title: Design, Synthesis, and Structural Optimization of Lycorine-Derived Phenanthridine Derivatives as Wnt/β-Catenin Signaling Pathway Agonists.
abstract: Lycorine is a benzylphenethylamine-type alkaloid member of the Amaryllidaceae family. A lycorine derivative, HLY78, was previously identified as a new Wnt/β-catenin signaling pathway agonist that targets the DAX domain of axin. Herein, the structural optimization of HLY78 and analyses of the structure-activity relationships of lycorine-derived phenanthridine derivatives as agonists of the Wnt/β-catenin signaling pathway are presented. This research suggests that triazole groups are important pharmacophores for Wnt activation; triazole groups at C-8 and C-9 of phenanthridine compounds markedly enhanced Wnt activation. A C-11-C-12 single bond is also important for Wnt activation. On the basis of these findings, two Wnt agonists were designed and synthesized. The results for these agonists indicated that the combination of a 4-ethyldihydrophenanthridine skeleton and a triazole substituent improves Wnt activation. These compounds may be useful in further pharmacological or biological studies.
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences , Kunming 650201, People's Republic of China.
authors.forename: Duo-Zhi
authors.initials: DZ
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences , Kunming 650201, People's Republic of China.
authors.forename: Chen-Xu
authors.initials: CX
authors.lastname: Jing
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences , Kunming 650201, People's Republic of China.
authors.forename: Jie-Yun
authors.initials: JY
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai 200000, People's Republic of China.
authors.forename: Ji-Bo
authors.initials: JB
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai 200000, People's Republic of China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences , Kunming 650201, People's Republic of China.
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences , Kunming 650201, People's Republic of China.
authors.forename: Xiao-Nian
authors.initials: XN
authors.lastname: Li
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai 200000, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences , Kunming 650201, People's Republic of China.
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Hao
mesh_terms: D047151:Amaryllidaceae Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D052117:Benzodioxoles / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010617:Phenanthridines / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000819:agonists / Q000378:metabolism*
chemical_list: C584141:4-ethyl-5-methyl-5,6-dihydro(1,3)dioxolo(4,5-j)phenanthridine; D047151:Amaryllidaceae Alkaloids; D052117:Benzodioxoles; D010617:Phenanthridines; D014230:Triazoles; D051153:Wnt Proteins; D051176:beta Catenin; C015330:lycorine