Skip to main content

Advertisement

SpringerLink
Log in

Novel 1-methoxyindole- and 2-alkoxyindole-based chalcones: design, synthesis, characterization, antiproliferative activity and DNA, BSA binding interactions

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

Indole-based chalcones have been identified as interesting compounds with anticancer properties. In the present study, we report the synthesis and evaluation of new 1-methoxyindole and 2-alkoxyindole chalcone hybrids as antiproliferative agents active against colorectal carcinoma cell line. Among the 19 investigated molecules, four inhibit the proliferation of colorectal cancer cells HCT-116 with IC50 values <8 µM and display low cytotoxicity to fibroblast cell line 3T3. The UV–visible, CD and fluorescence competitive displacement assays with ethidium bromide and Hoechst 33258 performed with two active chalcones demonstrated that investigated chalcones interact with calf thymus (CT) DNA through the groove binding mode. Likewise, the quenching interaction of chalcones with bovine serum albumin (BSA) was studied in vitro under optimal physiological condition (pH = 7.4). The Stern–Volmer constant for chalcone-BSA system was found in the range of 105 M−1.

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
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Zhou B. Diverse Molecular Targets for Chalcones with Varied Bioactivities. Med Chem (Los Angeles). 2015;5:388–404. https://doi.org/10.4172/2161-0444.1000291.

    Article  CAS  Google Scholar 

  2. Zhuang C, Zhang W, Sheng C, Zhang W, Xing C, Miao Z. Chalcone: a Privileged Structure in Medicinal Chemistry. Chem Rev. 2017;117:7762–810. https://doi.org/10.1021/acs.chemrev.7b00020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gomes MN, Muratov EN, Pereira M, Peixoto JC, Rosseto LP, Cravo PVL, et al. Chalcone derivatives: promising starting points for drug design. Molecules. 2017;22:1210. https://doi.org/10.3390/molecules22081210.

    Article  CAS  PubMed Central  Google Scholar 

  4. Mahapatra DK, Bharti SK, Asati V. Anti-cancer chalcones: structural and molecular target perspectives. Eur J Med Chem. 2015;98:69–114. https://doi.org/10.1016/j.ejmech.2015.05.004.

  5. Dadashpour S, Emami S. Indole in the target-based design of anticancer agents: a versatile scaffold with diverse mechanisms. Eur J Med Chem. 2018;150:9–29. https://doi.org/10.1016/j.ejmech.2018.02.065.

    Article  CAS  PubMed  Google Scholar 

  6. Kumar D, Kumar NM, Akamatsu K, Kusaka E, Harada H, Ito T. Synthesis and biological evaluation of indolyl chalcones as antitumor agents. Bioorg Med Chem Lett. 2010;20:3916–9. https://doi.org/10.1016/j.bmcl.2010.05.016.

    Article  CAS  PubMed  Google Scholar 

  7. Martel-Frachet V, Keramidas M, Nurisso A, DeBonis S, Rome C, Coll J-L, et al. IPP51, a chalcone acting as a microtubule inhibitor with <i>in vivo</i> antitumor activity against bladder carcinoma. Oncotarget. 2015;6:14669–86. https://doi.org/10.18632/oncotarget.4144.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Mirzaei H, Shokrzadeh M, Modanloo M, Ziar A, Hossein G, Emami S. New indole-based chalconoids as tubulin-targeting antiproliferative agents. Bioorg Chem. 2017;75:86–98. https://doi.org/10.1016/j.bioorg.2017.09.005.

  9. Boumendjel A, McLeer-Forin A, Champelovier P, et al. A novel chalcone derivative which acts as a microtubule depolymerising agent and an inhibitor of P-gp and BCRP in in-vitro and in-vivo glioblastoma models. BMC Cancer. 2009;9:242. https://doi.org/10.1186/1471-2407-9-242.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Pedras MSC, Yaya EE, Glawischnig E. The phytoalexins from cultivated and wild crucifers: chemistry and biology. Nat Prod Rep. 2011;28:1381. https://doi.org/10.1039/c1np00020a.

    Article  CAS  PubMed  Google Scholar 

  11. Chripkova M, Zigo F, Mojzis J. Antiproliferative Effect of Indole Phytoalexins. Molecules. 2016;21:6–8. https://doi.org/10.3390/molecules21121626.

