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Both butanoic (butyric) and bulkier 2\u2010propanepentanoic (valproic) esters were introduced. The goals of this design were to improve the drug\u2010like properties (e.g., log<jats:italic>D<\/jats:italic>) and to reduce the systemic toxicity of the pharmacophore. Two distinct pathways by which the target compounds undergo effective ester hydrolysis, the proposed activating step, have been confirmed: platinum\u2010assisted, self\u2010immolative ester cleavage in a low\u2010chloride environment (LC\u2010ESMS, NMR spectroscopy) and enzymatic cleavage by human carboxylesterase\u20102 (hCES\u20102) (LC\u2010ESMS). The valproic acid ester derivatives are the first example of a metal\u2010containing agent cleavable by the prodrug\u2010converting enzyme. They show excellent chemical stability and reduced systemic toxicity. Preliminary results from screening in lung adenocarcinoma cell lines (A549, NCI\u2010H1435) suggest that the mechanism of the valproic esters may involve intracellular deesterification.<\/jats:p>","DOI":"10.1002\/chem.201404675","type":"journal-article","created":{"date-parts":[[2014,10,10]],"date-time":"2014-10-10T09:08:10Z","timestamp":1412932090000},"page":"16164-16173","source":"Crossref","is-referenced-by-count":26,"title":["Design of Enzymatically Cleavable Prodrugs of a Potent Platinum\u2010Containing Anticancer Agent"],"prefix":"10.1002","volume":"20","author":[{"given":"Song","family":"Ding","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda J.","family":"Pickard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory L.","family":"Kucera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich","family":"Bierbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,10,10]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.110.003459"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2011.09.063"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1359-6446(03)02649-7"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201202050"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm800900g"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1021\/cb300320d"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1039\/c2mt20031g"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/ml2001888"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm900451y"},{"key":"e_1_2_6_10_2","first-page":"32","volume-title":"Color Atlas of Pharmacology","author":"Lullmann H.","year":"2000"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-1184"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm300879k"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.106.009381"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm301278c"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jorganchem.2005.01.005"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201100150"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/ic201151h"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.111.039628"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00775-012-0970-4"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-4-18"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm900694z"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm010293m"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-004-1875-x"}],"container-title":["Chemistry \u2013 A European Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fchem.201404675","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/chem.201404675","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T21:44:47Z","timestamp":1760305487000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/chem.201404675"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,10,10]]},"references-count":23,"journal-issue":{"issue":"49","published-print":{"date-parts":[[2014,12]]}},"alternative-id":["10.1002\/chem.201404675"],"URL":"https:\/\/doi.org\/10.1002\/chem.201404675","archive":["Portico"],"relation":{},"ISSN":["0947-6539","1521-3765"],"issn-type":[{"value":"0947-6539","type":"print"},{"value":"1521-3765","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,10,10]]}}}