Small Molecules Inspired by the Natural Product Withanolides as Potent Inhibitors of Wnt Signaling,ChemBioChem

当前位置： X-MOL 学术 › ChemBioChem › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Small Molecules Inspired by the Natural Product Withanolides as Potent Inhibitors of Wnt Signaling
ChemBioChem ( IF 2.6 ) Pub Date : 2017-07-31 03:49:26 , DOI: 10.1002/cbic.201700260
Michael Sheremet _{1,

2,

3} , Shobhna Kapoor _{1,

4} , Peter Schröder _{1,

2,

5} , Kamal Kumar _{1,

2} , Slava Ziegler ₁ , Herbert Waldmann _{1,

2}

Affiliation

Wnt signaling is a fundamental pathway that drives embryonic development and is essential for stem cell maintenance and tissue homeostasis. Dysregulation of Wnt signaling is linked to various diseases, and a constitutively active Wnt pathway drives tumorigenesis. Thus, disruption of the Wnt response is deemed a promising strategy for cancer drug discovery. However, only few clinical drug candidates that target Wnt signaling are available so far, and new small-molecule modulators of Wnt-related processes are in high demand. Here we describe the synthesis of small molecules inspired by withanolide natural products by using a pregnenolone-derived β-lactone as the key intermediate that was transformed into a δ-lactone appended to the D-ring of the steroidal scaffold. This natural-product-inspired compound library contained potent inhibitors of Wnt signaling that act upstream of the destruction complex to stabilize Axin in a tankyrase-independent manner.

中文翻译：

天然产物Withanolides激发的小分子作为Wnt信号的强抑制剂

Wnt信号传导是驱动胚胎发育的基本途径，对于干细胞维持和组织体内平衡至关重要。Wnt信号的失调与各种疾病有关，而组成型活跃的Wnt途径驱动肿瘤发生。因此，Wnt应答的破坏被认为是用于癌症药物发现的有前途的策略。然而，到目前为止，靶向Wnt信号的临床候选药物很少，并且对Wnt相关过程的新型小分子调节剂的需求也很高。在这里，我们描述了通过使用孕烯醇酮衍生的β-内酯作为关键中间体，并受甾醇骨架天然D环的作用而转化为δ-内酯的方法，该化学方法是受小醇天然产物的启发而合成的。

更新日期：2017-07-31

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11