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.

中文翻译：

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菲啶衍生物作为新型Wnt /β-catenin信号通路激动剂的设计，合成及构效关系优化。

菲啶衍生物HLY78先前已被确定为第一个靶向毒素DAX结构域的Wnt /β-catenin信号通路激动剂。然而，由于Wnt /β-catenin信号通路的激活相对较弱，HLY78不足以用于进一步的药理研究。本文介绍了HLY78的结构优化以及作为Wnt /β-catenin信号通路激动剂的HLY78菲啶衍生物的构效关系（SAR）的分析。在这项工作中，设计并合成了36种衍生物，其中一些衍生物表现出比HLY78活性更强的Wnt活性。特别地，它们中的一个，即8-（（（1,3-二甲基-吡唑-5-基）甲氧基）-5-乙基-4-甲基-5,6-二氢-菲啶-9-ol，具有强的Wnt活性。活性，比HLY78强10倍。以下SAR分析表明，吡唑基团（尤其是在C-8位置）对于Wnt激活很重要。C-4位置的甲基似乎比乙基更有利于Wnt活化；C-6位的氧化会降低Wnt活化。