Exploration of N-alkyl-2-[(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio]acetamide derivatives as anticancer and radiosensitizing agents |
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| Institution: | 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. Department of Pharmaceutical Chemistry, College of Pharmacy, Egyptian Russian University, P.O. Box 11829, Badr City, Cairo, Egypt;2. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;3. Department of Applied Organic Chemistry, National Research Center, P.O. Box 12622, Dokki, Giza, Egypt;4. Department of Biology, School of Sciences and Engineering (SSE), The American University in Cairo, P.O. Box 11835, New Cairo, Egypt;5. Department of Pharmacology and Toxicology, College of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt;1. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr Elini St., Cairo 11562, Egypt;2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, Egypt;3. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Egypt;4. National Cancer Institute, Cancer Biology Department, Cairo University, Egypt;5. Faculty of Science, Cairo University, Cairo, Egypt;6. Radioactive Isotopes and Generator Department, Hot Labs Center, Atomic Energy Authority, P.O. Box 13759, Cairo, Egypt;7. Labeled Compounds Department, Hot Labs Center, Atomic Energy Authority, P.O. Box 13759, Cairo, Egypt;8. Biochemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, Egypt;9. Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, 12578 Cairo, Egypt;1. Department of Chemistry, Bolu Abant ?zzet Baysal University, 14030 Bolu, Turkey;2. Hayat Kimya Sanayi Anonim ?irketi, 414250, Basiskele, Kocaeli, Turkey;3. University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy;1. Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China;2. Jiangsu Provincial Key Laboratory for Plant Ex Situ Conservation, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing 210014, China;1. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China;2. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China |
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| Abstract: | Multitargeted therapy is considered a successful approach to cancer treatment. The development of small molecule multikinase inhibitors through hybridization strategy can provide highly potent and selective anticancer agents. A library of N-alkyl-2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio]acetamide derivatives 5–18 was designed and synthesized. The synthesized compounds were screened for cytotoxic activity against MDA-MB-231 breast cancer cell line and showed IC50 in the range of 0.34–149.10 µM. The inhibition percentage of VEGFR-2 was measured for all the compounds and found to be in the range of 90.09–20.44%. The promising compounds 8, 12, 13, 16 and 17 were selected to measure their possible multikinase inhibitory activity against VEGFR-2 and EGFR. IC50 of the promising compounds were in the range of 247–793 nM for VEGFR-2 in reference to sunitinib (IC50 320 nM), and 369–725 nM for EGFR in reference to erlotinib (IC50 568 nM). Compounds 12 and 13 showed the most potent activity towards VEGFR-2 & EGFR, respectively. Measuring the cytotoxicity of 12 and 13 against MCF-10 normal breast cell line indicates their relative safety to normal breast cells (IC50 37 & 97 µM, respectively). As radiotherapy is considered the primary treatment for some types of solid tumors, the radiosensitizing ability of 12 and 13 was measured by subjecting the MDA-MB-231 cells to a single dose of 8 Gy of gamma radiation. IC50 of 12 and 13 decreased from 1.91 & 0.51 µM to 0.79 & 0.43 µM, respectively. Molecular docking was performed to gain insights into the ligand-binding interactions of 12 inside VEGFR-2 and EGFR binding sites in comparison to their co-crystallized ligands. |
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| Keywords: | Quinazolinone Benzenesulfonamide Tyrosine kinase Anticancer |
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