{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:22:40Z","timestamp":1790662960168,"version":"4.1.0"},"reference-count":26,"publisher":"American Chemical Society (ACS)","issue":"10","license":[{"start":{"date-parts":[[2015,4,21]],"date-time":"2015-04-21T00:00:00Z","timestamp":1429574400000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA163910"],"award-info":[{"award-number":["R01CA163910"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["IRG9303216"],"award-info":[{"award-number":["IRG9303216"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["IRG9309214"],"award-info":[{"award-number":["IRG9309214"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,5,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1021\/jm5002452","type":"journal-article","created":{"date-parts":[[2014,4,21]],"date-time":"2014-04-21T11:09:00Z","timestamp":1398078540000},"page":"4289-4301","source":"Crossref","is-referenced-by-count":37,"title":["Synthesis of Novel Tricyclic\nChromenone-Based Inhibitors\nof IRE-1 RNase Activity"],"prefix":"10.1021","volume":"57","author":[{"given":"Sujeewa","family":"Ranatunga","sequence":"first","affiliation":[{"name":"H. Lee Moffitt Cancer Center and Research Institute , , 12902 Magnolia Drive MRC3E , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Hang Anthony","family":"Tang","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center and Research Institute , , 12902 Magnolia Drive MRC3E , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang Won","family":"Kang","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center and Research Institute , , 12902 Magnolia Drive MRC3E , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystina L.","family":"Kriss","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center and Research Institute , , 12902 Magnolia Drive MRC3E , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard J.","family":"Kloppenburg","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center and Research Institute , , 12902 Magnolia Drive MRC3E , , ,","place":["Tampa, Florida, United States, 33612"]},{"name":"H. Lee Moffitt Cancer Center and Research Institute , , 12902 Magnolia Drive MRC3E , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Chi Andrew","family":"Hu","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center and Research Institute , , 12902 Magnolia Drive MRC3E , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan R.","family":"Del Valle","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center and Research Institute , , 12902 Magnolia Drive MRC3E , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,4,21]]},"reference":[{"key":"2026090201204429400_cit1","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1083\/jcb.201003138","article-title":"Regulation of basal\ncellular physiology by the homeostatic\nunfolded protein response","volume":"189","author":"Rutkowski","year":"2010","journal-title":"J. Cell Biol."},{"key":"2026090201204429400_cit2","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The unfolded protein\nresponse: from stress pathway to homeostatic\nregulation","volume":"334","author":"Walter","year":"2011","journal-title":"Science"},{"key":"2026090201204429400_cit3","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/S0092-8674(01)00612-2","article-title":"Complementary signaling\npathways\nregulate the unfolded protein response and are required for C. elegans development","volume":"107","author":"Shen","year":"2001","journal-title":"Cell"},{"key":"2026090201204429400_cit4","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/S0092-8674(01)00611-0","article-title":"XBP1 mRNA\nis induced by ATF6 and spliced by IRE1 in response to ER stress to\nproduce a highly active transcription factor","volume":"107","author":"Yoshida","year":"2001","journal-title":"Cell"},{"key":"2026090201204429400_cit5","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/415092a","article-title":"IRE1 couples endoplasmic\nreticulum load to secretory capacity by processing the XBP-1 mRNA","volume":"415","author":"Calfon","year":"2002","journal-title":"Nature"},{"key":"2026090201204429400_cit6","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1083\/jcb.201110131","article-title":"The impact\nof the unfolded protein response on human\ndisease","volume":"197","author":"Wang","year":"2012","journal-title":"J. Cell Biol."},{"key":"2026090201204429400_cit7","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.cell.2009.02.024","article-title":"Principles of cancer therapy: oncogene\nand non-oncogene addiction","volume":"136","author":"Luo","year":"2009","journal-title":"Cell"},{"key":"2026090201204429400_cit8","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1158\/1541-7786.MCR-05-0221","article-title":"The unfolded\nprotein response: a\nnovel component of the hypoxic stress response in tumors","volume":"3","author":"Feldman","year":"2005","journal-title":"Mol. Cancer Res."},{"key":"2026090201204429400_cit9","doi-asserted-by":"crossref","first-page":"5943","DOI":"10.1158\/0008-5472.CAN-04-1606","article-title":"XBP1 is essential for survival under\nhypoxic conditions and is required for tumor growth","volume":"64","author":"Romero-Ramirez","year":"2004","journal-title":"Cancer Res."