthesised compounds was evaluated using various assays, and their anticancer properties and toxicity were studied.

Methods:The proposed derivatives were obtained via the Claisen-Schmidt reaction of selected acetophenones and aldehydes in various conditions using both classical methods: the solutions and solvent-free microwave (MW) or ultrasound (US) variants. The most optimal synthetic method for the selected curcuminoid chalcones was the classical Claisen-Schmidt condensation in an alkaline (NaOH) medium. Spectral methods were used to confirm the structures of the compounds. The resazurin reduction assay, caspase-3 activity assay, and RT-qPCR method were performed, followed by measurements of the intracellular reactive oxygen species (ROS) level and the lactate dehydrogenase (LDH) release level.

Results:Twelve designed curcuminoid chalcones were successfully synthesized and structurally confirmed by NMR, MS, and IR spectroscopy. Examination of the anticancer activity was carried out for the three most interesting chalcone products.

Conclusion:The results suggested that compound 3a increased the metabolism and/or proliferation of the human colon carcinoma (Caco-2) cell line, while compounds 3b and 3f showed significant toxicity against the Caco-2 cell line. Overall, the preliminary results suggested that compound 3b exhibited the most favourable anticancer activity.

About the authors

Dorota Olender

Department of Organic Chemistry, Poznan University of Medical Sciences

Author for correspondence.
Email: info@benthamscience.net

Katarzyna Sowa-Kasprzak

Department of Organic Chemistry, Poznan University of Medical Sciences

Email: info@benthamscience.net

Anna Pawełczyk

Department of Organic Chemistry, Poznan University of Medical Sciences

Email: info@benthamscience.net

Bartosz Skóra

Department of Biotechnology and Cell Biology, University of Information Technology and Management in Rzeszow

Email: info@benthamscience.net

Lucjusz Zaprutko

Department of Organic Chemistry, Pharmaceutical Faculty, Poznan University of Medical Sciences

Email: info@benthamscience.net

Konrad Szychowski

Department of Biotechnology and Cell Biology, University of Information Technology and Management in Rzeszow

