Skip to main content

Advertisement

SpringerLink
Log in

In silico and in vitro studies of novel 7-azaindole and 7-azaisatin derivatives as potent anticancer agents

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

Abstract

A series of novel 7-azaindole (1a–j) and 7-azaisatin (2a–j) derivatives were screened for their in vitro breast, lung and liver cytotoxic activities against MCF-7, A549 and HEPG2 cell lines, respectively, by MTT assay method. Among them, compounds 1h, 1i, 2h and 2i have shown good breast cytotoxic activity, and compounds 1h and 1i showed good lung cytotoxic activity and liver cytotoxic activity. These derivatives were also subjected to molecular docking study to investigate the mode of binding with the EGFR kinase, and the compounds showing similar type of docking score and binding patterns with that of the existing drug molecules such as gefitinib. 3D-QSAR studies were done using V-Life Sciences MDS 4.3 drug designing module to explain the structural requirements for the anticancer activity. Since compounds 1h and 1i exhibited high potent activity against MCF-7, A549 and HEPG2 cell lines, they could be effective epidermal growth factor receptor kinase inhibitors.

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
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Ajmani S, Karanam S, Kulkarni SA (2009) Rationalizing protein ligand interactions for PTP1B inhibitors using computational methods. Chem Biol Drug Des 74:582–595

    Article  CAS  PubMed  Google Scholar 

  • Berridge MV, Tan AS (1993) Characterisation of the cellular reduction of 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT): subcellular localization, substrate dependence, and involvement of mitochondrial electron transport in MTT reduction. Arch Biochem Biophys 303:474–482

    Article  CAS  PubMed  Google Scholar 

  • Berridge MV, Herst PM, Tan AS (2005) Tetrazolium dyes as tools in cell biology: new insights into their cellular reduction. Biotechnol Ann Rev 11:127–152

    Article  CAS  Google Scholar 

  • Dunham W, (2007) Report sees 7.6 million global 2007 cancer deaths. American Cancer Society, Washington. http://www.reuters.com/article/idUSN1633064920071217

  • Fatima I, Ahmad I, Anis I, Malik A, Afza N (2007) Isatinones A and B, New antifungal oxindole alkaloids from Isatis costata. Molecules 12:155–162

    Article  CAS  PubMed  Google Scholar 

  • Gehlhaar DK, Verkhivker GM, Rejto PA, Sherman CJ, Fogel D et al (1995) Molecular recognition of the inhibitor AC-1343 by HIV-l protease: conformationally flexible docking by evolutionary programming. Chem Biol 2:317–324

    Article  CAS  PubMed  Google Scholar 

  • Gullick WJ (1991) Prevalence of aberrant expression of the epidermal growth factor receptor in human cancers. Br Med Bull 47:87–98

    CAS  PubMed  Google Scholar 

  • Kritsanida M, Magiatis P, Skaltsounis AL, Peng Y, Li P, Wennogle LP (2009) Synthesis and antiproliferative activity of 7-azaindirubin-30-oxime, a 7-aza isostere of the natural indirubin pharmacophore. J Nat Prod 72:2199–2202

    Article  CAS  PubMed  Google Scholar 

  • Mosmann T (1982) J Immunol Methods 65(1–2):55–63

    Google Scholar 

  • Pao W, Miller V, Zakowski M et al (2004) EGF receptor gene mutations are common in lung cancers from never smokers and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 36:13306–13311

    Article  Google Scholar 

  • Prakash CR, Raja S, Saravanan G (2010) Synthesis characterization and anti-inflammatory activity of novel Schiff base of isatin derivatives. Int J Pharm Sci Biotech 1:105–112

    Google Scholar 

  • Rottmann M, McNamara C, Yeung BKS, Lee MCS, Zou B, Russell B, Seitz P, Pluoffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, Gonalez-Paez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT (2010) Spiroindolones, a potent compound class for the treatment of malaria. Science 329:1175–1180

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sriram R, Sesha Sai Pavan Kumar CN, Raghunandan N, Ramesh V, Sarangapani M, Rao VJ (2012) AlCl3/PCC-SiO2-promotedoxidation of azaindoles and Indoles. Synth Commun 42:3419–3428

