51. Design, synthesis and structure-activity relationship optimization of phenanthridine derivatives as new Wnt/β-catenin signalling pathway agonists.
- Author
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Chen DZ, Yang BJ, He XL, Fan SR, Cai JY, Jing CX, Zhang H, Zhang Y, Li L, and Hao XJ
- Subjects
- Benzodioxoles chemistry, Binding Sites, HEK293 Cells, Humans, Molecular Docking Simulation, Phenanthridines metabolism, Phenanthridines pharmacology, Structure-Activity Relationship, Wnt Proteins metabolism, Wnt Signaling Pathway drug effects, beta Catenin metabolism, Drug Design, Phenanthridines chemistry, Wnt Proteins chemistry, beta Catenin chemistry
- Abstract
Phenanthridine derivativeHLY78 has previously been identified as the first Wnt/β-catenin signalling pathway agonist that targets the DAX domain of axin. However, due to the relatively weak activation on the Wnt/β-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/β-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., (Copyright © 2018. Published by Elsevier Inc.)
- Published
- 2019
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