Email: info@benthamscience.net

References

  1. Tiwari, A.K. Imbalance in antioxidant defence and human diseases: Multiple approach of natural antioxidants therapy. Curr. Sci., 2001, 81(9)
  2. Zhang, Y.J.; Gan, R.Y.; Li, S.; Zhou, Y.; Li, A.N.; Xu, D.P.; Li, H.B. Antioxidant phytochemicals for the prevention and treatment of chronic diseases. Molecules, 2015, 20(12), 21138-21156. doi: 10.3390/molecules201219753 PMID: 26633317
  3. Soobrattee, M.A.; Neergheen, V.S.; Luximon-Ramma, A.; Aruoma, O.I.; Bahorun, T. Phenolics as potential antioxidant therapeutic agents: Mechanism and actions. Mutat. Res., 2005, 579(1-2), 200-213. doi: 10.1016/j.mrfmmm.2005.03.023 PMID: 16126236
  4. Shahidi, F.; Ambigaipalan, P. Phenolics and polyphenolics in foods, beverages and spices: Antioxidant activity and health effects - A review. J. Funct. Foods, 2015, 18(Part B), 820-897. doi: 10.1016/j.jff.2015.06.018
  5. Sorolla, M.A.; Hidalgo, I.; Sorolla, A.; Montal, R.; Pallisé, O.; Salud, A.; Parisi, E. Microenvironmental reactive oxygen species in colorectal cancer: Involved processes and therapeutic opportunities. Cancers, 2021, 13(20), 5037. doi: 10.3390/cancers13205037 PMID: 34680186
  6. Mishra, S.; Kapoor, N.; Mubarak Ali, A.; Pardhasaradhi, B.V.V.; Kumari, A.L.; Khar, A.; Misra, K. Differential apoptotic and redox regulatory activities of curcumin and its derivatives. Free Radic. Biol. Med., 2005, 38(10), 1353-1360. doi: 10.1016/j.freeradbiomed.2005.01.022 PMID: 15855053
  7. Shiels, M.S.; Haque, A.T.; Berrington de González, A.; Freedman, N.D. Leading causes of death in the US during the COVID-19 pandemic, March 2020 to October 2021. JAMA Intern. Med., 2022, 182(8), 883-886. doi: 10.1001/jamainternmed.2022.2476 PMID: 35788262
  8. Xi, Y.; Xu, P. Global colorectal cancer burden in 2020 and projections to 2040. Transl. Oncol., 2021, 14(10), 101174. doi: 10.1016/j.tranon.2021.101174 PMID: 34243011
  9. Pawełczyk, A.; Sowa-Kasprzak, K.; Olender, D.; Zaprutko, L. Molecular consortia-various structural and synthetic concepts for more effective therapeutics synthesis. Int. J. Mol. Sci., 2018, 19(4), 1104. doi: 10.3390/ijms19041104 PMID: 29642417
  10. Edwards, R.L.; Luis, P.B.; Varuzza, P.V.; Joseph, A.I.; Presley, S.H.; Chaturvedi, R.; Schneider, C. The anti-inflammatory activity of curcumin is mediated by its oxidative metabolites. J. Biol. Chem., 2017, 292(52), 21243-21252. doi: 10.1074/jbc.RA117.000123 PMID: 29097552
  11. Wilken, R.; Veena, M.S.; Wang, M.B.; Srivatsan, E.S. Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Mol. Cancer, 2011, 10(1), 12. doi: 10.1186/1476-4598-10-12 PMID: 21299897
  12. Llano, S.; Gómez, S.; Londoño, J.; Restrepo, A. Antioxidant activity of curcuminoids. Phys. Chem. Chem. Phys., 2019, 21(7), 3752-3760. doi: 10.1039/C8CP06708B PMID: 30702098
  13. Chainoglou, E.; Hadjipavlou-Litina, D. Curcumin in health and diseases: Alzheimer’s disease and curcumin analogues, derivatives, and hybrids. Int. J. Mol. Sci., 2020, 21(6), 1975. doi: 10.3390/ijms21061975 PMID: 32183162
  14. Burgos-Morón, E.; Calderón-Montaño, J.M.; Salvador, J.; Robles, A.; López-Lázaro, M. The dark side of curcumin. Int. J. Cancer, 2010, 126(7), NA. doi: 10.1002/ijc.24967 PMID: 19830693
  15. Nelson, K.M.; Dahlin, J.L.; Bisson, J.; Graham, J.; Pauli, G.F.; Walters, M.A. The essential medicinal chemistry of curcumin. J. Med. Chem., 2017, 60(5), 1620-1637. doi: 10.1021/acs.jmedchem.6b00975 PMID: 28074653
  16. Elias, G.; Jacob, P.J.; Hareeshbabu, E.; Mathew, V.B.; Krishnan, B.; Krishnakumar, K. Curcumin: Transforming the spice to a wonder drug. Int. J. Pharm. Sci. Res., 2015, 6, 2671-2680. doi: 10.13040/IJPSR.0975-8232.6(7).2671-80
