Design,synthesis and biological evaluation of anthranilamide derivatives as potent SMO inhibitors |
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| Institution: | 1. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China;2. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China;1. Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, University Campus, S.P. n° 8, Km 0.700, I-09042 Monserrato (CA), Italy;2. Department NEUROFARBA – Pharmaceutical and Nutraceutical Section, University of Firenze, via Ugo Schiff 6, I-50019 Sesto Fiorentino, Firenze, Italy;3. Pharmacelera, Placa Pau Vila, 1, Sector 1, Edificio Palau de Mar, Barcelona 08039, Spain;4. Chemistry Department, College of Science, King Saud University, P. O. Box 2455, Riyadh 11451, Saudi Arabia;1. School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan;2. Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan;3. Department of Biological Science and Technology, I-Shou University, Kaohsiung, Taiwan;4. Department of Pharmacy, Sunshine Psychiatric Hospital, Taichung, Taiwan;5. Drug Development Center, China Medical University, Taichung, Taiwan;1. School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China;2. Department of Medicinal, The Second Clinical Medical College of Northwest Minzu University & The Second Provincial People’s Hospital of Gansu Province, Lanzhou 730000, PR China;1. School of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan;2. Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan;3. Institute of New Drug Development, China Medical University, No. 91 Hsueh-Shih Rd., Taichung 40402, Taiwan;4. Master Program for Pharmaceutical Manufacture, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan;5. Division of Metabolism, Department of Internal Medicine, China Medical University, Taichung 40402, Taiwan;6. Department of Food Nutrition and Health Biotechnology, Asia University, No. 500, Liufeng Rd., Wufeng Dist., Taichung City 413, Taiwan;1. Department of Natural Products Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China;2. School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, PR China;3. Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai 201203, PR China;1. Department of Chemistry, Centre for Advanced Studies, Guru Nanak Dev University, Amritsar 143005, India;2. Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143005, India |
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| Abstract: | A series of anthranilamide derivatives were designed and synthesized as novel smoothened (SMO) inhibitors based on the SMO inhibitor taladegib (LY2940680), which can also inhibit the SMO-D473H mutant, via a ring-opening strategy. The phthalazine core in LY2940680 was replaced with anthranilamide, which retained the inhibitory activity towards the hedgehog (Hh) signaling pathway as evidenced by a dual luciferase reporter gene assay. Compound 12a displayed the best inhibitory activity against the Hh signaling pathway with IC50 value of 34.09 nM, and exhibited better proliferation inhibitory activity towards the Daoy cell line (IC50 = 0.48 μM) than LY2940680 (IC50 = 0.79 μM). |
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| Keywords: | Smoothened inhibitor Hedgehog signaling pathway Ring-opening Anthranilamide Molecular dynamics |
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