    Article  CAS  Google Scholar 

  12. Pilátová M, Šarišský M, Kutschy P, et al. Cruciferous phytoalexins: antiproliferative effects in T-Jurkat leukemic cells. Leuk Res. 2005;29:415–21. https://doi.org/10.1016/j.leukres.2004.09.003.

    Article  CAS  PubMed  Google Scholar 

  13. Chripkova M, Drutovic D, Pilatova M, Mikes J, Budovska M, Vaskova J, et al. Brassinin and its derivatives as potential anticancer agents. Toxicol Vitr. 2014;28:909–15. https://doi.org/10.1016/j.tiv.2014.04.002.

    Article  CAS  Google Scholar 

  14. Rozmer Z, Perjési P. Naturally occurring chalcones and their biological activities. Phytochem Rev. 2016;15:87–120. https://doi.org/10.1007/s11101-014-9387-8.

    Article  CAS  Google Scholar 

  15. Martel-Frachet V, Kadri M, Boumendjel A, Ronot X. Structural requirement of arylindolylpropenones as anti-bladder carcinoma cells agents. Bioorganic Med Chem. 2011;19:6143–8. https://doi.org/10.1016/j.bmc.2011.08.015.

    Article  CAS  Google Scholar 

  16. Valdameri G, Gauthier C, Terreux R, et al. Investigation of chalcones as selective inhibitors of the breast cancer resistance protein: Critical role of methoxylation in both inhibition potency and cytotoxicity. J Med Chem. 2012;55:3193–3200. https://doi.org/10.1021/jm2016528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chirkova ZV, Prituzhalov IV, Filimonov SI, Abramov IG. Synthesis of chalcones from 2-substituted 1-hydroxyindole-5,6-dicarbonitriles. Russ J Org Chem. 2017;53:879–85. https://doi.org/10.1134/s1070428017060112.

    Article  CAS  Google Scholar 

  18. Somei M, Kawasaki T, Kodama A, Nishida T, Shimizu K. Preparation of 1-Hydroxyindole Derivatives and a New Route to 2-Substituted Indoles. Heterocycles. 1991;32:221 https://doi.org/10.3987/COM-90-5647.

    Article  Google Scholar 

  19. Acheson BRM, Hunt PG, Littlewood DM, Murrer BA, Rosenberg HE. The synthesis, reactions, and spectra of 1-acetoxy-, 1-hydroxy-, and 1-methoxy-indoles. J Chem Soc, Perkin Trans. 1978;1:1117–25. https://doi.org/10.1039/P19780001117.

    Article  Google Scholar 

  20. Somei M, Nakajou M, Teramoto T, Tanimoto A, Yamada F. Nucleophilic substitution reaction of 3-acetyl-1-methoxyindole and its application for the synthesis of novel 2-substituted methyl 2,3-dihydro-1-methyl-3-oxo-5H-pyrido-[4,3-b]indole-4-carboxylates. Heterocycles. 1999;51:1949–56. https://doi.org/10.3987/COM-99-860.

    Article  CAS  Google Scholar 

  21. Sasidharan R, Manju SL, Uçar G, Baysal I, Mathew B. Identification of Indole-Based Chalcones: discovery of a Potent, Selective, and Reversible Class of MAO-B Inhibitors. Arch Pharm (Weinheim). 2016;349:627–37. https://doi.org/10.1002/ardp.201600088.

    Article  CAS  Google Scholar 

  22. Petrov O, Ivanova Y, Gerova M. SOCl2/EtOH: Catalytic system for synthesis of chalcones. Catal Commun. 2008;9:315–6. https://doi.org/10.1016/j.catcom.2007.06.013.

    Article  CAS  Google Scholar 

  23. Venkatesan P, Sumathi S. Piperidine Mediated Synthesis of N-Heterocyclic Chalcones and Their Antibacterial Activity. J Heterocycl Chem. 2010;47:81–4. https://doi.org/10.1002/jhet.268.

    Article  CAS  Google Scholar 

  24. Somei M, Kawasaki T. A New and Simple Synthesis of 1-Hydroxyindole derivatives. Heterocycles. 1989;29:1251–4. https://doi.org/10.3987/COM-89-5037.

    Article  CAS  Google Scholar 

  25. Somei M, Tanimoto A, Orita H, Yamada F, Ohta T. Syntheses of wasabi phytoalexin (methyl 1-methoxyindole-3-carboxylate) and its 5-iodo derivative, and their nucleophilic substitution reactions. Heterocycles. 2001;54:425–32. https://doi.org/10.3987/COM-00-S(I)12.