  17. Chainoglou, E.; Siskos, A.; Pontiki, E.; Hadjipavlou-Litina, D. Hybridization of curcumin analogues with cinnamic acid derivatives as multi-target agents against Alzheimer’s disease targets. Molecules, 2020, 25(21), 4958. doi: 10.3390/molecules25214958 PMID: 33114751
  18. Ding, L.; Ma, S.; Lou, H.; Sun, L.; Ji, M. Synthesis and biological evaluation of curcumin derivatives with water-soluble groups as potential antitumor agents: An in vitro investigation using tumor cell lines. Molecules, 2015, 20(12), 21501-21514. doi: 10.3390/molecules201219772 PMID: 26633344
  19. Cao, Y.K.; Li, H.J.; Song, Z.F.; Li, Y.; Huai, Q.Y. Synthesis and biological evaluation of novel curcuminoid derivatives. Molecules, 2014, 19(10), 16349-16372. doi: 10.3390/molecules191016349 PMID: 25314599
  20. Cazarolli, L.H.; Demarchi Kappel, D.; Zanatta, A.P.; Hisayasu Suzuki, D.O.; Yunes, R.A.; Nunes, R.J.; Pizzolatti, M.G.; Mena Barreto Silva, F.R. Chapter 2 - Natural and synthetic chalcones: Tools for the study of targets of actioninsulin secretagogue or insulin mimetic? In: Studies in Natural Products Chemistry; Elsevier, 2013; 39, pp. 47-89. doi: 10.1016/B978-0-444-62615-8.00002-3
  21. Rudrapal, M.; Khan, J.; Dukhyil, A.A.B.; Alarousy, R.M.I.I.; Attah, E.I.; Sharma, T.; Khairnar, S.J.; Bendale, A.R. Chalcone scaffolds, bioprecursors of flavonoids: Chemistry, bioactivities, and pharmacokinetics. Molecules, 2021, 26(23), 7177. doi: 10.3390/molecules26237177 PMID: 34885754
  22. Salehi, B.; Quispe, C.; Chamkhi, I.; El Omari, N.; Balahbib, A.; Sharifi-Rad, J.; Bouyahya, A.; Akram, M.; Iqbal, M.; Docea, A.O.; Caruntu, C.; Leyva-Gómez, G.; Dey, A.; Martorell, M.; Calina, D.; López, V.; Les, F. Pharmacological properties of chalcones: A review of preclinical including molecular mechanisms and clinical evidence. Front. Pharmacol., 2021, 11, 592654. doi: 10.3389/fphar.2020.592654 PMID: 33536909
  23. Elkanzi, N.A.A.; Hrichi, H.; Alolayan, R.A.; Derafa, W.; Zahou, F.M.; Bakr, R.B. Synthesis of chalcones derivatives and their biological activities: A review. ACS Omega, 2022, 7(32), 27769-27786. doi: 10.1021/acsomega.2c01779 PMID: 35990442
  24. Tekale, S.; Mashele, S.; Pooe, O.; Thore, S.; Kendrekar, P.; Pawar, R. Biological Role of Chalcones in Medicinal Chemistry. In: Vector-Borne Diseases; IntechOpen, 2020. doi: 10.5772/intechopen.91626
  25. Janaki, P.; Bhadraiah, B.; Nagarjuna, P.A.; Subhashini, N.J.P. Synthesis and antibacterial activity of novel chalcone derivatives of apocynin. Lett. Drug Des. Discov., 2013, 10(10), 923-927. doi: 10.2174/15701808113109990081
  26. Kamel, M.G.; Sroor, F.M.; Othman, A.M.; Mahrous, K.F.; Saleh, F.M.; Hassaneen, H.M.; Abdallah, T.A.; Abdelhamid, I.A.; Teleb, M.A.M. Structure-based design of novel pyrazolyl–chalcones as anti-cancer and antimicrobial agents: Synthesis and in vitro studies. Monatsh. Chem., 2022, 153(2), 211-221. doi: 10.1007/s00706-021-02886-5
  27. Rammohan, A.; Reddy, J.S.; Sravya, G.; Rao, C.N.; Zyryanov, G.V. Chalcone synthesis, properties and medicinal applications: A review. Environ. Chem. Lett., 2020, 18(2), 433-458. doi: 10.1007/s10311-019-00959-w
  28. Kumar, N.; Drabu, S.; Shalini, K. Synthesis and pharmacological screening of 4, 6-substituted di-(phenyl) pyrimidin-2-amines. Arab. J. Chem., 2017, 10, S877-S880. doi: 10.1016/j.arabjc.2012.12.023
  29. Bhale, P.S.; Chavan, H.V.; Dongare, S.B.; Shringare, S.N.; Mule, Y.B.; Nagane, S.S.; Bandgar, B.P. Synthesis of extended conjugated indolyl chalcones as potent anti-breast cancer, anti-inflammatory and antioxidant agents. Bioorg. Med. Chem. Lett., 2017, 27(7), 1502-1507. doi: 10.1016/j.bmcl.2017.02.052 PMID: 28258796
