Skip to main content
SpringerLink
Log in

Development trans-N-benzyl hydroxyl cinnamamide based compounds from cinnamic acids and characteristics anticancer potency

  • Original Paper
  • Published:
Journal of the Iranian Chemical Society Aims and scope Submit manuscript

Abstract

The derivatization of three hydroxycinnamamides becomes trans-N-benzylhydroxycinnamamides, and their potential assay as anticancer agents has been carried out. N-benzyl-p-coumaramide (5a), N-benzylcaffeamide (5b), and N-benzylferulamide (5c) were obtained from p-coumaric, caffeic, and ferulic acid, respectively, with benzylamine via four reaction steps, i.e., acetylation, chlorination, amidation, and deacetylation. All products characterize using FTIR, 1H-NMR, and 13C-NMR spectroscopy, and their cytotoxicity were tested against P388 leukemia murine cells by MTT method. Although compound 5b and 5c have no and low anticancer activity with IC50 sequentially of 674.38 and 179.56 µg/mL, compound 5a showed potentially use as an anticancer agent with IC50 of 16.15 µg/mL Molecular modelling studies were performed to understand the interactions with the activity against murine leukemia P388 cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. L.H. Boudreau, J. Maillet, L.M. Leblanc, T.M. Jean-franc, Caffeic acid phenethyl ester and its amide analogue are potent inhibitors of leukotriene biosynthesis in human polymorphonuclear leukocytes. PLoS ONE 7(2), 31833 (2012). https://doi.org/10.1371/journal.pone.0031833

    Article  CAS  Google Scholar 

  2. M.G. Chochkova, E.Y. Chorbadzhiyska, G.I. Ivanova, H. Najdenski, M. Ninova, T.S. Milkova, Antimicrobial and radical scavenging activities of N-hydroxycinnamoyl-L-antimicrobial and radical scavenging activities of N-Hydroxycinnamoyl-L-cysteine and -L-proline ethyl esters. Nat. Prod. J. 2(1), 1–5 (2012). https://doi.org/10.2174/2210315511202010050

    Article  Google Scholar 

  3. M.G. Chochkova, P.P. Petrova, B.M. Stoykova, G.I. Ivanova, M. Sticha, G. Dibo, T.S. Milkova, Structure-activity relationships of n-cinnamoyl and hydroxycinnamoyl amides on α-glucosidase inhibition. J. Chem. 2017, 1–5 (2017)

    Article  Google Scholar 

  4. C. Cui, Z.P. Wang, X.J. Du, L.Z. Wang, S.J. Yu, X.H. Liu, Z.M. Li, W.G. Zhao, Synthesis and antiviral activity of hydrogenated ferulic acid derivatives. J. Chem. 2013, 1–5 (2013)

    Article  Google Scholar 

  5. D. Systemes, Biovia discovery studio visualizer (Dassault Systemes, San Diego, 2019)

    Google Scholar 

  6. M. De Armas-ricard, E. Ruiz-reyes, O. Ramírez-rodríguez, Caffeates and caffeamides: synthetic methodologies and their antioxidant properties. Int. J. Med. Chem. 2019, 1–15 (2019)

    Google Scholar 

  7. H.D.R. Firdaus, T. Naid, N.H. Soekamto, S. Sumarna, M.F. Islam, Synthesis of piperidine and morpholine amides of ferulic acid and their bioactivity against P-388 leukemia cells. Int. J. ChemTech Res. 10(1), 27–33 (2017)

    CAS  Google Scholar 

  8. S. Firdaus, D. Husain, H. Rasyid, Sukarti, Methylation of p-coumaric acid with dimethyl sulfate and sodium hydoxide as catalyst. Proc. First Int. Conf. Sci. 1, 339–344 (2014)

    Google Scholar 

  9. Firdaus, Seniwati, N. Alamsyah, S. Paramita, Synthesis and activity of N-(o-tolyl)caffeamide and N-(o-tolyl)-p-coumaramide against P388 leukemia murine cells. J. Phys. Conf. Ser. 1341(3), 032005 (2019)

    Article  CAS  Google Scholar 

  10. S.N.H. Firdaus, S. Firdausiah, H. Rasyid, N. Asmi, M. Waelulu, Novel hydroxycinnamamide from morpholine and pyrrolidine: synthesis, characterization, docking study, and anticancer activity against P388 leukemia murine cells. J. Appl. Pharm. Sci. 11(1), 40–48 (2021). https://doi.org/10.7324/JAPS.2021.110104

