Prabhakar B T1, Shaukath Ara Khanum2, Fares Hezam Al-Ostoot3,4, Ankith Sherapura5, Vigneshwaran V5,6, Giridhara Basappa5, Vivek H K7. 1. Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, Karnataka, India. prabhakarbt1@kussc.org. 2. Department of Chemistry, Yuvaraja's College, University of Mysore, Mysuru, India. shaukathah@ycm.uni-mysore.ac.in. 3. Department of Chemistry, Yuvaraja's College, University of Mysore, Mysuru, India. 4. Department of Biochemistry, Faculty of Education and Science, Al-Baydha University, Mecca, Yemen. 5. Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, Karnataka, India. 6. Department of Pharmacology, University of Illinois at Chicago, Chicago, USA. 7. Faculty of Natural Sciences, Adichunchanagiri University-Center for Research and Innovation, Adichunchanagiri University, BGSIT Campus, B.G. Nagara, Mandya, Karnataka, 571448, India.
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.
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.
Authors: Ankith Sherapura; Vikas H Malojirao; B S Sharath; Prabhu Thirusangu; Riaz Mahmood; N Suchetha Kumari; Shrinath M Baliga; Shaukath Ara Khanum; B T Prabhakar Journal: Pharmacol Rep Date: 2022-01-10 Impact factor: 3.024