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Exploration of novel isoxazole-fused quinone derivatives as anti-colorectal cancer agents through inhibiting STAT3 and elevating ROS level

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资源类型：
Pubmed体系：
作者：
Zhang Lidan[1,2,3] * ; Liu Pingxian[1,2,3] * ; Jiang Yunhan[1,3,4] * ; Fan Dongmei[1,3] ; He Xinlian[1,2,3] ; Zhang Jiangnan[2] ; Luo Baozhu[2] ; Sui Jing[2] ; Luo Youfu[2,*2] ; Fu Xinyuan[1,2,3,*3] ; Yang Tao[1,2,3,*1] ;
机构： [1]Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Chengdu, 610041, China [2]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China [3]Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China [4]Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
出处：
DOI： 10.1016/j.ejmech.2024.116448
ISSN：

关键词： Colorectal cancer Dual-action Signal transducer and activator of transcription 3 (STAT3) Phosphorylation Reactive oxygen species (ROS)

摘要：
Colorectal cancer (CRC) is trending to be a major health problem throughout the world. Therapeutics with dual modes of action have shown latent capacity to create ideal anti-tumor activity. Signal transducer and activator of transcription 3 (STAT3) has been proved to be a potential target for the development of anti-colon cancer drug. In addition, modulation of tumor redox homeostasis through deploying exogenous reactive oxygen species (ROS)-enhancing agents has been widely applied as anti-tumor strategy. Thus, simultaneously targeting STAT3 and modulation ROS balance would offer a fresh avenue to combat CRC. In this work, we designed and synthesized a novel series of isoxazole-fused quinones, which were evaluated for their preliminary anti-proliferative activity against HCT116 cells. Among these quinones, compound 41 exerted excellent in vitro anti-tumor effect against HCT116 cell line with an IC50 value of 10.18 ± 0.4 nM. Compound 41 was proved to bind to STAT3 by using Bio-Layer Interferometry (BLI) assay, and can significantly inhibit phosphorylation of STAT3. It also elevated ROS of HCT116 cells by acting as a substrate of NQO1. Mitochondrial dysfunction, apoptosis, and cell cycle arrest, which was caused by compound 41, might be partially due to the inhibition of STAT3 phosphorylation and ROS production induced by 41. Moreover, it exhibited ideal anti-tumor activity in human colorectal cancer xenograft model and good safety profiles in vivo. Overall, this study provided a novel quinone derivative 41 with excellent anti-tumor activity by inhibiting STAT3 and elevating ROS level, and gave insights into designing novel anti-tumor therapeutics by simultaneously modulation of STAT3 and ROS.Copyright © 2024 Elsevier Masson SAS. All rights reserved.

基金：
This work was financially supported by grants from the National Natural Science Foundation of China (21977076). We sincerely appreciate the HEK293-SOCS3-Luc cells, a gift from GenEros BioPharma Ltd. We thank Qifeng Liu and Feijing Su (Core Facilities of West China Hospital) for NMR recording, as well as Qianlun Pu (Mass Spectrometry Center of West China Hospital) for HRMS recording.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2024]版：
无
最新[2023]版：
大类 | 2 区 医学
小类 | 1 区 药物化学
第一作者：
第一作者机构： [1]Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Chengdu, 610041, China [2]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China [3]Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
共同第一作者：
通讯作者：
通讯机构： [1]Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Chengdu, 610041, China [2]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China [3]Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China [*1]State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, and Laboratory of Human Disease and Immunotherapies, West China Hospital, Sichuan University, Chengdu, 610041, China. [*2]State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. [*3]Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Chengdu, 610041, China.
推荐引用方式(GB/T 7714)：
Zhang Lidan,Liu Pingxian,Jiang Yunhan,et al.Exploration of novel isoxazole-fused quinone derivatives as anti-colorectal cancer agents through inhibiting STAT3 and elevating ROS level[J].European Journal Of Medicinal Chemistry.2024,272:116448.doi:10.1016/j.ejmech.2024.116448.
APA：
Zhang Lidan,Liu Pingxian,Jiang Yunhan,Fan Dongmei,He Xinlian...&Yang Tao.(2024).Exploration of novel isoxazole-fused quinone derivatives as anti-colorectal cancer agents through inhibiting STAT3 and elevating ROS level.European Journal Of Medicinal Chemistry,272,
MLA：
Zhang Lidan,et al."Exploration of novel isoxazole-fused quinone derivatives as anti-colorectal cancer agents through inhibiting STAT3 and elevating ROS level".European Journal Of Medicinal Chemistry 272.(2024):116448

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