首页|Chalcone derivatives as novel,potent and selective inhibitors against human Notum:Structure-activity relationships and biological evaluations
Chalcone derivatives as novel,potent and selective inhibitors against human Notum:Structure-activity relationships and biological evaluations
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Human Notum(hNotum)inhibitors could be used for treating Wnt signalling-associated diseases includ-ing colorectal cancer.Herein,two series of chalcone derivatives were designed and synthesized aiming to find selective and potent hNotum inhibitors.Structure-activity relationship(SAR)studies showed that 2-methoxyl and 5-bromine substitutions on A-ring significantly enhanced anti-hNotum effect,while 4'-ethoxyl and 3'-alkyl substitutions on B-ring were beneficial for hNotum inhibition.Among all tested chalcones,B11 displayed the most potent anti-Notum effect(IC50=3.6nmol/L),good selectivity,excel-lent chemical stability and suitable metabolic stability.Further investigations showed that B11 acted as a competitive inhibitor of hNotum,while this agent(5 μmol/L)significantly weaken the migration abilities of colorectal cancer cells.Collectively,this study deciphers the SARs of chalcones as hNotum inhibitors and reports a novel and potent hNotum inhibitor with the anti-migration effect on colorectal cancer cells,which offers a promising lead compound to develop novel anti-cancer agents.
Human notum(hNotum)ChalconeComputer-assisted drug discoveryStructure-activity relationship(SAR)Anti-colorectal cancer agent
Shanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine Research,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China
Laboratory of Single-Molecule Cell Biology,Kyoto University Graduate School of Biostudies,Kyoto 606-8501,Japan
Dalian Engineering Research Center for Carbohydrate Agricultural Preparations,Liaoning Provincial Key Laboratory of Carbohydrates,Dalian Institute of Chemical Physics,Chinese Academy of Sciences,Dalian 116023,China
Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine,Shanghai 200137,China
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国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金Shanghai Municipal Health Commission's TCM research projectInnovation Team and Talents Cultivation Program of National Administration of Traditional Chinese MedicineThreeyear Action Plan for Shanghai TCM Development and Inheritance Program
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