Previously, HLY78, a lycorine derivative, was identified as the first Wnt/beta-catenin signaling agonist through binding to the DAX domain of Axin, a scaffold of Wnt/beta-catenin complex. In this study, to obtain more potent Wnt/beta-catenin agonist, the structure optimization of HLY78 was carried out by design and synthesis of six phenanthridine derivatives, which afforded five active ones. In particular, 8,9-bis((1,3-dimethyl-1H-pyrazol)methoxy)-5-ethyl-4-methyl-5,6-dihydrophenanthridine showed the most potent activity (0.15/mu M) that was increased nearly 30 times as that of the lead HLY78. These compounds may be valuable in future pharmacological or biological studies. (C) 2018 Elsevier Masson SAS. All rights reserved.