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Molecular docking, synthesis, and biological evaluation of 7-azaindole-derivative (7AID) as novel anti-cancer agent and potent DDX3 inhibitor:—an in silico and in vitro approach

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Abstract

The DEAD-box helicase family member DDX3 is involved in many diseases, such as viral infection, inflammation, and cancer. Many studies in the last decade have revealed the role of DDX3 in tumorigenesis and metastasis. DDX3 has both tumour suppressor and oncogenic effect, in the present study we have evaluated the expression levels of DDX3 in cervical squamous cell carcinoma at mRNA level via real-time PCR and protein level via Immunohistochemistry. DDX3 has become a molecule of interest in cancer biology that promotes drug resistance by adaptive response inevitably leading to treatment failure. One approach to avoid the development of resistant to disease is to create novel drugs that target the overexpressed proteins, we designed and synthesized a novel 7-azaindole derivative (7-AID) compound, {5-[1H-pyrrolo (2, 3-b) pyridin-5-yl] pyridin-2-ol]} that could lodge within the adenosine-binding pocket of the DDX3 (PDB ID: 2I4I). The binding efficacy of 7-AID compound with DDX3 was analysed by molecular docking studies. 7-AID was found to interact with the key residues Tyr200 and Arg202 from the Q-motif rendered by π-interactions and hydrogen bonds within the binding pocket with good docking score − 7.99 kcal/mol. The cytotoxicity effect of 7-AID compound was evaluated using MTT assay on human cervical carcinoma cells (HeLa) and breast cancer cells (MCF-7 and MDA MB-231) and the compound shown effective inhibitory concentration (IC50) on Hela cells 16.96 µM/ml and 14.12 and 12.69 µM/ml on MCF-7 and MDA MB-231, respectively. Further, the in-vitro, in-vivo anti-cancer and anti-angiogenic assessment of 7-AID compound was evaluated on Hela cells using scratch wound-healing assay, DAPI staining, cell cycle analysis, immunoblotting, and chorioallontoic membrane assay. Furthermore, the inhibitory effect of derivative compound on DDX3 was investigated in HeLa, MCF-7, and MDA MB-231 cells at the mRNA and protein levels. The results showed that the 7-AID compound effectively inhibited DDX3 in a dose-dependent manner, and the findings suggest that the compound could be used as a potential DDX3 inhibitor.

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Acknowledgements

SERB Project reference no.SB/EMEQ-471/2014; Date: 17/06/2014; EEQ/2019/000569, Dated: 02/01/2020. DBT-BUILDER, Level – III Sanction Lr. No: BT/INF/22/SP41415/2021, Akbar Pasha was supported by CSIR-UGC fellowship, reference Nos. 648, at the Department of Genetics, Osmania University.

Funding

DST-SERB,SB/EMEQ-471/2014,Smita C Pawar,Date: 17/06/2014,Smita C Pawar,DSt-SERB,EEQ/2019/000569,Smita C Pawar,Dated: 02/01/202,Smita C Pawar,DBT-BUILDER,Level – III,BT/INF/22/SP41415/2021,Smita C Pawar

Author information

Author notes

  1. Doneti Ravinder and Akbar Pasha have contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics & Biotechnology, Osmania University, Hyderabad, Telangana, 500 007, India

    Ravinder Doneti, Akbar Pasha & Smita C. Pawar

  2. School of Biosciences Engineering and Technology, VIT Bhopal University, Bhopal, Madhya Pradesh, 466114, India

    Mahendran Botlagunta

  3. Department of Pathology, Osmania Medical College, Hyderabad, Telangana, 500095, India

    S. K. Heena

  4. Department of Chemistry, T John Institute of Technology, Bangalore, Karnataka, 560076, India

    Veera Venkata Vara Prasad Mutyala

Authors
  1. Ravinder Doneti
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  2. Akbar Pasha
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  3. Mahendran Botlagunta
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  4. S. K. Heena
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  5. Veera Venkata Vara Prasad Mutyala
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  6. Smita C. Pawar
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Contributions

DR, AP, MB, and SCP: conceptualization of work plan, synthesis and characterization of the small molecule 7AID, in vitro and clinical studies, manuscript writing. DR, AP, MB, and SCP: data analysis and interpretation. DR and AP: manuscript writing & review and editing. AP and SKH: performed IHC data analysis and interpretation. MVVVP: synthesis and characterization of the small molecule 7AID & Molecular Docking, data analysis. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Smita C. Pawar.

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Conflict of interest

All the authors declare that there is no conflict of interest and no additional benefits or personal relationships that could have appeared to influence the work reported in this paper.

Ethical approval

The study was approved by the ethics committee of MNJ Institute of Oncology & Regional Cancer Centre and institutional ethical committee for biomedical research for the collection of cervical tissue samples. Prior informed written consent & clinical information were collected from the patients.

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Doneti, R., Pasha, A., Botlagunta, M. et al. Molecular docking, synthesis, and biological evaluation of 7-azaindole-derivative (7AID) as novel anti-cancer agent and potent DDX3 inhibitor:—an in silico and in vitro approach. Med Oncol 39, 179 (2022). https://doi.org/10.1007/s12032-022-01826-5

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