Skip to main content

Advertisement

SpringerLink
Log in

A novel chromonyl thiohydantoin with anti-proliferative action on primary hepatocellular carcinoma cells

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

Abstract

Chromone, imidazolidinedione, thiohydantoin and 2,4-thiazolidinedione structures are known to be cytotoxic to cancer cells. In this study, biological activities of previously synthesized 18 chromonyl-2,4-thiazolidinediones/imidazolidinediones/thiohydantoins were tested by sulforhodamine B assay in five liver and one breast cancer cell lines. It was shown that a hybrid chromonyl thiohydantoin derivative C9 was able to significantly suppress the proliferation of the liver cancer cell lines which are very resistant to anticancer drugs. According to 50% growth inhibition concentrations of C9, well differentiated hepatocellular carcinoma cell line Huh7 and breast adenocarcinoma cell line Mcf7 cells are found to be highly sensitive to C9 with IC50 values between 4.9–5.2 µM. Poorly differentiated human liver cancer cell line Snu449 is found to be the most resistant to C9. Further studies show that C9 causes morphological changes in Snu449 cells. However, it does not induce significant senescence response or cell cycle arrest. On the other hand, Huh7 cells are found to be arrested in G2/M phase of the cell cycle after 24 and 72 h treatment. In conclusion, a novel chromonyl thiohydantoin hybrid molecule effectively stops or slows down the proliferation of well-differentiated hepatocellular carcinoma cells that exist in primary tumors.

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
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • AbuHammad S, Zihlif M (2013) Gene expression alterations in doxorubicin resistant MCF7 breast cancer cell line. Genomics 101(4):213–220

    Article  CAS  PubMed  Google Scholar 

  • Abul Kashem Liton M, Salma U, Chandra Bhowmick A (2014) Cytotoxicity and 2D-QSAR study of some heterocyclic compounds. Arabian J Chem 7:639–646

    Article  Google Scholar 

  • Azizmohammadi M, Khoobi M, Ramazani A, Emami S, Zarrin A, Firuzi O, Miri R, Shafiee A (2013) 2H-chromene derivatives bearing thiazolidine-2,4-dione, rhodanine or hydantoin moieties as potential anticancer agents. Eur J Med Chem 59:15–22

    Article  CAS  PubMed  Google Scholar 

  • Bae MA, Rhee H, Song BJ (2003) Troglitazone but not rosiglitazone induces G1 cell cycle arrest and apoptosis in human and rat hepatoma cell lines. Toxicol Lett 139(1):67–75

    Article  CAS  PubMed  Google Scholar 

  • Ceylan-Unlusoy M, Verspohl EJ, Ertan R (2010) Synthesis and antidiabetic activity of some new chromonyl-2,4-thiazolidinediones. J Enzyme Inhib Med Chem 25(6):784–789

    Article  PubMed  Google Scholar 

  • Ceylan-Unlusoy M, Kazak C, Bayro O, Verspohl EJ, Ertan R, Bozdag-Dundar O (2013) Synthesis and antidiabetic activity of 2,4-thiazolidinedione, imidazolidinedione and 2-thioxo-imidazolidine-4-one derivatives bearing 6-methyl chromonyl pharmacophore. J Enzyme Inhib Med Chem 28(6):1205–1210

    Article  Google Scholar 

  • Cragg GM, Grothaus PG, Newman DJ (2009) Impact of natural products on developing new anti-cancer agents. Chem Rev 109:3012–3043

    Article  CAS  PubMed  Google Scholar 

  • De Luca P, De Siervi A (2016) Critical role for BRCA1 expression as a marker of chemosensitivity response and prognosis. Front Biosci (Elite Ed) 1(8):72–83

    Google Scholar 

  • Di Braccio M, Grossi G, Roma G, Marzano C, Baccichetti F, Simonato M, Bordin F (2003) Pyran derivatives: part XXI. Antiproliferative and cytotoxic properties of novel N-substituted 4-aminocoumarins, their benzo-fused derivatives, and some related 2-aminochromones. II Farmaco 58:1083–1097

    Article  Google Scholar 

  • Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92(20):9363–9367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • El-Serag HB (2011) Hepatocellular carcinoma. N Engl J Med 365(12):1118–1127

    Article  CAS  PubMed  Google Scholar 

  • Forner A, Gilabert M, Bruix J, Raoul JL (2014) Treatment of intermediate-stage hepatocellular carcinoma. Nat Rev Clin Oncol 11(9):525–535

