Design, synthesis and structure-activity relationship optimization of phenanthridine derivatives as new Wnt/beta-catenin signalling pathway agonists
Chen, Duo-zhi1; Yang, Bi-juan1,3; He, Xiao-li2; Fan, Shi-rui1; Cai, Jie-yun4; Jing, Chen-xu1; Zhang, Heng2; Zhang, Yu1; Li, Lin2; Hao, Xiao-jiang1
2019-03-01
Source PublicationBIOORGANIC CHEMISTRY
ISSN0045-2068
Volume84Pages:285-294
AbstractPhenanthridine 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.
KeywordWnt/beta-catenin signalling pathway agonist Phenanthridine derivatives Structural optimization Structure-activity relationships (SARs)
Indexed BySCI
Language英语
Document Type期刊论文
Identifierhttp://ir.kib.ac.cn/handle/151853/64208
Collection植物化学与西部植物资源持续利用国家重点实验室
Corresponding AuthorLi, Lin; Hao, Xiao-jiang
Affiliation1.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
Recommended Citation
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.
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