    Article  CAS  Google Scholar 

  26. Yamada F, Shinmyo D, Nakajou M, Somei M. Nucleophilic Substitution Reaction of 1-Methoxyindole-3-carbaldehyde. Heterocycles. 2012;86:435 https://doi.org/10.3987/com-12-s(n)41.

    Article  CAS  Google Scholar 

  27. Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Acenã JL, et al. Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II-III Clinical Trials of Major Pharmaceutical Companies: new Structural Trends and Therapeutic Areas. Chem Rev. 2016;116:422–518. https://doi.org/10.1021/acs.chemrev.5b00392.

    Article  CAS  PubMed  Google Scholar 

  28. Hagmann WK. The many roles for fluorine in medicinal chemistry. J Med Chem. 2008;51:4359–69. https://doi.org/10.1021/jm800219f.

    Article  CAS  PubMed  Google Scholar 

  29. Burmaoglu S, Algul O, Anil DA, Gobek A, Duran GG, Ersan RH, et al. Synthesis and anti-proliferative activity of fluoro-substituted chalcones. Bioorg Med Chem Lett. 2016;26:3172–6. https://doi.org/10.1016/j.bmcl.2016.04.096.

  30. Roman BI, Ryck TDE, Patronov A, Slavov SH, Vanhoecke BWA, Katritzky AR, et al. 4-Fluoro-3´,4´,5´-trimethoxychalcone as a new anti-invasive agent. From discovery to initial validation in an in vivo metastasis model. Eur J Med Chem. 2015;101:627–39. https://doi.org/10.1016/j.ejmech.2015.06.029.

    Article  CAS  PubMed  Google Scholar 

  31. Bhaduri S, Ranjan N, Arya DP. An overview of recent advances in duplex DNA recognition by small molecules. Beilstein J Org Chem. 2018;14:1051–86. https://doi.org/10.3762/bjoc.14.93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tripathi M, Giri CG, Das D, Pande R, Giri S, Roymahapatra G, et al. Synthesis, characterization and nucleic acid binding studies of mononuclear copper (II) complexes derived from azo containing O, O donor ligands. Nucleosides, Nucleotides and Nucleic Acids. 2018;37:563–84. https://doi.org/10.1080/15257770.2018.1508694.

    Article  CAS  PubMed  Google Scholar 

  33. Rizvi MA, Dangat Y, Yaseen Z, Gupta V, Khan KZ. Synthesis, Crystal Structure and in vitro DNA Binding Studies of Combretastatin A-4 Analogue. Croat Chem Acta. 2015;88:289–96. https://doi.org/10.5562/cca2662.

    Article  CAS  Google Scholar 

  34. Ashraf R, Hamidullah, Hasanain M, et al. Coumarin-chalcone hybrid instigates DNA damage by minor groove binding and stabilizes p53 through post translational modifications. Sci Rep. 2017;7:45287 https://doi.org/10.1038/srep45287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lázaro E, Lowe PJ, Briand X, Faller B. New Approach To Measure Protein Binding Based on a Parallel Artificial Membrane Assay and Human Serum Albumin. J Med Chem. 2008;51:2009–17. https://doi.org/10.1021/jm7012826.

    Article  CAS  PubMed  Google Scholar 

  36. Buddanavar AT, Nandibewoor ST. Multi-spectroscopic characterization of bovine serum albumin upon interaction with atomoxetine. J Pharm Anal. 2017;7:148–55. https://doi.org/10.1016/j.jpha.2016.10.001.

    Article  PubMed  Google Scholar 

  37. Choudhury JR, Guddneppanavar R, Saluta G, Kucera GL, Bierbach U. Tuning the DNA Conformational Perturbations Induced by Cytotoxic Platinum—Acridine Bisintercalators: effect of Metal Cis / Trans Isomerism and DNA Threading Groups. J Med Chem. 2008;51:3069–72. https://doi.org/10.1021/jm8003569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Paramasivan S, Rujan I, Bolton PH. Circular dichroism of quadruplex DNAs: applications to structure, cation effects and ligand binding. Methods. 2007;43:324–31. https://doi.org/10.1016/j.ymeth.2007.02.009.

    Article  CAS  PubMed  Google Scholar 

  39. Erxleben A. Investigation of Non-covalent Interactions of Metal Complexes with DNA in Cell-free Systems. Chimia (Aarau). 2017;71:102–11. https://doi.org/10.2533/chimia.2017.102.

