Design,synthesis, biological evaluation and dynamics simulation of indazole derivatives with antiangiogenic and antiproliferative anticancer activity |
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| Institution: | 1. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt;2. Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt;3. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada;4. Li KaShing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada;5. Li KaShing Applied Virology Institute, University of Alberta, Edmonton, Alberta, Canada;6. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Nahda University, Beni Suef, Egypt;7. Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Menoufia, Egypt;1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, PR China;2. Central laboratory, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250012, PR China;1. Pharmaceutical Chemistry Department, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo 12311, Egypt;2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt;1. Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China;2. Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, PR China;3. Biomedical Department, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, PR China;4. Institute of Drug Research and Development, Kunming Pharmaceutical Corporation, Kunming 650100, PR China;5. Pharmaceutical Department, Kunming General Hospital of Chengdu Military Command, Kunming 650118, PR China;1. Dept. of Chemistry, Govt. College of Arts & Science, Aurangabad 431001, India;2. Dept. of Chemistry, Deogiri College, Aurangabad 431001, India;3. School of Pharmacy, Department of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel |
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| Abstract: | VEGFR-2 has a pivotal role in promoting cancer angiogenesis. Herein, two series of novel indazole-based derivatives were designed, synthesized and evaluated for their in vitro inhibitory action against VEGFR-2 kinase enzyme. The second series 11a-e exhibited better potency than the first one 7a-d and 8a-f. Compounds 11b, 11c and 11e exhibited the most potent action, with IC50 of 5.4 nM, 5.6 nM and 7 nM, respectively. As a measure of cellular VEGFR-2 inhibition, compounds 11b and 11c showed strong inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 80% and 99.6% inhibition at 10 μM concentration, respectively. Attempting to interpret SAR of the synthesized compounds, and provide a basis for further optimization; a comprehensive modeling study was implemented. Molecular docking, dynamics simulation and free energy calculation of the synthesized compounds along with known VEGFR-2 inhibitors were applied. The study illustrated the effect of several factors on VEGFR-2 inhibition, such as the interaction with solvent accessible region of the enzyme, the presence of NH linker and the degree of conformational restriction. Finally, our compounds were evaluated for their in vitro anti-proliferative effect against the full NCI panel of cancer cell lines, where compounds 11a and 11c displayed mean GI% of 93 and 130%, respectively, and showed partly a better behavior than the FDA approved drug sorafenib, with respect to activity (GI50) and safety (LC50) against several cell lines. Thus, compound 11c represents a promising candidate for cancer treatment through antiangiogenic dependent and antiangiogenic independent modes of action. |
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| Keywords: | Indazole Dynamics VEGFR-2 Anticancer |
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