    Article  CAS  Google Scholar 

  • Tatsugi J, Zhiwei T, Tsuchiya Y, Takayoshi I (2009) Halogenation of 1-alkyl-7-azaisatins using N-halosuccinimides: regioselective synthesis of 1-alkyl-5-halo-7-azaisatins. Arkivoc 2:132–137

    Article  Google Scholar 

  • Varma RS, Nobles WL (1975) Antiviral antibacterial and antifungal activities of isatin N-Mannich bases. J Pharm Sci 64:881–882

    Article  CAS  PubMed  Google Scholar 

  • Verkhivker GM, Bouzida D, Gehlhaar DK, Rejto PA, Arthurs S et al (2000) Deciphering common failures in molecular docking of ligand–protein complexes. J Comput Aided Mol Des 14:731–751

    Article  CAS  PubMed  Google Scholar 

  • Verma M, Pandeya SN, Singh KN, Stables JP (2004) Anticonvulsant activity of Schiff bases of isatin derivatives. Acta Pharm 54:49–56

    CAS  PubMed  Google Scholar 

  • Vine KL, Locke JM, Ranson M, Pyne SG, Bremner JB (2007) An investigation into the cytotoxicity and mode of action of some novel N-alkyl-substituted isatins. J Med Chem 50:5109–5117

    Article  CAS  PubMed  Google Scholar 

  • Wood ER, Kuyper L, Petrov KG, Hunter RN, Harris PA, Lackey K (2004) Discovery and in vitro evaluation of potent TrkA kinase inhibitors: oxindole and azaoxindoles. Bioorg Med Chem Lett 14:953–957

    Article  CAS  PubMed  Google Scholar 

  • World Health Organization (2006) Reproductive Health, World Health Organization. Chronic Diseases & Health Promotion. Comprehensive cervical cancer control: a guide to essential practice. World Health Organization

  • Yardern Y, Ullrich A (1988) Growth factor receptor tyrosine kinases. Annu Rev Biochem 57:443–478

    Article  Google Scholar 

  • Yasuda H, Park E, Yun CH, Sng NJ, Lucena-Araujo AR, Yeo WL, Huberman MS, Cohen DW, Nakayama S, Ishioka K, Yamaguchi N, Hanna M, Oxnard GR, Lathan CS, Moran T, Sequist LV, Chaft JE, Riely GJ, Arcila ME, Soo RA, Meyerson M, Eck MJ, Kobayashi SS, Costa DB (2014) Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med 26:225–247

    Google Scholar 

  • Zwick E, Bange J, Ullrich A (2001) Receptor tyrosine kinase signalling as a target for cancer intervention strategies. Endocr Relat Cancer 8:161–173

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We are thankful to Indian Institute of Chemical Technology (IICT) and thank the director, IICT, and the head of the Division Organic II for encouragement. Authors J.R and M.S thank the University Grants Commission, New Delhi, for project, and R. S. thanks the Department of Science and Technology (Inspire), New Delhi, for fellowships.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, 506 009, Telangana, India

    Sriram Rekulapally, Ravi Jarapula & Sarangapani Manda

  2. Organic Chemistry Division II, Indian Institute of Chemical Technology, Tarnaka, Hyderabad, Telangana, India

    Sriram Rekulapally & Jayathirtha Rao Vaidya

  3. Department of Pharmaceutical Chemistry, Chaitanya Institute of Pharmaceutical Sciences, Warangal, Telangana, India

    Kiran Gangarapu

Authors
  1. Sriram Rekulapally
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ravi Jarapula
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kiran Gangarapu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sarangapani Manda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jayathirtha Rao Vaidya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sriram Rekulapally.

Ethics declarations

Conflict of interest

The authors declare that there is 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

Rekulapally, S., Jarapula, R., Gangarapu, K. et al. In silico and in vitro studies of novel 7-azaindole and 7-azaisatin derivatives as potent anticancer agents. Med Chem Res 24, 3412–3422 (2015). https://doi.org/10.1007/s00044-015-1390-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-015-1390-0

Keywords

Search

Navigation