{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T04:50:58Z","timestamp":1790052658092,"version":"4.0.1"},"reference-count":47,"publisher":"American Chemical Society (ACS)","issue":"10","license":[{"start":{"date-parts":[[2017,10,27]],"date-time":"2017-10-27T00:00:00Z","timestamp":1509062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000165","name":"National Science Foundation","doi-asserted-by":"publisher","award":["1413074"],"award-info":[{"award-number":["1413074"]}],"id":[{"id":"10.13039\/100000165","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001309","name":"Research Corporation for Science Advancement","doi-asserted-by":"publisher","award":["22679"],"award-info":[{"award-number":["22679"]}],"id":[{"id":"10.13039\/100001309","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,10,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The electrophilic natural product parthenolide has generated significant interest as a model for potential chemotherapeutics. Similar to other \u03b1,\u03b2-unsaturated carbonyl electrophiles, parthenolide induces the heat shock response in leukemia cells, potentially through covalent adduction of heat shock proteins. Other thiol-reactive electrophiles have also been shown to induce the heat shock response as well as to covalently adduct members of the heat shock protein family, such as heat shock protein 72 (Hsp72). To identify sites of modification of Hsp72 by parthenolide, we used high-resolution tandem mass spectrometry to detect 10 lysine, histidine, and cysteine residues of recombinant Hsp72 as modified in vitro by 10 and 100 \u03bcM parthenolide. To further ascertain that modification of Hsp72 by parthenolide occurs inside cells and not simply as an in vitro artifact, an alkyne-labeled derivative of parthenolide was synthesized to enable enrichment and detection of protein targets of parthenolide using copper-catalyzed [3 + 2] azide\u2013alkyne cycloaddition. The alkyne-labeled parthenolide derivative displays an half maximal inhibitory concentration (IC50) in undifferentiated acute monocytic leukemia cells (THP-1) of 13.1 \u00b1 1.1 \u03bcM, whereas parthenolide has an IC50 of 4.7 \u00b1 1.1 \u03bcM. Concentration dependence of protein modification by the alkyne\u2013parthenolide derivative was demonstrated, as well as in vitro adduction of Hsp72. Following treatment of THP-1 cells in culture by the alkyne\u2013parthenolide, adducted proteins were isolated with neutravidin resin and detected by immunoblotting in the enriched protein fraction. Hsp70 proteins were detected in the enriched proteins, indicating that Hsp70 proteins were adducted intracellularly by the alkyne\u2013parthenolide derivative.<\/jats:p>","DOI":"10.1021\/acsomega.7b00954","type":"journal-article","created":{"date-parts":[[2017,10,27]],"date-time":"2017-10-27T08:21:39Z","timestamp":1509092499000},"page":"7267-7274","source":"Crossref","is-referenced-by-count":26,"title":["Hsp72 Is an Intracellular\nTarget of the \u03b1,\u03b2-Unsaturated\nSesquiterpene Lactone, Parthenolide"],"prefix":"10.1021","volume":"2","author":[{"given":"Myungsun","family":"Shin","sequence":"first","affiliation":[{"name":"Dickinson College , , , ,","place":["Carlisle, Pennsylvania, United States, 17013"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"McGowan","sequence":"additional","affiliation":[{"name":"Dickinson College , , , ,","place":["Carlisle, Pennsylvania, United States, 17013"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel J.","family":"DiNatale","sequence":"additional","affiliation":[{"name":"Dickinson College , , , ,","place":["Carlisle, Pennsylvania, United States, 17013"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thanprakorn","family":"Chiramanewong","sequence":"additional","affiliation":[{"name":"Dickinson College , , , ,","place":["Carlisle, Pennsylvania, United States, 17013"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyi","family":"Cai","sequence":"additional","affiliation":[{"name":"Dickinson College , , , ,","place":["Carlisle, Pennsylvania, United States, 17013"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8685-5242","authenticated-orcid":true,"given":"Rebecca E.","family":"Connor","sequence":"additional","affiliation":[{"name":"Dickinson College , , , ,","place":["Carlisle, Pennsylvania, United States, 