A Double Prodrug with Improved Membrane Permeability over the Parent Chelator HBED Provides Superior Cytoprotection against Hydrogen Peroxide

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 H₂O₂to give HBED (k=1.82 m⁻¹min⁻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 H₂O₂(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.