{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T19:50:15Z","timestamp":1789156215126,"version":"build-2803163510"},"reference-count":18,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2016,7,21]],"date-time":"2016-07-21T00:00:00Z","timestamp":1469059200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2016,8,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The clinical use of <jats:italic>N<\/jats:italic>,<jats:italic>N<\/jats:italic>\u2032\u2010bis(2\u2010hydroxybenzyl)ethylenediamine\u2010<jats:italic>N<\/jats:italic>,<jats:italic>N<\/jats:italic>\u2032\u2010diacetic acid (HBED) has been hindered by its lack of bioavailability. <jats:italic>N<\/jats:italic>,<jats:italic>N<\/jats:italic>\u2032\u2010bis(2\u2010boronic pinacol ester benzyl)ethylenediamine\u2010<jats:italic>N<\/jats:italic>,<jats:italic>N<\/jats:italic>\u2032\u2010diacetic acid methyl, ethyl, and isopropyl esters <jats:bold>7\u2009a<\/jats:bold>\u2013<jats:bold>c<\/jats:bold>, respectively, and their dimesylate salts <jats:bold>8\u2009a<\/jats:bold>\u2013<jats:bold>c<\/jats:bold>, are double prodrugs that mask the two phenolate and two carboxylate donors of HBED as boronic esters and carboxylate esters, respectively. Their activation by chemical hydrolysis and oxidation, their passive diffusivity, and their cytoprotective capabilities have been investigated here. <jats:bold>8\u2009a<\/jats:bold>\u2013<jats:bold>c<\/jats:bold> hydrolyzed in minimum essential medium at 37\u2009\u00b0C with half\u2010lives of 0.69, 0.81, and 2.28\u2005h, respectively. The intermediate formed, <jats:bold>9<\/jats:bold> [<jats:italic>N<\/jats:italic>,<jats:italic>N<\/jats:italic>\u2032\u2010bis(2\u2010boronic acid benzyl)ethylenediamine\u2010<jats:italic>N<\/jats:italic>,<jats:italic>N<\/jats:italic>\u2032\u2010diacetic acid], then underwent oxidative deboronation by H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> to give HBED (<jats:italic>k<\/jats:italic>=1.82\u2009<jats:sc>m<\/jats:sc><jats:sup>\u22121<\/jats:sup>\u2009min<jats:sup>\u22121<\/jats:sup>). Solubility measurements in mineral oil and in phosphate buffer indicated that <jats:bold>7\u2009a<\/jats:bold> had a better balance between lipid and aqueous solubilities than did HBED. <jats:bold>7\u2009a<\/jats:bold> was also able to passively diffuse across a lipid\u2010like silicone membrane (log flux=\u22120.36), whereas HBED\u2010HCl was not. <jats:bold>8\u2009c<\/jats:bold> provided better protection to retinal cells than did HBED against a lethal dose of H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> (84\u2009% vs. 28\u2009% protection, respectively, at 44\u2005\u03bc<jats:sc>m<\/jats:sc>). These results suggest that the double prodrugs have better membrane permeability than does HBED, and therefore could be therapeutically useful for improving the delivery of HBED.<\/jats:p>","DOI":"10.1002\/cmdc.201600197","type":"journal-article","created":{"date-parts":[[2016,7,21]],"date-time":"2016-07-21T07:16:51Z","timestamp":1469085411000},"page":"1596-1599","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Double Prodrug with Improved Membrane Permeability over the Parent Chelator HBED Provides Superior Cytoprotection against Hydrogen Peroxide"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3301-0849","authenticated-orcid":false,"given":"Nikki A.","family":"Thiele","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry University of Florida  Gainesville FL 32610 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth B.","family":"Sloan","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry University of Florida  Gainesville FL 32610 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,7,21]]},"reference":[{"key":"e_1_2_2_1_1","unstructured":"\u00a0"},{"key":"e_1_2_2_2_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00980a019"},{"key":"e_1_2_2_3_2","first-page":"133","volume-title":"Development of Iron Chelators for Clinical Use: Proceedings of the Second Symposium on the Development of Iron Chelators for Clinical Use","author":"Grady R. 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