Synthesis of novel tricyclic chromenone-based inhibitors of IRE-1 rnase activity

Sujeewa Ranatunga, Chih Hang Anthony Tang, Chang Won Kang, Crystina L. Kriss, Bernhard J. Kloppenburg, Chih Chi Andrew Hu, Juan R. Del Valle

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)4289-4301
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number10
StatePublished - May 22 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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