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 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.
Fares Hezam Al-Ostoot, Obtained his MSc at SRTM University in 2015 goting first class with distinction, and he is a Ph.D. research scholar, currently works at the Department of Medical Biochemistry, Mysore University, Mysuru, India. He joined as an assistant professor at Al-Baydha University, Yemen in 2008. He is an academic lecturer in the Department of Biochemistry, Faculty of Education and Science, University of Al-Baydaah, Yemen. He has published more than 34 research articles in reputed journals.