},{"key":"2026090201204429400_cit10","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/nrd3976","article-title":"Targeting the unfolded protein response\nin disease","volume":"12","author":"Hetz","year":"2013","journal-title":"Nat. Rev. Drug Discovery"},{"key":"2026090201204429400_cit11","doi-asserted-by":"crossref","first-page":"11868","DOI":"10.1128\/JVI.00879-06","article-title":"Flavivirus infection\nactivates the XBP1 pathway of the unfolded protein response to cope\nwith endoplasmic reticulum stress","volume":"80","author":"Yu","year":"2006","journal-title":"J. Virol."},{"key":"2026090201204429400_cit12","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/ni.1857","article-title":"TLR activation of\nthe transcription factor XBP1 regulates innate immune responses in\nmacrophages","volume":"11","author":"Martinon","year":"2010","journal-title":"Nat. Immunol."},{"key":"2026090201204429400_cit13","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1084\/jem.20090738","article-title":"XBP1 governs\nlate events in plasma cell differentiation and is not required for\nantigen-specific memory B cell development","volume":"206","author":"Todd","year":"2009","journal-title":"J. Exp. Med."},{"key":"2026090201204429400_cit14","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1182\/blood-2010-08-303099","article-title":"Identification\nof an Ire1alpha endonuclease specific inhibitor with cytotoxic activity\nagainst human multiple myeloma","volume":"117","author":"Papandreou","year":"2011","journal-title":"Blood"},{"key":"2026090201204429400_cit15","doi-asserted-by":"crossref","first-page":"E869","DOI":"10.1073\/pnas.1115623109","article-title":"The molecular\nbasis for selective inhibition of unconventional\nmRNA splicing by an IRE1-binding small molecule","volume":"109","author":"Cross","year":"2012","journal-title":"Proc. Nat. Acad. Sci. 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Chem."},{"key":"2026090201204429400_cit18","doi-asserted-by":"crossref","first-page":"e79","DOI":"10.1038\/bcj.2012.26","article-title":"Identification of toyocamycin,\nan agent cytotoxic for multiple myeloma\ncells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing","volume":"2","author":"Ri","year":"2012","journal-title":"Blood Cancer J."},{"key":"2026090201204429400_cit19","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1038\/nchembio.1094","article-title":"Divergent allosteric\ncontrol of the\nIRE1alpha endoribonuclease using kinase inhibitors","volume":"8","author":"Wang","year":"2012","journal-title":"Nat. Chem. Biol."},{"key":"2026090201204429400_cit20","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/nrd3410","article-title":"The resurgence of covalent\ndrugs","volume":"10","author":"Singh","year":"2011","journal-title":"Nat. Rev. Drug Discovery"},{"key":"2026090201204429400_cit21","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1039\/C3MB70234K","article-title":"Selective\ninhibition of the unfolded protein response: targeting catalytic sites\nfor Schiff base modification","volume":"9","author":"Tomasio","year":"2013","journal-title":"Mol. BioSyst."},{"key":"2026090201204429400_cit22","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1182\/blood-2011-11-394346","article-title":"Overexpression of\nTCL1 activates the endoplasmic reticulum stress\nresponse: a novel mechanism of leukemic progression in mice","volume":"120","author":"Kriss","year":"2012","journal-title":"Blood"},{"key":"2026090201204429400_cit23","doi-asserted-by":"crossref","first-page":"5001","DOI":"10.1016\/S0040-4020(01)88408-8","article-title":"Kinetics and mechanism of the Duff\nreaction","volume":"24","author":"Ogata","year":"1968","journal-title":"Tetrahedron"},{"key":"2026090201204429400_cit24","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1055\/s-1979-28602","article-title":"Hexamethylenetetramine,\na versatile reagent in organic synthesis","author":"Blazzevic","year":"1979","journal-title":"Synthesis"},{"key":"2026090201204429400_cit25","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1038\/emboj.2009.117","article-title":"XBP-1 regulates\nsignal transduction, transcription factors and bone marrow colonization\nin B cells","volume":"28","author":"Hu","year":"2009","journal-title":"EMBO J."},{"key":"2026090201204429400_cit26","doi-asserted-by":"crossref","first-page":"5772","DOI":"10.1182\/blood-2011-07-366633","article-title":"Blockade\nof XBP1 splicing by inhibition of IRE1\u03b1 is a promising therapeutic\noption in multiple myeloma","volume":"119","author":"Mimura","year":"2012","journal-title":"Blood"}],"container-title":["Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jm5002452","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/57\/10\/4289\/15120332\/jm5002452.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article-pdf\/57\/10\/4289\/15120332\/jm5002452.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T05:20:51Z","timestamp":1788326451000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jmcmar\/article\/57\/10\/4289\/1435687\/Synthesis-of-Novel-Tricyclic-Chromenone-Based"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,4,21]]},"references-count":26,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2014,4,21]]},"published-print":{"date-parts":[[2014,5,22]]}},"URL":"https:\/\/doi.org\/10.1021\/jm5002452","relation":{},"ISSN":["0022-2623","1520-4804"],"issn-type":[{"value":"0022-2623","type":"print"},{"value":"1520-4804","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,4,21]]}}}