Synthesis of novel tricyclic chromenone-based inhibitors of IRE-1 RNase activity.

Inositol-requiring enzyme 1 (IRE-1) is a kinase/RNase ER stress sensor that is activated in response to excessive accumulation of unfolded proteins, hypoxic conditions, calcium imbalance, and other stress stimuli. Activation of IRE-1 RNase function exerts a cytoprotective effect and has been implicated in the progression of cancer via increased expression of the transcription factor XBP-1s. Here, we describe the synthesis and biological evaluation of novel chromenone-based covalent inhibitors of IRE-1. Preparation of a family of 8-formyltetrahydrochromeno[3,4-c]pyridines was achieved via a Duff formylation that is attended by an unusual cyclization reaction. Biological evaluation in vitro and in whole cells led to the identification of 30 as a potent inhibitor of IRE-1 RNase activity and XBP-1s expression in wild type B cells and human mantle cell lymphoma cell lines.

需肌醇酶1（IRE - 1）是一种激酶/核糖核酸酶内质网应激传感器，它在响应未折叠蛋白过度积累、缺氧条件、钙失衡以及其他应激刺激时被激活。IRE - 1核糖核酸酶功能的激活具有细胞保护作用，并且通过转录因子XBP - 1s的表达增加而与癌症进展有关。在此，我们描述了新型基于色烯酮的IRE - 1共价抑制剂的合成及生物学评价。通过达夫甲酰化反应（同时伴有一个不寻常的环化反应）制备了一系列8 - 甲酰基四氢色烯并[3,4 - c]吡啶。在体外和全细胞中的生物学评价鉴定出化合物30是野生型B细胞和人套细胞淋巴瘤细胞系中IRE - 1核糖核酸酶活性以及XBP - 1s表达的强效抑制剂。