  30. Ahmed, M.F.; Santali, E.Y.; El-Haggar, R. Novel piperazine–chalcone hybrids and related pyrazoline analogues targeting VEGFR-2 kinase; design, synthesis, molecular docking studies, and anticancer evaluation. J. Enzyme Inhib. Med. Chem., 2021, 36(1), 308-319. doi: 10.1080/14756366.2020.1861606 PMID: 33349069
  31. Asiri, A.M.; Al-Amari, M.M.; Ullah, Q.; Khan, S.A. Ultrasound-assisted synthesis and photophysical investigation of a heterocyclic alkylated chalcone: A sensitive and selective fluorescent chemosensor for Fe3+ in aqueous media. J. Coord. Chem., 2020, 73(20-22), 2987-3002. doi: 10.1080/00958972.2020.1838490
  32. Asiri, A.M.; Khan, S.A. Synthesis, characterization and optical properties of mono- and bis-chalcone. Mater. Lett., 2011, 65(12), 1749-1752. doi: 10.1016/j.matlet.2011.03.059
  33. Alfaifi, S.Y.; Khan, S.A. Multi-step synthesis, photophysical and physicochemical properties of novel push- π -Pull AADC chromophores. Polycycl. Aromat. Compd., 2023, 43(2), 1219-1231. doi: 10.1080/10406638.2022.2026985
  34. Mellado, M.; Reyna-Jeldes, M.; Weinstein-Oppenheimer, C.; Coddou, C.; Jara-Gutierrez, C.; Villena, J.; Aguilar, L.F. Inhibition of Caco-2 and MCF-7 cancer cells using chalcones: Synthesis, biological evaluation and computational study. Nat. Prod. Res., 2022, 36(17), 4404-4410. doi: 10.1080/14786419.2021.1984465 PMID: 34583595
  35. Ouyang, Y.; Li, J.; Chen, X.; Fu, X.; Sun, S.; Wu, Q. Chalcone derivatives: role in anticancer therapy. Biomolecules, 2021, 11, 894. doi: 10.3390/biom11060894
  36. Mulugeta, D. A review of synthesis methods of chalcones, flavonoids, and coumarins. Sci. J. Chem., 2022, 10(2), 41-52. doi: 10.11648/j.sjc.20221002.12
  37. Gaonkar, S.L.; Vignesh, U.N. Synthesis and pharmacological properties of chalcones: A review. Res. Chem. Intermed., 2017, 43(11), 6043-6077. doi: 10.1007/s11164-017-2977-5
  38. Farooq, S.; Ngaini, Z. Recent synthetic methodologies for chalcone synthesis (2013-2018). Curr. Organocatal., 2019, 6(3), 184-192. doi: 10.2174/2213337206666190306155140
  39. Yadav, G.D.; Wagh, D.P. Claisen‐schmidt condensation using green catalytic processes: A critical review. ChemistrySelect, 2020, 5(29), 9059-9085. doi: 10.1002/slct.202001737
  40. Evranos Aksöz, B.; Ertan, R. Chemical and structural properties of chalcones I. FABAD. J. Pharm. Sci., 2011, 36, 223-242.
  41. Patil, C.B.; Mahajan, S.K.; Katti, S.A. Chalcone: A versatile molecule. J. Pharm. Sci. Res., 2009, 1(3), 11-22.
  42. Weber, W.M.; Hunsaker, L.A.; Abcouwer, S.F.; Deck, L.M.; Vander Jagt, D.L. Anti-oxidant activities of curcumin and related enones. Bioorg. Med. Chem., 2005, 13(11), 3811-3820. doi: 10.1016/j.bmc.2005.03.035 PMID: 15863007
  43. Watanabe, K.; Imazawa, A. Aldol condensations catalyzed by Co (II) complexes of pyridine-containing copolymers. Bull. Chem. Soc. Jpn., 1982, 55(10), 3208-3211. doi: 10.1246/bcsj.55.3208
  44. Raghavan, S.; Manogaran, P.; Kalpattu Kuppuswami, B.; Venkatraman, G.; Gadepalli Narasimha, K.K. Synthesis and anticancer activity of chalcones derived from vanillin and isovanillin. Med. Chem. Res., 2015, 24(12), 4157-4165. doi: 10.1007/s00044-015-1453-2
  45. Kumar, S.N.; Bavikar, S.R.; Pavan Kumar, C.N.S.S.; Yu, I.F.; Chein, R.J. From carbamate to chalcone: Consecutive anionic fries rearrangement, anionic Si → C alkyl rearrangement, and claisen–schmidt condensation. Org. Lett., 2018, 20(17), 5362-5366. doi: 10.1021/acs.orglett.8b02269 PMID: 30148638
