Design, synthesis and structure-activity relationship optimization of phenanthridine derivatives as new Wnt/beta-catenin signalling pathway agonists

CORC > 昆明植物研究所 > 中国科学院昆明植物研究所 > 植物化学与西部植物资源持续利用国家重点实验室

	Design, synthesis and structure-activity relationship optimization of phenanthridine derivatives as new Wnt/beta-catenin signalling pathway agonists
	Chen, Duo-zhi 1; Yang, Bi-juan 1,3; He, Xiao-li 2; Fan, Shi-rui 1; Cai, Jie-yun 4; Jing, Chen-xu 1; Zhang, Heng 2; Zhang, Yu1 ; Li, Lin 2; Hao, Xiao-jiang1
刊名	BIOORGANIC CHEMISTRY
	2019-03-01
卷号	84 页码:285-294
关键词	Wnt/beta-catenin signalling pathway agonist Phenanthridine derivatives Structural optimization Structure-activity relationships (SARs)
ISSN号	0045-2068
英文摘要	Phenanthridine derivativeHLY78 has previously been identified as the first Wnt/beta-catenin signalling pathway agonist that targets the DAX domain of axin. However, due to the relatively weak activation on the Wnt/beta-catenin signalling pathway, HLY78 is insufficient for further pharmacological study. Herein, the structural optimization of HLY78 and analyses of the structure-activity relationships (SARs) of HLY78-derived phenanthridine derivatives as agonists of the Wnt/beta-catenin signalling pathway are presented. In this work, 36 derivatives were designed and synthesized with some derivatives exhibiting stronger Wnt activity than the activity of HLY78. In particular, one of them, 8-((1,3-dimethy-pyrazol-5-yl)methoxy)-5-ethyl-4-methyl-5,6-dihydro-phenanthridin-9-ol, exhibited strong Wnt active activity and is 10 times more potent than HLY78. The following SAR analysis suggests that a pyrazole group, especially at the C-8 position, is important for Wnt activation; a methyl group at the C-4position seems to be more beneficial for Wnt activation than ethyl; and oxidation of the C-6 position reduces the Wnt activation.
资助项目	National Natural Science Foundation of China[81773610] ; National Natural Science Foundation of China[21432010] ; Central Asian Drug Discovery and Development Centre of Chinese Academy of Sciences[CAM201702] ; Youth Innovation Promotion Association of CAS[2018429] ; Yunnan Applied Basic Research Projects[2016FB015]
语种	英语
资助机构	National Natural Science Foundation of China ; Central Asian Drug Discovery and Development Centre of Chinese Academy of Sciences ; Youth Innovation Promotion Association of CAS ; Yunnan Applied Basic Research Projects
内容类型	期刊论文
源URL	[http://ir.kib.ac.cn/handle/151853/64207]
专题	昆明植物研究所_植物化学与西部植物资源持续利用国家重点实验室
通讯作者	Li, Lin; Hao, Xiao-jiang
作者单位	1.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming, Yunnan, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, Shanghai, Peoples R China 3.Univ Chinese Acad Sci, Shanghai, Peoples R China 4.Yunnan CT Qual Inspect & Text Stn, Kunming 650106, Yunnan, Peoples R China
推荐引用方式 GB/T 7714	Chen, Duo-zhi,Yang, Bi-juan,He, Xiao-li,et al. Design, synthesis and structure-activity relationship optimization of phenanthridine derivatives as new Wnt/beta-catenin signalling pathway agonists[J]. BIOORGANIC CHEMISTRY,2019,84:285-294.
APA	Chen, Duo-zhi.,Yang, Bi-juan.,He, Xiao-li.,Fan, Shi-rui.,Cai, Jie-yun.,...&Hao, Xiao-jiang.(2019).Design, synthesis and structure-activity relationship optimization of phenanthridine derivatives as new Wnt/beta-catenin signalling pathway agonists.BIOORGANIC CHEMISTRY,84,285-294.
MLA	Chen, Duo-zhi,et al."Design, synthesis and structure-activity relationship optimization of phenanthridine derivatives as new Wnt/beta-catenin signalling pathway agonists".BIOORGANIC CHEMISTRY 84(2019):285-294.