Chalcone derivatives as novel,potent and selective inhibitors against human Notum:Structure–activity relationships and biological evaluations  

作　　者：Jin-Hui Shi Bei Zhao Li-Lin Song Yu-Qing Song Meng-Ru Sun Tian Tian Hong-Yu Chen Yun-Qing Song Jian-Ming Sun Guang-Bo Ge 

机构地区：[1]Shanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine Research,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China [2]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 [3]Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine,Shanghai 200137,China

出　　处：《Chinese Chemical Letters》2024年第3期321-325,共5页中国化学快报（英文版）

基　　金：financially supported by the National Natural Science Foundation of China(Nos.82104281,81922070,81973286,81801818 and 82273897);Shanghai Municipal Health Commission’s TCM research project(No.2022CX005);Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTD-D-202004);Three-year Action Plan for Shanghai TCM Development and Inheritance Program[No.ZY(2021–2023)-0401]。

摘　　要：Human Notum(hNotum)inhibitors could be used for treating Wnt signalling-associated diseases including 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(IC_(50)=3.6 nmol/L),good selectivity,excellent chemical stability and suitable metabolic stability.Further investigations showed that B11 acted as a competitive inhibitor of hNotum,while this agent(5μmol/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.

关 键 词：Human notum(hNotum) CHALCONE Computer-assisted drug discovery Structure–activity relationship(SAR) Anti-colorectal cancer agent 

分 类 号：TQ460.1[化学工程—制药化工]