- Novel double prodrugs of the iron chelator N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED): Synthesis, characterization, and investigation of activation by chemical hydrolysis and oxidation
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The development of iron chelators suitable for the chronic treatment of diseases where iron accumulation and subsequent oxidative stress are implicated in disease pathogenesis is an active area of research. The clinical use of the strong chelator N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) and its alkyl ester prodrugs has been hindered by poor oral bioavailability and lack of conversion to the parent chelator, respectively. Here, we present novel double prodrugs of HBED that have the carboxylate and phenolate donors of HBED masked with carboxylate esters and boronic acids/esters, respectively. These double prodrugs were successfully synthesized as free bases (7a-f) or as dimesylate salts (8a-c,e), and were characterized by 1H, 13C, and 11B NMR; MP; MS; and elemental analysis. The crystal structure of 8a was solved. Three of the double prodrugs (8a-c) were selected for further investigation into their abilities to convert to HBED by stepwise hydrolysis and H2O2 oxidation. The serial hydrolysis of the pinacol and methyl esters of N,N'-bis(2-boronic acid pinacol ester benzyl)ethylenediamine-N,N'-diacetic acid methyl ester dimesylate (8a) was verified by LC-MS. The macro half-lives for the hydrolyses of 8a-c, measured by UV, ranged from 3.8 to 26.3 h at 37 °C in pH 7.5 phosphate buffer containing 50% MeOH. 9, the product of hydrolysis of 8a-c and the intermediate in the conversion pathway, showed little-to-no affinity for iron or copper in UV competition experiments. 9 underwent a serial oxidative deboronation by H2O2 in N-methylmorpholine buffer to generate HBED (k Combining double low line 10.3 M-1min-1). The requirement of this second step, oxidation, before conversion to the active chelator is complete may confer site specificity when only localized iron chelation is needed. Overall, these results provide proof of principle for the activation of the double prodrugs by chemical hydrolysis and H2O2 oxidation, and merit further investigation into the protective capabilities of the prodrugs against H2O2-induced cell death.
- Thiele, Nikki A.,Abboud, Khalil A.,Sloan, Kenneth B.
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- PROCESS TO PREPARE PHENOLIC ETHYLENEDIAMINE DIACETIC ACID COMPOUNDS
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The present invention relates to a process to prepare N,N'-di(2-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid and salts thereof comprising a reaction between formaldehyde, ethylenediamine diacetic acid or a salt thereof and phenol at a pH of between 3 and 7 and a temperature below 60°Cwherein the reaction mixture contains 0.2 to 1.1 molar equivalents of alkali metalions on the molar amount of EDDA.
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Page/Page column 8; 9
(2017/01/09)
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- PROCESS TO PREPARE PHENOLIC ETHYLENEDIAMINE DIACETIC ACID COMPOUNDS
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The present invention relates to a process to prepare N,N'-di(2-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid and salts thereof (HBED) comprising a reaction between formaldehyde, ethylenediamine diacetic acid or a salt thereof (EDDA) and phenol, wherein the reaction mixture contains 0.2 to 1.1 molar equivalents of alkali metal ions on the basis of the molar amount of EDDA and the reaction mixture is processed by a step in which at least part of the organic compounds other than the formed HBED are removed from the reaction mixture, and optionally recycled, during which step at least 50% and up to and including 100% of the alkali metal ions in the reaction mixture are potassium ions, to products obtainable by such process and their use.
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Page/Page column 10
(2017/04/19)
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- A Double Prodrug with Improved Membrane Permeability over the Parent Chelator HBED Provides Superior Cytoprotection against Hydrogen Peroxide
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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.
- Thiele, Nikki A.,Sloan, Kenneth B.
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p. 1596 - 1599
(2016/08/28)
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- A process for the preparation of N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid and its derivatives
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The invention relates to a process for the preparation of N,N'-bis(2-hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid and its derivatives of general formula I, wherein both R have the same meaning and are selected from H, C1-C4alkyl, CH2OH, SO3M, and COOM; and all M have the same meaning and represent hydrogen atom, Na, K or NH4; which comprises reductive amination of glyoxylic acid with a salan compound of general formula (II), in the presence of an amine proton acceptor. The compounds of formula (I) can be used as chelating agents for micronutrients in fertilizer preparations for plants.
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Page/Page column 10-11
(2009/04/23)
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- N,N'-bis(2-hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid in iron chelating therapy
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The use of a mono-cationic salt of N,N′-bis(2-hydroxybenzyl)-ethylenediamine-N,N′-diacetic acid (HBED) in iron chelating therapy is disclosed. In particular, the invention relates to the intravenous use of a mono-cationic salt of HBED for treating a primate with a condition treatable by an iron chelator such as iron overload, especially transfusional iron overload.
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- Polypeptide derivatives
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A biologically active peptide selected from growth factors, peptide hormones, interferons and cytokines and analogues and derivatives thereof, and bearing at least one chelating group linked to an amino group of said peptide, the chelating group being capable of complexing a detectable element and such amino group having no significant binding affinity to target receptors, are complexed with a detectable element and are useful as a pharmaceutical, e.g. a radiopharmaceutical for in vivo imaging of target tissues or for therapy.
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- Synthesis of N,N'-di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) and derivatives
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Two synthetic approaches for the synthesis of N,N'-di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) and derivatives are reported.The first involves conversion of N,N'-di(2-hydroxybenzyl)ethylenediamine to the diamide HBEDDA via reaction with f
- Martell, Arthur E.,Motekaitis, Ramunas J.,Clarke, Eric T.,Harrison, J.J.
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p. 449 - 456
(2007/10/02)
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