    Article  CAS  Google Scholar 

  11. Firdaus, N.H. Soekamto, Seniwati, M.F. Islam, Sultan, Phenethyl ester and amide of ferulic acids: synthesis and bioactivity against p388 leukemia murine cells. J. Phys. Conf. Ser. 979, 012016 (2018)

    Article  Google Scholar 

  12. L. Georgiev, M. Chochkova, G. Ivanova, H. Najdenski, M. Ninova, T. Milkova, Radical scavenging and antimicrobial activities of cinnamoyl amides of biogenic monoamines. La Riv. Ital. Delle Sostanze Grasse 89(2), 91 (2012)

    CAS  Google Scholar 

  13. B. Godlewska-żyłkiewicz, R. Swisloscka, M. Kalinowska, A. Golonko, G. Swiderslo, Z. Arciszewska, E. Nalewajko-Sielowoniuk, M. Naumowies, W. Lewandowski, Biologically active compounds of plants: structure-related antioxidant, microbiological and cytotoxic activity of selected carboxylic acid. Materials 13(19), 1–37 (2020). https://doi.org/10.3390/ma13194454

    Article  CAS  Google Scholar 

  14. J.D. Guzman, Natural cinnamic acids, synthetic derivatives and hybrids with antimicrobial activity. Molecules 19, 19292–19349 (2014). https://doi.org/10.3390/molecules191219292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. M.D. Hanwell, D.E. Curtis, D.C. Lonie, T. Vandermeersch, E. Zurek, G.R. Hutchison, Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J. Cheminform. 4, 1–17 (2012)

    Article  Google Scholar 

  16. R.F. Helm, J. Ralph, R.D. Hatfield, Synthesis of feruloylated methyl glycosides and p-coumaroylated. Carbohydr. Res. 229, 183–194 (1992)

    Article  CAS  Google Scholar 

  17. R. Huey, G.M. Morris, A.J. Olson, D.S. Goodsell, A semiempirical free energy force field with charge-based desolvation. J. Comput. Chem. 28(6), 1145–1152 (2007)

    Article  CAS  Google Scholar 

  18. P.A. Jackson, J.C. Widen, D.A. Harki, K.M. Brummond, Covalent modifiers: a chemical perspective on the reactivity of α, β-unsaturated carbonyls with thiols via hetero-Michael addition reactions. J. Med. Chem. 60(3), 839–885 (2017). https://doi.org/10.1021/acs.jmedchem.6b00788

    Article  CAS  PubMed  Google Scholar 

  19. S.M. Jakoveti, B.Z. Jugovi, M.M. Gvozdenovi, D.I. Bezbradica, Synthesis of aliphatic esters of cinnamic acid as potential lipophilic antioxidants catalyzed by lipase B from Candida antarctica. Appl Biochem Biotechnol 170, 1560–1573 (2013). https://doi.org/10.1007/s12010-013-0294-z

    Article  CAS  Google Scholar 

  20. A. Jitareanu, G. Tataringa, C. Tuchilus, M. Balan, U. Stanescu, Cinnamic acid derivatives and 4-aminoantipyrine amides—synthesis and evaluation of biological properties. Res. J. Chem. Sci. 3(3), 9–13 (2013)

    CAS  Google Scholar 

  21. A. Khatkar, A. Nanda, P. Kumar, B. Narasimhan, Synthesis, antimicrobial evaluation and QSAR studies of p-coumaric acid derivatives. Arab. J. Chem. 10, 3804–3815 (2017). https://doi.org/10.1016/j.arabjc.2014.05.018

    Article  CAS  Google Scholar 

  22. B. Korošec, M. Sova, S. Turk, N. Krasevec, M. Novak, L. Lah, J. Stojan, B. Pobobnik, S. Berne, N. Zupanec, M. Bunc, S. Gobec, R. Komel, Antifungal activity of cinnamic acid derivatives involves inhibition of benzoate 4-hydroxylase (CYP53). J. Appl. Microbiol. 116(4), 955–966 (2014). https://doi.org/10.1111/jam.12417