17013"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2017,10,27]]},"reference":[{"key":"2026090208035194400_cit1","doi-asserted-by":"publisher","first-page":"4163","DOI":"10.1182\/blood-2004-10-4135","article-title":"The sesquiterpene lactone parthenolide\ninduces apoptosis of human acute myelogenous leukemia stem and progenitor\ncells","volume":"105","author":"Guzman","year":"2005","journal-title":"Blood"},{"key":"2026090208035194400_cit2","doi-asserted-by":"publisher","first-page":"4427","DOI":"10.1182\/blood-2007-05-090621","article-title":"An orally\nbioavailable parthenolide analog selectively eradicates acute myelogenous\nleukemia stem and progenitor cells","volume":"110","author":"Guzman","year":"2007","journal-title":"Blood"},{"key":"2026090208035194400_cit3","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1126\/science.168.3929.376","article-title":"Reactions of alpha\nmethylene lactone tumor inhibitors with model biological nucelophiles","volume":"168","author":"Kupchan","year":"1970","journal-title":"Science"},{"key":"2026090208035194400_cit4","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1021\/tx700235t","article-title":"Protein\ndamage by reactive electrophiles: targets and consequences","volume":"21","author":"Liebler","year":"2008","journal-title":"Chem. 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Cancer Ther."},{"key":"2026090208035194400_cit30","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1016\/j.chembiol.2012.07.026","article-title":"Cysteine reactivity distinguishes\nredox sensing by the heat-inducible and constitutive forms of heat\nshock protein 70","volume":"19","author":"Miyata","year":"2012","journal-title":"Chem. Biol."},{"key":"2026090208035194400_cit31","doi-asserted-by":"publisher","first-page":"10521","DOI":"10.1021\/bi060535q","article-title":"Covalent adduction\nof human serum albumin by 4-hydroxy-2-nonenal: kinetic analysis of\ncompeting alkylation reactions","volume":"45","author":"Szapacs","year":"2006","journal-title":"Biochemistry"},{"key":"2026090208035194400_cit32","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1021\/acs.chemrestox.5b00308","article-title":"Reactivity\nof Biliatresone, a Natural Biliary Toxin, with Glutathione, Histamine,\nand Amino Acids","volume":"29","author":"Koo","year":"2016","journal-title":"Chem. Res. 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Haematol."},{"key":"2026090208035194400_cit42","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1021\/tx100292n","article-title":"Structure\u2013activity\ncomparison\nof the cytotoxic properties of diethyl maleate and related molecules:\nidentification of diethyl acetylenedicarboxylate as a thiol cross-linking\nagent","volume":"24","author":"West","year":"2011","journal-title":"Chem. Res. Toxicol."},{"key":"2026090208035194400_cit43","doi-asserted-by":"publisher","first-page":"2853","DOI":"10.1021\/ol0493094","article-title":"Polytriazoles as\ncopper(I)-stabilizing ligands in catalysis","volume":"6","author":"Chan","year":"2004","journal-title":"Org. Lett."},{"key":"2026090208035194400_cit44","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.chembiol.2004.03.012","article-title":"Profiling enzyme\nactivities in vivo using click chemistry\nmethods","volume":"11","author":"Speers","year":"2004","journal-title":"Chem. Biol."},{"key":"2026090208035194400_cit45","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1101\/gad.6.7.1153","article-title":"The human heat shock\nprotein hsp70 interacts with HSF, the transcription factor that regulates\nheat shock gene expression","volume":"6","author":"Abravaya","year":"1992","journal-title":"Genes Dev."},{"key":"2026090208035194400_cit46","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1002\/anie.197805221","article-title":"4-Dialkylaminopyridines as Acylation\nCatalysts. 5.\nSimple Method for Esterification of Carboxylic-Acids","volume":"17","author":"Neises","year":"1978","journal-title":"Angew. Chem., Int. Ed. Engl."},{"key":"2026090208035194400_cit47","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1021\/tx100323m","article-title":"Structure\u2013activity\nanalysis of diffusible lipid electrophiles associated with phospholipid\nperoxidation: 4-hydroxynonenal and 4-oxononenal analogues","volume":"24","author":"McGrath","year":"2011","journal-title":"Chem. Res. 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