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Identification and optimization of 3-bromo-N'-(4-hydroxybenzylidene)-4-methylbenzohydrazide derivatives as mTOR inhibitors that induce autophagic cell death and apoptosis in triple-negative breast cancer.

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文献详情

资源类型：
Pubmed体系：
作者：
Xu Tian[1] * ; Zhang Jifa[1] * ; Yang Chengcan[1] ; Pluta Ryszard[3] ; Wang Guan[1] ; Ye Tinghong[1] ; Ouyang Liang[1,2,*1] ;
机构： [1]State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China [2]State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450001, China [3]Laboratory of Ischemic and Neurodegenerative Brain Research, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
出处：
DOI： 10.1016/j.ejmech.2021.113424
ISSN：

关键词： TNBC mTOR Pharmacophore-based virtual screening Autophagy mTOR inhibitors

摘要：
Triple negative breast cancer (TNBC) has a worse prognosis than other types of breast cancer due to its special biological behavior and clinicopathological characteristics. TNBC cell proliferation and progression to metastasis can be suppressed by inducing cytostatic autophagy. mTOR is closely related to autophagy and is involved in protein synthesis, nutrient metabolism and activating mTOR promotes tumor growth and metastasis. In this paper, we adopted the strategy of structure simplification, aimed to look for novel small-molecule inhibitors of mTOR by pharmacophore-based virtual screening and biological activity determination. We found a lead compound with 3-bromo-N'-(4-hydroxybenzylidene)-4-methylbenzohydrazide for rational drug design and structural modification, then studied its structure-activity relationship. After that, compound 7c with the best TNBC cells inhibitory activities and superior mTOR enzyme inhibitory activity was obtained. In addition, we found that compound 7c could induce autophagic cell death and apoptosis in MDA-MB-231 and MDA-MB-468 cell lines. In conclusion, these findings provide new clues for our 3-bromo-N'-(4-hydroxybenzylidene)-4-methylbenzohydrazide derivatives, which are expected to become drug candidates for the treatment of TNBC in the future. Copyright © 2021 Elsevier Masson SAS. All rights reserved.

基金：
National Science and Technology Major Project of the Ministry of Science and Technology of China (No. 2018ZX09735005); National Natural Science Foundation of China, Grant Numbers: 81922064, 81874290, and 81903502; China Postdoctoral Science Foundation, Grant Number: 2020M673268; The Fundamental Research Funds for the Central Universities, Grant Number: 2021SCU12102; Opening fund of State Key Laboratory of Esophageal Cancer Prevention and Treatment(Zhengzhou University), Grant Number: K2020-001.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2021]版：
大类 | 1 区 医学
小类 | 1 区 药物化学
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]State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
共同第一作者：
通讯作者：
通讯机构： [1]State Key Laboratory of Biotherapy and Cancer Center, Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China [2]State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450001, China [*1]State Key Laboratory of Biotherapy and Cancer Center,Sichuan University-Oxford University Huaxi Gastrointestinal Cancer Centre, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China.
推荐引用方式(GB/T 7714)：
Xu Tian,Zhang Jifa,Yang Chengcan,et al.Identification and optimization of 3-bromo-N'-(4-hydroxybenzylidene)-4-methylbenzohydrazide derivatives as mTOR inhibitors that induce autophagic cell death and apoptosis in triple-negative breast cancer.[J].European journal of medicinal chemistry.2021,219:113424.doi:10.1016/j.ejmech.2021.113424.
APA：
Xu Tian,Zhang Jifa,Yang Chengcan,Pluta Ryszard,Wang Guan...&Ouyang Liang.(2021).Identification and optimization of 3-bromo-N'-(4-hydroxybenzylidene)-4-methylbenzohydrazide derivatives as mTOR inhibitors that induce autophagic cell death and apoptosis in triple-negative breast cancer..European journal of medicinal chemistry,219,
MLA：
Xu Tian,et al."Identification and optimization of 3-bromo-N'-(4-hydroxybenzylidene)-4-methylbenzohydrazide derivatives as mTOR inhibitors that induce autophagic cell death and apoptosis in triple-negative breast cancer.".European journal of medicinal chemistry 219.(2021):113424

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