    Article  CAS  Google Scholar 

  40. Kypr J, Kejnovská I, Renčiuk D, Vorlíčková M. Circular dichroism and conformational polymorphism of DNA. Nucleic Acids Res. 2009;37:1713–25. https://doi.org/10.1093/nar/gkp026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sathyaraj G, Weyhermu T, Nair BU. Synthesis, characterization and DNA binding studies of new ruthenium (II) bisterpyridine complexes. Eur J Med Chem. 2010;45:284–91. https://doi.org/10.1016/j.ejmech.2009.10.008.

    Article  CAS  PubMed  Google Scholar 

  42. Norden B, Tjerneld F. Structure of Methylene Blue-DNA Complexes Studied by Linear and Circular Dichroism Spectroscopy. Biopolymers. 1982;21:1713–34.

    Article  CAS  Google Scholar 

  43. Kvasnica M, Oklestkova J, Bazgier V, et al. Design, synthesis and biological activities of new brassinosteroid analogues with a phenyl group in the side chain. Org Biomol Chem. 2016;14:8691–701. https://doi.org/10.1039/c6ob01479h.

    Article  CAS  PubMed  Google Scholar 

  44. Rendošová M, Vargová Z, Sabolová D, Hudecová D, Gyepes R, Lakatoš B, et al. Silver pyridine-2-sulfonate complex—its characterization, DNA binding, topoisomerase I inhibition, antimicrobial and anticancer response. J Inorg Biochem. 2018;186:206–2016. https://doi.org/10.1016/j.jinorgbio.2018.06.006.

    Article  CAS  PubMed  Google Scholar 

  45. Sabolová D, Vilková M, Imrich J, Potočňák I. New spiroacridine derivatives with DNA-binding and topoisomerase I inhibition activity. Tetrahedron Lett. 2016;57:5592–5. https://doi.org/10.1016/j.tetlet.2016.10.108.

    Article  CAS  Google Scholar 

  46. Takac P, Kello M, Bago M, Kudlickova Z, Vilkova M, Slepcikova P, et al. New chalcone derivative exhibits antiproliferative potential by inducing G2 / M cell cycle arrest, mitochondrial-mediated apoptosis and modulation of MAPK signalling pathway. Chem Biol Interact. 2018;292:37–49. https://doi.org/10.1016/j.cbi.2018.07.005.

Download references

Acknowledgements

This research was supported by the Grant Agency of Ministry of the Education, Science, Research and Sport of the Slovak Republic [VEGA project no. 2/0044/18, VEGA project no. 1/0753/17, VEGA project no. 1/0016/18, VEGA project no. 1/0138/20]. The support of Slovak Research and Development Grant Agency [project APVV-18-0357] is also gratefully acknowledged.

Author information

Authors and Affiliations

  1. Department of Chemistry, Biochemistry and Biophysics, University of Veterinary Medicine and Pharmacy, Košice, Slovak Republic

    Zuzana Kudličková

  2. Department of Pharmacology and Toxicology, University of Veterinary Medicine and Pharmacy, Košice, Slovak Republic

    Peter Takáč

  3. Department of Biochemistry, Institute of Chemistry, Faculty of Science, P. J. Šafárik University, Košice, Slovak Republic

    Danica Sabolová

  4. Laboratory of NMR, Institute of Chemistry, Faculty of Science, P. J. Šafárik University, Košice, Slovak Republic

    Mária Vilková

  5. Department of Mechanochemistry, Institute of Geotechnics, Slovak Academy of Sciences, Košice, Slovak Republic

    Matej Baláž

  6. Central Laboratories and Research Support, Centre of the Region Haná for Biotechnological and Agricultural Research, Faculty of Science, Palacký University, Olomouc, Czech Republic

    Tibor Béres

  7. Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovak Republic

    Ján Mojžiš

Authors
  1. Zuzana Kudličková
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Takáč
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Danica Sabolová
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mária Vilková
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matej Baláž
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tibor Béres
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ján Mojžiš
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zuzana Kudličková.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kudličková, Z., Takáč, P., Sabolová, D. et al. Novel 1-methoxyindole- and 2-alkoxyindole-based chalcones: design, synthesis, characterization, antiproliferative activity and DNA, BSA binding interactions. Med Chem Res 30, 897–912 (2021). https://doi.org/10.1007/s00044-020-02690-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-020-02690-6

Keywords

Search

Navigation