Skip to main content
SpringerLink
Log in

Design and synthesis of benzimidazole derivatives as apoptosis-inducing agents by targeting Bcl-2 protein

  • Original Article
  • Published:
Molecular Diversity Aims and scope Submit manuscript

Abstract

Bcl-2, an anti-apoptotic protein, is a well-known and appealing cancer therapy target. Novel series of benzimidazole derivatives were synthesized and tested for their activity as Bcl-2 inhibitors on T98G glioblastoma, PC3 prostate, MCF-7 breast, and H69AR lung cancer cells. MTT assay was used to evaluate the cytotoxic effect. PI Annexin V Apoptosis Detection Kit was used to detect apoptosis. Expression levels of the Bcl-2 protein were examined by the Western blot analysis and qRT-PCR. All synthesized benzimidazole derivatives exhibited a cytotoxic effect on cancer cells with IC50 values in the range of 25.2–88.2 µg/mL. Among all derivatives, compounds C1 and D1 demonstrated a higher cytotoxic effect on cancer cells with IC50 values < 50 µg/mL, while a lower cytotoxic effect against human embryonic kidney cells with IC50 values of > 100 µg/mL. C1 and D1 caused a significant increase in the percentage of apoptotic cells in all types of cancer cell cells and both Bcl-2 mRNA and protein levels were significantly reduced. These results suggest that the novel benzimidazole derivatives may be candidates for apoptosis-inducing agents in cancer treatment by targeting anti-Bcl-2 proteins in cancer cells.

Graphical abstract

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

Similar content being viewed by others

References

  1. Atmaca H, İlhan S, Batır MB et al (2020) Novel benzimidazole derivatives: synthesis, in vitro cytotoxicity, apoptosis and cell cycle studies. Chem Biol Interact 327:109163. https://doi.org/10.1016/j.cbi.2020.109163

    Article  CAS  PubMed  Google Scholar 

  2. Sridhar Goud N, Pooladanda V, Muni Chandra K et al (2020) Novel benzimidazole-triazole hybrids as apoptosis inducing agents in lung cancer: design, synthesis, 18F-radiolabeling & galectin-1 inhibition studies. Bioorg Chem 102:104125. https://doi.org/10.1016/j.bioorg.2020.104125

    Article  CAS  PubMed  Google Scholar 

  3. Perini GF, Ribeiro GN, Pinto Neto JV et al (2018) BCL-2 as therapeutic target for hematological malignancies. J Hematol Oncol 11:1–15. https://doi.org/10.1186/s13045-018-0608-2

    Article  CAS  Google Scholar 

  4. Chen K, Chu BZ, Liu F et al (2015) New benzimidazole acridine derivative induces human colon cancer cell apoptosis in vitro via the ROS-JNK signaling pathway. Acta Pharmacol Sin 36:1074–1084. https://doi.org/10.1038/aps.2015.44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Vogler M (2014) Targeting BCL2-proteins for the treatment of solid tumours. Adv Med 2014:1–14. https://doi.org/10.1155/2014/943648

    Article  Google Scholar 

  6. Kang MH, Reynolds CP (2009) BcI-2 Inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 15:1126–1132. https://doi.org/10.1158/1078-0432.CCR-08-0144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Leber B, Geng F, Kale J, Andrews DW (2010) Drugs targeting Bcl-2 family members as an emerging strategy in cancer. Expert Rev Mol Med 12:1–19. https://doi.org/10.1017/S1462399410001572

    Article  CAS  Google Scholar 

  8. Campbell KJ, Tait SWG (2018) Targeting BCL-2 regulated apoptosis in cancer. Open Biol 8(5):180002

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ilhan S (2020) Essential oils from Vitex agnus castus L. leaves induces caspase-dependent apoptosis of human multidrug-resistant lung carcinoma cells through intrinsic and extrinsic pathways. Nutr Cancer. https://doi.org/10.1080/01635581.2020.1823439

    Article  PubMed  Google Scholar 

  10. Zugazagoitia J, Guedes C, Ponce S et al (2016) Current challenges in cancer treatment. Clin Ther 38:1551–1566. https://doi.org/10.1016/j.clinthera.2016.03.026