  46. Szychowski, K.A.; Leja, M.L.; Kaminskyy, D.V.; Kryshchyshyn, A.P.; Binduga, U.E.; Pinyazhko, O.R.; Lesyk, R.B.; Tobiasz, J.; Gmiński, J. Anticancer properties of 4-thiazolidinone derivatives depend on peroxisome proliferator-activated receptor gamma (PPARγ). Eur. J. Med. Chem., 2017, 141, 162-168. doi: 10.1016/j.ejmech.2017.09.071 PMID: 29031063
  47. Skóra, B.; Matuszewska, P.; Masicz, M.; Sikora, K.; Słomczewska, M.; Sołtysek, P.; Szychowski, K.A. Crosstalk between the aryl hydrocarbon receptor (AhR) and the peroxisome proliferator-activated receptor gamma (PPARγ) as a key factor in the metabolism of silver nanoparticles in neuroblastoma (SH-SY5Y) cells in vitro. Toxicol. Appl. Pharmacol., 2023, 458, 116339. doi: 10.1016/j.taap.2022.116339 PMID: 36473513
  48. Bar, M.; Skóra, B.; Tabęcka-Łonczyńska, A.; Holota, S.; Khyluk, D.; Roman, O.; Lesyk, R.; Szychowski, K.A. New 4-thiazolidinone-based molecules Les-2769 and Les-3266 as possible PPARγ modulators. Bioorg. Chem., 2022, 128, 106075. doi: 10.1016/j.bioorg.2022.106075 PMID: 35952447
  49. Skóra, B.; Lewińska, A.; Kryshchyshyn-Dylevych, A.; Kaminskyy, D.; Lesyk, R.; Szychowski, K.A. Evaluation of anticancer and antibacterial activity of four 4-thiazolidinone-based derivatives. Molecules, 2022, 27(3), 894. doi: 10.3390/molecules27030894 PMID: 35164157
  50. Skóra, B.; Szychowski, K.A. Molecular mechanism of the uptake and toxicity of EGF-LipoAgNPs in EGFR-overexpressing cancer cells. Biomed. Pharmacother., 2022, 150, 113085. doi: 10.1016/j.biopha.2022.113085 PMID: 35658239
  51. Mellado-García, M.; Reyna, M.; Weinstein-Oppenheimer, C.; Cuellar, M.; Aguilar, L.F. Preliminary evaluation of cytotoxicity for small chalcones on breast and colorectal cancer cell lines: Synthesis and structure - activity relationship. J. Pharmacol. Ther. Forecast., 2018, 1(1), 1003.
  52. Anwar, C.; Prasetyo, Y.D.; Matsjeh, S.; Haryadi, W.; Sholikhah, E.N.; Nendrowati, N. Synthesis of chalcone derivatives and their in vitro anticancer test against breast (T47D) and Colon (WiDr) cancer cell line. Indian J. Chem., 2018, 18(1), 102-107. doi: 10.22146/ijc.26864
  53. Palleros, D.R. Solvent-free synthesis of chalcones. J. Chem. Educ., 2004, 81(9), 1345-1347. doi: 10.1021/ed081p1345
  54. Jayapal, M.R.; Sreedhar, N.Y. Anhydrous K2CO3 as catalyst for the synthesis of chalcones under microwave irradiation. J. Pharm. Sci. Res., 2010, 2(10), 644-647.
  55. Aksöz, B.E.; Ertan, R. Spectral properties of chalcones II. FABAD J. Pharm. Sci., 2012, 37(4), 205-216.
  56. Batovska, D.; Parushev, S.; Stamboliyska, B.; Tsvetkova, I.; Ninova, M.; Najdenski, H. Examination of growth inhibitory properties of synthetic chalcones for which antibacterial activity was predicted. Eur. J. Med. Chem., 2009, 44(5), 2211-2218. doi: 10.1016/j.ejmech.2008.05.010 PMID: 18584918
  57. Simon, H.U.; Haj-Yehia, A.; Levi-Schaffer, F. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis, 2000, 5(5), 415-418. doi: 10.1023/A:1009616228304 PMID: 11256882
  58. Berghe, T.V.; Vanlangenakker, N.; Parthoens, E.; Deckers, W.; Devos, M.; Festjens, N.; Guerin, C.J.; Brunk, U.T.; Declercq, W.; Vandenabeele, P. Necroptosis, necrosis and secondary necrosis converge on similar cellular disintegration features. Cell Death Differ., 2010, 17(6), 922-930. doi: 10.1038/cdd.2009.184 PMID: 20010783
  59. Park, J.E.; Ahn, C.H.; Lee, H.J.; Sim, D.Y.; Park, S.Y.; Kim, B.; Shim, B.S.; Lee, D.Y.; Kim, S.H. Antioxidant-based preventive effect of phytochemicals on anticancer drug-induced hepatotoxicity. Antioxid. Redox Signal., 2023, 38(16-18), 1101-1121. doi: 10.1089/ars.2022.0144 PMID: 36242510

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers