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Targeting HIF-1α by newly synthesized Indolephenoxyacetamide (IPA) analogs to induce anti-angiogenesis-mediated solid tumor suppression

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Abstract

Background

Hypoxic microenvironment is a common feature of solid tumors, which leads to the promotion of cancer. The transcription factor, HIF-1α, expressed under hypoxic conditions stimulates tumor angiogenesis, favoring HIF-1α as a promising anticancer agent. On the other hand, synthetic Indolephenoxyacetamide derivatives are known for their pharmacological potentiality. With this background here, we have synthesized, characterized, and validated the new IPA (8a–n) analogs for anti-tumor activity.

Methods

The new series of IPA (8a–n) were synthesized through a multi-step reaction sequence and characterized based on the different spectroscopic analysis FT-IR, 1H, 13C NMR, mass spectra, and elemental analyses. Cell-based screening of IPA (8a–n) was assessed by MTT assay. Anti-angiogenic efficacy of IPA (8k) validated through CAM, Rat corneal, tube formation and migration assay. The underlying molecular mechanism is validated through zymogram and IB studies. The in vivo anti-tumor activity was measured in the DLA solid tumor model.

Results

Screening for anti-proliferative studies inferred, IPA (8k) is a lead molecule with an IC50 value of ˜5 μM. Anti-angiogenic assays revealed the angiopreventive activity through inhibition of HIF-1α and modulation downstream regulatory genes, VEGF, MMPs, and P53. The results are confirmative in an in vivo solid tumor model.

Conclusion

The IPA (8k) is a potent anti-proliferative molecule with anti-angiogenic activity and specifically targets HIF1α, thereby modulates its downstream regulatory genes both in vitro and in vivo. The study provides scope for new target-specific drug development against HIF-1α for the treatment of solid tumors.

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Acknowledgements

Fares Hezam Al-Ostoot is thankful to the government of Yemen and Al-Baydha University, Yemen, for providing financial assistance under the teacher's fellowship and also thankful to the University of Mysore, Mysore, India. Ankith Sherapur thanks the Lady Tata Memorial Trust for JRS (2020–2021) and B.T. Prabhakar gratefully acknowledges the grant support by VGST (VGST/P-2/CISEE/GRD-231/2013-14) and SERB [EMR/2017/00088/dated 3/01/2019]. Shaukath Ara Khanum thankfully acknowledges the financial support provided by VGST, Bangalore, under CISEE Program [Project sanction order: No. VGST/CISEE/282/2012-13].

Author information

Author notes

  1. Fares Hezam Al-Ostoot

    Present address: Department of Chemistry, Yuvaraja’s College, University of Mysore, Mysuru, India

  2. Vigneshwaran V

    Present address: Department of Pharmacology, University of Illinois at Chicago, Chicago, USA

  3. B.T. Prabhakar and Shaukath Ara Khanum contributed equally.

Authors and Affiliations

  1. Department of Chemistry, Yuvaraja’s College, University of Mysore, Mysuru, India

    Shaukath Ara Khanum

  2. Department of Biochemistry, Faculty of Education and Science, Al-Baydha University, Mecca, Yemen

    Fares Hezam Al-Ostoot

  3. Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, Karnataka, India

    Ankith Sherapura, Vigneshwaran V, Giridhara Basappa & Prabhakar B.T

  4. Faculty of Natural Sciences, Adichunchanagiri University-Center for Research and Innovation, Adichunchanagiri University, BGSIT Campus, B.G. Nagara, Mandya, Karnataka, 571448, India

    Vivek H.K.

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  1. Fares Hezam Al-Ostoot
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Contributions

FHA and AS performed all the experiments, VV and HKV assisted in experiments, GB supported through statistical analysis, SAK and PBT designed the experiments, wrote the manuscript and monitored the entire investigation.

Corresponding authors

Correspondence to Prabhakar B.T or Shaukath Ara Khanum.

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The authors declare that there are no conflicts of interest.

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Al-Ostoot, F.H., Sherapura, A., V, V. et al. Targeting HIF-1α by newly synthesized Indolephenoxyacetamide (IPA) analogs to induce anti-angiogenesis-mediated solid tumor suppression. Pharmacol. Rep 73, 1328–1343 (2021). https://doi.org/10.1007/s43440-021-00266-8

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  • DOI: https://doi.org/10.1007/s43440-021-00266-8

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