    Article  PubMed  Google Scholar 

  11. Siegel RL, Miller KD, Jemal A (2020) Cancer statistics, 2020. CA Cancer J Clin. https://doi.org/10.3322/caac.21590

    Article  PubMed  Google Scholar 

  12. Mostaghni F, Taat F (2020) CoFe2O4as green and efficient catalyst for synthesis of multisubstituted imidazoles. Eurasian Chem Commun. https://doi.org/10.33945/SAMI/ECC.2020.4.1

  13. Hakimi F, Fallah-Mehrjardi M, Golrasan E (2020) Yttrium aluminum garnet (YAG: Al5Y3O12) as an efficient catalyst for the synthesis of benzimidazole and benzoxazole derivatives. Chem Methodol 4:234–244

    CAS  Google Scholar 

  14. Rehan TA, Al-Lami N, Alanee RS (2021) Anti-cancer and antioxidant activities of some new synthesized 3-secondary amine derivatives bearing imidazo [1,2-A] pyrimidine. Eurasian Chem Commun 3:339–351

    CAS  Google Scholar 

  15. Haddazadeh E, Mohammadi MK (2020) One-pot synthesize of phenyl phenanthro ımidazole derivatives catalyzed by lewis acid in the presence of ammonium acetate. Chem Methodol 4:324–332

    Google Scholar 

  16. El Rashedy A, Aboul-Enein H (2013) Benzimidazole derivatives as potential anticancer agents. Mini-Reviews Med Chem 13:399–407. https://doi.org/10.2174/1389557511313030008

    Article  Google Scholar 

  17. Yadav S, Narasimhan B, Kaur H (2016) Perspectives of benzimidazole derivatives as anticancer agents in the new era. Anticancer Agents Med Chem 16:1403–1425. https://doi.org/10.2174/1871520616666151103113412

    Article  CAS  PubMed  Google Scholar 

  18. Shinde VS, Lawande PP, Sontakke VA, Khan A (2020) Synthesis of benzimidazole nucleosides and their anticancer activity. Carbohydr Res 498:108178. https://doi.org/10.1016/j.carres.2020.108178

    Article  CAS  PubMed  Google Scholar 

  19. Shrivastava N, Naim MJ, Alam MJ et al (2017) Benzimidazole scaffold as anticancer agent: synthetic approaches and structure-activity relationship. Arch Pharm (Weinheim) 350:1–80. https://doi.org/10.1002/ardp.201700040

    Article  CAS  Google Scholar 

  20. Henderson JP, Byun J, Williams MV et al (2001) Bromination of deoxycytidine by eosinophil peroxidase: a mechanism for mutagenesis by oxidative damage of nucleotide precursors. Proc Natl Acad Sci U S A 98:1631–1636. https://doi.org/10.1073/pnas.98.4.1631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hładoń B, Gośliński T, Laskowska H et al (2002) In vitro cytostatic activity of 8-substituted and tricyclic analogues of acyclovir. Pol J Pharmacol 54:45–53

    PubMed  Google Scholar 

  22. Wong RSY (2011) Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res 30:1–14. https://doi.org/10.1186/1756-9966-30-87

    Article  CAS  Google Scholar 

  23. International BMR (2020) Retracted: apoptosis and molecular targeting therapy in cancer. Biomed Res Int 2020:2451249. https://doi.org/10.1155/2020/2451249

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biology, Faculty of Science and Letters, Celal Bayar University, 45140, Manisa, Turkey

    Suleyman Ilhan, Ferdi Oguz & Harika Atmaca

  2. Applied Science Research Center, Manisa Celal Bayar University, Manisa, Turkey

    Çisil Çamli Pulat

  3. Department of Chemistry, Faculty of Science and Art, Giresun University, Giresun, Turkey

    Hakan Bektaş

  4. Department of Chemistry, Faculty of Science and Art, Recep Tayyip Erdogan University, Rize, Turkey

    Emre Menteşe

Authors
  1. Suleyman Ilhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Çisil Çamli Pulat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ferdi Oguz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hakan Bektaş
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Emre Menteşe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Harika Atmaca
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Harika Atmaca.

Ethics declarations

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ilhan, S., Çamli Pulat, Ç., Oguz, F. et al. Design and synthesis of benzimidazole derivatives as apoptosis-inducing agents by targeting Bcl-2 protein. Mol Divers 27, 1703–1712 (2023). https://doi.org/10.1007/s11030-022-10524-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11030-022-10524-3

Keywords

Search

Navigation