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AL414 was a more potent inhibitor of EGFR tyrosine kinase than AL232. Both combi\u2010molecules blocked EGFR phosphorylation in whole cells and downregulated extracellular signaling\u2010regulated kinases (ERK1,2). However, only AL414 was capable of inducing DNA damage. Thus, it was taken<jats:italic>in vivo<\/jats:italic>for metabolic analysis. The results showed that 3\u2003h after injection, AL414 was hydrolyzed to an EGFR inhibitor FD105, which was further acetylated to FD105Ac, a more potent inhibitor of EGFR. The detected flavone derivative was PD98059 linked to the hydroxyalkyl moiety resulting from the decomposition of the alkyldiazonium species. Independent synthesis of the latter metabolite and further<jats:italic>in vitro<\/jats:italic>analysis showed that it was deprived of antiproliferative activity. The results<jats:italic>in toto<\/jats:italic>suggest that while AL414 is a three\u2010compartment combi\u2010molecule, only the EGFR and DNA targeting species can be released and the cleavage to the intact MEK inhibitor PD98059 was mitigated by the stability of the carbamate.<\/jats:p>","DOI":"10.1111\/j.1747-0285.2011.01098.x","type":"journal-article","created":{"date-parts":[[2011,2,5]],"date-time":"2011-02-05T09:15:32Z","timestamp":1296897332000},"page":"309-318","source":"Crossref","is-referenced-by-count":4,"title":["Synthesis and Studies on Three\u2010Compartment Flavone\u2010Containing Combi\u2010Molecules Designed to Target EGFR, DNA, and MEK"],"prefix":"10.1111","volume":"77","author":[{"given":"Anne\u2010Laure","family":"Larroque\u2010Lombard","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margarita","family":"Todorova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiu","family":"Qiyu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bertrand","family":"Jean\u2010Claude","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2011,3,25]]},"reference":[{"key":"e_1_2_5_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4827(02)00098-8"},{"key":"e_1_2_5_3_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-0993"},{"key":"e_1_2_5_4_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2003.10.038"},{"key":"e_1_2_5_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1525-1438.2005.00137.x"},{"key":"e_1_2_5_6_2","doi-asserted-by":"publisher","DOI":"10.1177\/1078155208095141"},{"key":"e_1_2_5_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2008.04.018"},{"key":"e_1_2_5_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.21460"},{"key":"e_1_2_5_9_2","first-page":"3263","article-title":"Flavopiridol, a cyclin\u2010dependent kinase inhibitor, enhances radiosensitivity of ovarian carcinoma cells","volume":"63","author":"Raju U.","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_5_10_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.109.160085"},{"key":"e_1_2_5_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm030142e"},{"key":"e_1_2_5_12_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.104.071977"},{"key":"e_1_2_5_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2005.04.037"},{"key":"e_1_2_5_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6603973"},{"key":"e_1_2_5_15_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.05.4171"},{"key":"e_1_2_5_16_2","first-page":"911","article-title":"Combi\u2010molecules: a global approach towards better chemoselectivity of cytotoxic agents and chemoresistance of refractory tumors","volume":"91","author":"Matheson S.","year":"2004","journal-title":"Bull Cancer"},{"key":"e_1_2_5_17_2","unstructured":"BanerjeeR.(2006)A novel small molecule\u2010based multi\u2010targeting approach for the selective therapy of epidermal growth factor receptor (EGFR)\u2010 or Her2\u2010expressing carcinomas.Ph D dissertation Faculty of Medicine."},{"key":"e_1_2_5_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.14.4979-4989.2000"},{"key":"e_1_2_5_19_2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2003-0064OC"},{"key":"e_1_2_5_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.46.27489"},{"key":"e_1_2_5_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1206701"},{"key":"e_1_2_5_22_2","doi-asserted-by":"publisher","DOI":"10.1667\/0033-7587(2003)159[0439:EGFAIR]2.0.CO;2"},{"key":"e_1_2_5_23_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-09-0673"},{"key":"e_1_2_5_24_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm9016043"},{"key":"e_1_2_5_25_2","doi-asserted-by":"publisher","DOI":"10.1097\/00001813-200602000-00007"},{"key":"e_1_2_5_26_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00106a047"},{"key":"e_1_2_5_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00046a020"},{"key":"e_1_2_5_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/82.13.1107"},{"key":"e_1_2_5_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.5"},{"key":"e_1_2_5_30_2","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/S0022-3565(24)38824-X","article-title":"Design of a chimeric 3\u2010methyl\u20101,2,3\u2010triazene with mixed receptor tyrosine kinase and DNA damaging properties: a novel tumor targeting strategy","volume":"296","author":"Matheson S.L.","year":"2001","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_5_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1383-5718(00)00004-8"},{"key":"e_1_2_5_32_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm030399c"},{"key":"e_1_2_5_33_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja0738125"}],"container-title":["Chemical Biology &amp; 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