    Article  CAS  PubMed  Google Scholar 

  23. Y. Kuo, W. Jim, L. Su, C. Chung, C. Lin, Caffeic acid phenethyl ester is a potential therapeutic agent for oral cancer. Int. J. Mol. Sci. 16, 10748–10766 (2015). https://doi.org/10.3390/ijms160510748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. H. Kuncoro, L. Rijai, E. Julaeha, U. Supratman, Cytotoxic activity against P-388 murine Leukemia cell from Lygodium microphyllum herb. J. Farm. Galen. 3(1), 13–16 (2003)

    Google Scholar 

  25. R.A. Laskowski, M.B. Swindells, LigPlot+: multiple ligand–protein interaction diagrams for drug discovery. J. Chem. Inf. Model. 51(10), 2778–2786 (2011)

    Article  CAS  Google Scholar 

  26. G.E. Magoulas, D. Papaioannou, Bioinspired syntheses of dimeric hydroxycinnamic acids (Lignans) and hybrids, using phenol oxidative coupling as key reaction, and medicinal significance thereof. Molecules 19, 19769–19835 (2014). https://doi.org/10.3390/molecules191219769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. T. Matsubara, S. Asako, L. Ilies, E. Nakamura, Synthesis of anthranilic acid derivatives through iron-catalyzed ortho amination of aromatic carboxamides with N-chloroamines. J. Am. Chem. Soc. 136, 646–649 (2014)

    Article  CAS  Google Scholar 

  28. G. Morris, R. Huey, AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J. Comput. Chem. 30(16), 2785–2791 (2009). https://doi.org/10.1002/jcc.21256.AutoDock4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. T. Nakazawa, K. Ohsawa, Metabolism of rosmarinic acid in rats. J. Nat. Prod. 2(98), 993–996 (1998)

    Article  Google Scholar 

  30. S.B. Nimse, D. Pal, A. Mazumder, R. Mazumder, Synthesis of cinnamanilide derivatives and their antioxidant and antimicrobial activity. J. Chem. 2015, 1–6 (2015)

    Article  Google Scholar 

  31. W. Peng, J.G. Wu, Y.B. Jiang, Y.J. Liu, T. Sun, N. Wu, C.J. Wu, Antitumor activity of 4-O-(2″-O-acetyl-6″-O-p-coumaroyl-β-d-glucopyranosyl)-p-coumaric acid against lung cancers via mitochondrial-mediated apoptosis. Chem. Interact. J. 233, 8–13 (2015). https://doi.org/10.1016/j.cbi.2015.03.014

    Article  CAS  Google Scholar 

  32. E.F. Pettersen, T.D. Goddard, C.C. Huang, G.S. Couch, D.M. Greenblatt, E.C. Meng, T.E. Ferrin, UCSF chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004)

    Article  CAS  Google Scholar 

  33. K. Saritha, G. Rajitha, Synthesis, antimicrobial and antioxidant activity of N-dimethylaminophenylallylidene cinnamide derivatives. Int. Res. J. Pharm. 9(12), 120–127 (2018). https://doi.org/10.7897/2230-8407.0912304

    Article  CAS  Google Scholar 

  34. A. Rauf, H. Parveen, Direct esterification of fatty acids with phenylalkanols by using dicyclohexylcarbodiimide. Eur. J. Lipid Sci. Technol. 106, 97–100 (2004). https://doi.org/10.1002/ejlt.200300887

    Article  CAS  Google Scholar 

  35. S. Salahuddin, M. Hanafi, H. Hariyanti, Synthesis and anticancer activity test of 2-hydroxy-n-phenylnicotinamide. Indones. J. Chem. 13(2), 166–170 (2013)

    Article  CAS  Google Scholar 

  36. U.Y. Shaheen, P-coumaric acid ester with potential antioxidant activity from the genus salvia. Free Radic. Antioxid. 1(1), 23–27 (2011). https://doi.org/10.5530/ax.2011.1.5

    Article  CAS  Google Scholar 

  37. B.L. Staker, C.M. FeeseMD, Y. Pommier, D. Zembower, L. Stewart, A.B. Burgin, Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex. J. Med. Chem. 48(7), 2336–2345 (2005). https://doi.org/10.1021/jm049146p

