title: A Double Prodrug with Improved Membrane Permeability over the Parent Chelator HBED Provides Superior Cytoprotection against Hydrogen Peroxide.
abstract: The clinical use of N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) has been hindered by its lack of bioavailability. N,N'-bis(2-boronic pinacol ester benzyl)ethylenediamine-N,N'-diacetic acid methyl, ethyl, and isopropyl esters 7 a-c, respectively, and their dimesylate salts 8 a-c, 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. 8 a-c hydrolyzed in minimum essential medium at 37 °C with half-lives of 0.69, 0.81, and 2.28 h, respectively. The intermediate formed, 9 [N,N'-bis(2-boronic acid benzyl)ethylenediamine-N,N'-diacetic acid], then underwent oxidative deboronation by H2 O2 to give HBED (k=1.82 m(-1)  min(-1) ). Solubility measurements in mineral oil and in phosphate buffer indicated that 7 a had a better balance between lipid and aqueous solubilities than did HBED. 7 a was also able to passively diffuse across a lipid-like silicone membrane (log flux=-0.36), whereas HBED-HCl was not. 8 c provided better protection to retinal cells than did HBED against a lethal dose of H2 O2 (84 % vs. 28 % protection, respectively, at 44 μm). 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.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, FL, 32610, USA. nikkithiele@yahoo.com.
authors.forename: Nikki A
authors.identifier: 0000-0003-3301-0849
authors.initials: NA
authors.lastname: Thiele
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, FL, 32610, USA.
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Sloan
mesh_terms: D001897:Boronic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D004058:Diffusion; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D006868:Hydrolysis; D007502:Iron Chelating Agents / Q000138:chemical synthesis / Q000494:pharmacology; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology*; D020011:Protective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D012995:Solubility
chemical_list: D001897:Boronic Acids; D007502:Iron Chelating Agents; D011355:Prodrugs; D020011:Protective Agents; C037740:N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid; D004492:Edetic Acid; D006861:Hydrogen Peroxide
keywords: boronic acids; chelation therapy; hydrogen peroxide; iron; prodrugs