    Article  CAS  PubMed  Google Scholar 

  • Germano D, Daniele B (2014) Systemic therapy of hepatocellular carcinoma: current status and future perspectives. World J Gastroenterol 20(12):3087–3099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Germano D, Tinessa V, Barletta E, Cannella L, Daniele B (2013) Medical treatment of hepatocellular carcinoma. Minerva Med 104(5):545–561

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Koga H, Harada M, Ohtsubo M, Shishido S, Kumemura H, Hanada S, Taniguchi E, Yamashita K, Kumashiro R, Ueno T, Sata M (2003) Troglitazone induces p27Kip1-associated cell-cycle arrest through down-regulating Skp2 in human hepatoma cells. Hepatology 37(5):1086–1096

    Article  CAS  PubMed  Google Scholar 

  • Martens S, Mithofer A (2005) Flavones and flavone synthases. Phytochemistry 66:2399–2407

    Article  CAS  PubMed  Google Scholar 

  • Middleton Jr E, Kandaswami C, Theoharides TC (2000) The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease and cancer. Pharmacol Rev 52:673–751

    CAS  PubMed  Google Scholar 

  • Parveen M, Malla AM, Yaseen Z, Ali A, Alam M (2014) Synthesis, characterization, DNA-binding studies and acetylcholinesterase inhibition activity of new 3-formyl chromone derivatives. J Photochem Photobiol B 130:179–187

    Article  CAS  PubMed  Google Scholar 

  • Rodier F, Campisi J (2011) Four faces of cellular senescence. J Cell Biol 192(4):547–556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen Y-C, Hsu C, Chen J-Y, Cheng A-L (2004) Lack of efficacy of troglitazone at clinically achievable concentrations, with or without 9-cis retinoic acid or cytotoxic agents, for hepatocellular carcinoma cell lines. Br J Cancer 91(8):1561–1565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thun MJ, DeLancey JO, Center MM, Jemal A, Ward EM (2010) The global burden of cancer: priorities for prevention. Carcinogenesis 31(1):100–110

    Article  CAS  PubMed  Google Scholar 

  • Vichai V, Kirtikara K (2006) Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 1(3):1112–1116

    Article  CAS  PubMed  Google Scholar 

  • Villanueva A, Hernandez-Gea V, Llovet JM (2013) Medical therapies for hepatocellular carcinoma: a critical view of the evidence. Nat Rev Gastroenterol Hepatol 10(1):34–42

    Article  CAS  PubMed  Google Scholar 

  • Wörns MA, Galle PR (2010) Novel inhibitors in development for hepatocellular carcinoma. Expert Opin Investig Drugs 19(5):615–629

    Article  PubMed  Google Scholar 

  • Yuzugullu H, Benhaj K, Ozturk N, Senturk S, Celik E, Toylu A, Tasdemir N, Yilmaz M, Erdal E, Akcali KC, Atabey N, Ozturk M (2009) Canonical Wnt signaling is antagonized by noncanonical Wnt5a in hepatocellular carcinoma cells. Mol Cancer 8:90

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhu AX (2012) Molecularly targeted therapy for advanced hepatocellular carcinoma in 2012: current status and future perspectives. Semin Oncol 39(4):493–502

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Research Organization of Ankara University, Turkey (No: 09B3336003 and 12B3336003). One of the authors was supported by TUBA DSAP program. Biological part of the study was supported by the Scientific and Technological Research Council of Turkey with project 113S389.

Author information

Authors and Affiliations

  1. Izmir International Biomedicine and Genome Center, iBG-Izmir, Dokuz Eylul University, 35340, Balcova, Izmir, Turkey

    Cigdem Ozen & Mehmet Ozturk

  2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, 06100, Tandogan, Ankara, Turkey

    Meltem Ceylan-Unlusoy & Oya Bozdag-Dundar

Authors
  1. Cigdem Ozen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meltem Ceylan-Unlusoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mehmet Ozturk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Oya Bozdag-Dundar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Oya Bozdag-Dundar.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ozen, C., Ceylan-Unlusoy, M., Ozturk, M. et al. A novel chromonyl thiohydantoin with anti-proliferative action on primary hepatocellular carcinoma cells. Med Chem Res 27, 153–160 (2018). https://doi.org/10.1007/s00044-017-2037-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-017-2037-0

Keywords

Search

Navigation