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. 2014 May 22;57(10):4289-301.
doi: 10.1021/jm5002452. Epub 2014 May 2.

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

Sujeewa Ranatunga  1 , Chih-Hang Anthony Tang, Chang Won Kang, Crystina L Kriss, Bernhard J Kloppenburg, Chih-Chi Andrew Hu, Juan R Del Valle
Affiliations

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

Sujeewa Ranatunga et al. J Med Chem. .

Abstract

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.

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Figures

Figure 1
Figure 1
Selected known inhibitors of IRE-1 RNase activity.
Figure 2
Figure 2
Compounds evaluated for anti-IRE-1 RNase activity by FRET-suppression assay. IC50 and CI values are reported as the mean of four separate experiments.
Figure 3
Figure 3
Synthesis of substituted bicyclic and tricyclic 8-formyl chromenones.
Scheme 1
Scheme 1. Proposed Mechanism of Cyclization during Duff Formylation
Figure 4
Figure 4
In vitro inhibition of IRE-1 RNase activity by compounds 20 and 21. IC50 and CI values are reported as the mean of four separate experiments.
Scheme 2
Scheme 2. Synthesis of O- and N-Substituted Analogues
Scheme 3
Scheme 3. Synthesis of Analogues with Aldehyde Surrogates
Figure 5
Figure 5
Inhibition of XBP-1s expression in whole cells. (A) B cells were purified from the spleens of wild-type mice, stimulated with LPS for 48 h, treated with the indicated inhibitors at 20 μM for 24 h, lysed, and analyzed for expression of the indicated proteins by immunoblots. (B) Mino and (C) Jeko cells were treated with the indicated inhibitors at 20 μM for 24 h, lysed, and analyzed for the expression of indicated proteins by immunoblots. (D) Mino and (E) Jeko cells were treated with the indicated inhibitors at various doses for 48 h, lysed, and analyzed for the expression of indicated proteins by immunoblots. (F) Mino and (G) Jeko dose–response curves and IC50 values for inhibition of XBP-1s expression by indicated inhibitors as determined by immunoblots and densitometry (N = 3).
Figure 6
Figure 6
Growth inhibition and induction of apoptosis by 30. (A) Human Mino and Jeko cells were cultured in the presence of 30 at various concentrations for 48 h and subjected to XTT assay. Percentages of cell growth were calculated relative to DMSO-treated (control) groups. (B) Human Mino and Jeko cells were cultured for 72 h in the presence of DMSO (control), 30 (50 μM), 21b (50 μM), and 5 (50 μM). Cells were lysed for the analysis of the indicated proteins by immunoblot.
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References

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