Design and Synthesis of Novel Nordihydroguaiaretic Acid (NDGA) Analogues as Potential FGFR1 Kinase Inhibitors With Anti-Gastric Activity and Chemosensitizing Effect

doi:10.3389/fphar.2020.518068

科研成果详情

题名	Design and Synthesis of Novel Nordihydroguaiaretic Acid (NDGA) Analogues as Potential FGFR1 Kinase Inhibitors With Anti-Gastric Activity and Chemosensitizing Effect
作者	Chen, Qian1,2; Zhu, Min 2; Xie, Jingwen 2; Dong, Zhaojun 2; Khushafah, Fatehi 2; Yun, Di 2; Fu, Weitao 2; Wang, Ledan3; Wei, Tao2; Liu, Zhiguo2; Qiu, Peihong 2; Wu, Jianzhang2; Li, Wulan1,2
发表日期	2020-09-11
发表期刊	FRONTIERS IN PHARMACOLOGY 影响因子和分区
语种	英语
原始文献类型	Article
关键词	fibroblast growth factor receptor-1 inhibitor synthesis gastric cancer chemosensitizing effect nordihydroguaiaretic acid analogues
其他关键词	GASTRIC-CANCER ; GENE AMPLIFICATION ; BREAST-CANCER ; PHASE-I ; GROWTH ; DISCOVERY ; TERAMEPROCOL ; CHALLENGES ; AGENTS
摘要	Aberrant fibroblast growth factor receptor-1 (FGFR1), a key driver promoting gastric cancer (GC) progression and chemo-resistance, has been increasingly recognized as a potential therapeutic target in GC. Hereon, we designed and synthesized a series of asymmetric analogues usingAf23and NDGA as lead compounds by retaining the basic structural framework (bisaryl-1,4-dien-3-one) and the unilateral active functional groups (3,4-dihydroxyl). Thereinto,Y14showed considerable inhibitory activity against FGFR1. Next, pharmacological experiments showed thatY14could significantly inhibit the phosphorylation of FGFR1 and its downstream kinase AKT and ERK, thus inhibiting the growth, survival, and migration of gastric cancer cells. Furthermore, compared with 5-FU treatment alone, the combination ofY14and 5-FU significantly reduced the phosphorylation level of FGFR1, and enhanced the anti-cancer effect by inhibiting the viability and colony formation in two gastric cancer cell lines. These results confirmed thatY14exerted anti-gastric activity and chemosensitizing effect by inhibiting FGFR1 phosphorylation and its downstream signaling pathwayin vitro. This work also provides evidence thatY14, an effective FGFR1 inhibitor, could be used alone or in combination with chemotherapy to treat gastric cancer in the future.
资助项目	National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81803580, 81803421, 81773579]; Zhejiang Province Natural Science Fund of China [LY19H310003, LGF20H310003, LQ18H280008]; Natural Science Foundation of Wenzhou City [Y20170158]; Opening Project of Zhejiang Provincial Top Key Discipline of Pharmaceutical Sciences
出版者	FRONTIERS MEDIA SA
出版地	LAUSANNE
ISSN	1663-9812
卷号	11 页码:518068
DOI	10.3389/fphar.2020.518068
页数	15
WOS类目	Pharmacology & Pharmacy
WOS研究方向	Pharmacology & Pharmacy
WOS记录号	WOS:000576019000001
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	33041789
PMC记录号	PMC7517944
SCOPUSEID	2-s2.0-85091585809
通讯作者地址	[Li, Wulan]The First Affiliated Hospital of Wenzhou Medical University,Wenzhou,China ; [Wu, Jianzhang]Chemical Biology Research Center,College of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,China ; [Li, Wulan]Chemical Biology Research Center,College of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,China
Scopus学科分类	Pharmacology;Pharmacology (medical)
引用统计	被引频次：2[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/13781
专题	附属第一医院附属第二医院第二临床医学院，附属第二医院、育英儿童医院药学院（分析测试中心）_生物有机与药物化学研究中心
通讯作者	Wu, Jianzhang; Li, Wulan
作者单位	1.The First Affiliated Hospital of Wenzhou Medical University,Wenzhou,China; 2.Chemical Biology Research Center,College of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou,China; 3.Department of Gynecology and Obstetrics,The Second Affiliated Hospital of Wenzhou Medical University,Wenzhou,China
第一作者单位	附属第一医院; 药学院（分析测试中心）_生物有机与药物化学研究中心
通讯作者单位	附属第一医院; 药学院（分析测试中心）_生物有机与药物化学研究中心
第一作者的第一单位	附属第一医院
推荐引用方式 GB/T 7714	Chen, Qian,Zhu, Min,Xie, Jingwen,et al. Design and Synthesis of Novel Nordihydroguaiaretic Acid (NDGA) Analogues as Potential FGFR1 Kinase Inhibitors With Anti-Gastric Activity and Chemosensitizing Effect[J]. FRONTIERS IN PHARMACOLOGY,2020,11:518068.
APA	Chen, Qian., Zhu, Min., Xie, Jingwen., Dong, Zhaojun., Khushafah, Fatehi., ... & Li, Wulan. (2020). Design and Synthesis of Novel Nordihydroguaiaretic Acid (NDGA) Analogues as Potential FGFR1 Kinase Inhibitors With Anti-Gastric Activity and Chemosensitizing Effect. FRONTIERS IN PHARMACOLOGY, 11, 518068.
MLA	Chen, Qian,et al."Design and Synthesis of Novel Nordihydroguaiaretic Acid (NDGA) Analogues as Potential FGFR1 Kinase Inhibitors With Anti-Gastric Activity and Chemosensitizing Effect".FRONTIERS IN PHARMACOLOGY 11(2020):518068.