    Article  CAS  PubMed  Google Scholar 

  38. K. Takao, K. Toda, T. Saito, Y. Sugita, Synthesis of amide and ester derivatives of cinnamic acid and its analogs: evaluation of their free radical scavenging and monoamine oxidase and cholinesterase inhibitory activities. Chem. Pharm. Bull. 65(11), 1020–1027 (2017)

    Article  CAS  Google Scholar 

  39. P. Tang, Boric Acid Catalyzed Amide Formation from Carboxylic Acids and Amines: N-Benzyl-4-Phenylbutyramide. Organic Syntheses (Wiley, Hoboken, 2005), pp. 262–272

    Google Scholar 

  40. O. Taofiq, A.M. González-Paramás, M.F. Barreiro, I.C.F.R. Ferreira, Hydroxycinnamic acids and their derivatives: future perspectives, a review. Molecules 22(281), 1–24 (2017). https://doi.org/10.3390/molecules22020281

    Article  CAS  Google Scholar 

  41. J. Teixeira, A. Gaspar, E.M. Garrido, J. Garrido, F. Borges, Hydroxycinnamic acid antioxidants: an electrochemical overview. Biomed. Res. Int. 2013, 1–11 (2013)

    Google Scholar 

  42. T. Tokoroyama, Discovery of the Michael reaction. Eur. J. Org. Chem. 2010, 2009–2016 (2010). https://doi.org/10.1002/ejoc.200901130

    Article  CAS  Google Scholar 

  43. G. Wang, Q.Y. Yu, J. Wang, S. Wang, S.Y. Chen, X.Q. Yu, Iodide-catalyzed amide synthesis from alcohols and amines. RSC Adv. 3(44), 21306–21310 (2013). https://doi.org/10.1039/C3RA43799J

    Article  CAS  Google Scholar 

  44. Y. Xiao, X. Yang, B. Li, H. Yuan, S. Wan, Y. Xu, Design, synthesis and antifungal/insecticidal evaluation of novel cinnamide derivatives. Molecules 16, 8945–8957 (2011). https://doi.org/10.3390/molecules16118945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Y.H. Yang, T. Raku, E. Song, S.H. Park, D. Yoo, H.Y. Park, B.G. Kim, H.J. Kim, S.H. Lee, H.S. Kim, Y. Tokiwa, Lipase catalyzed reaction of L-ascorbic acid with cinnamic acid esters and substituted cinnamic acids. Biotechnol. Bioprocess Eng. 17, 50–54 (2012). https://doi.org/10.1007/s12257-011-0071-1

    Article  CAS  Google Scholar 

  46. K. Zhou, D. Chen, B. Li, B. Zhang, F. Miao, L. Zhou, Bioactivity and structure-activity relationship of cinnamic acid esters and their derivatives as potential antifungal agents for plant protection. PLoS ONE 12(4), 0176189 (2017)

    Google Scholar 

Download references

Acknowledgements

Authors thank the Ministry of Education and Culture as well as Rector of Hasanuddin University for a research grant on the scheme of Academic Supervision of Magister Student. We also thank Chemistry Laboratory and Natural Products Laboratory of Mathematics and Science Faculty, Institute Technology of Bandung for accessing the NMR measurements and the facilities in performing the antitumor analysis. We also thank the Integrated Chemistry Laboratory of Chemistry Department, Mathematics and Science Faculty, Hasanuddin University, for FTIR measurements.

Author information

Authors and Affiliations

  1. Department of Chemistry, Hasanuddin University, Makassar, Indonesia

    Firdaus Zenta, Nunuk Hariani Soekamto, Seniwati Dali, Syadza Firdausiah, Herlina Rasyid, Bahriah Bahriah & Agustan Agustan

  2. Department of Physics, Hasanuddin University, Makassar, Indonesia

    Dahlang Tahir

Authors
  1. Firdaus Zenta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nunuk Hariani Soekamto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seniwati Dali
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Syadza Firdausiah
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Herlina Rasyid
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bahriah Bahriah
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Agustan Agustan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dahlang Tahir
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dahlang Tahir.

Ethics declarations

Conflict of interest

All authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zenta, F., Soekamto, N.H., Dali, S. et al. Development trans-N-benzyl hydroxyl cinnamamide based compounds from cinnamic acids and characteristics anticancer potency. J IRAN CHEM SOC 19, 2845–2853 (2022). https://doi.org/10.1007/s13738-022-02499-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13738-022-02499-7

Keywords

Search

Navigation