title: Prochelators triggered by hydrogen peroxide provide hexadentate iron coordination to impede oxidative stress.
abstract: Prochelators are agents that have little affinity for metal ions until they undergo a chemical conversion. Three new aryl boronate prochelators are presented that are responsive to hydrogen peroxide to provide hexadentate ligands for chelating metal ions. TRENBSIM (tris[(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)-2-aminoethyl]amine), TRENBSAM (tris[(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)-2-aminoethyl]amine), and TB (tris[(2-boronic acid-benzyl)2-aminoethyl]amine) convert to TRENSIM (tris[(salicylideneamino)ethyl]amine), TRENSAM (tris[(2-hydroxybenzoyl)-2-aminoethyl]amine), and TS (tris[2-hydroxybenzyl)2-aminoethyl]amine), respectively. The prochelators were characterized by (11)B NMR, and the structures of TRENBSAM, TRENBSIM, and the Fe(III) complex of TS were determined by X-ray crystallography. Of the three prochelator/chelator pairs, TB/TS was identified as the most promising for biological applications, as they prevent iron and copper-induced hydroxyl radical generation in an in vitro assay. TB has negligible interactions with metal ions, whereas TS has apparent binding constants (log K') at pH 7.4 of 15.87 for Cu(II), 9.67 Zn(II) and 14.42 for Fe(III). Up to 1 mMTB was nontoxic to retinal pigment epithelial cells, whereas 10 μM TS induced cell death. TS protected cells against H(2)O(2)-induced death, but only within a 1-10 μM range. TB, on the other hand, had a much broader window of protection, suggesting that it may be a useful agent for preventing metal-promoted oxidative damage.
authors.affiliation: Department of Chemistry, Duke University, Durham, NC 27708-0346, USA.
authors.forename: Marina G D
authors.initials: MG
authors.lastname: Leed
authors.forename: Natalie
authors.initials: N
authors.lastname: Wolkow
authors.forename: David M
authors.initials: DM
authors.lastname: Pham
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Daniel
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Dunaief
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Franz
mesh_terms: D000588:Amines / Q000737:chemistry; D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology; D001896:Boron Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003300:Copper / Q000737:chemistry; D018360:Crystallography, X-Ray; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000009:adverse effects / Q000494:pharmacology; D017665:Hydroxyl Radical; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000588:Amines; D000975:Antioxidants; D001896:Boron Compounds; D002614:Chelating Agents; D008024:Ligands; D011355:Prodrugs; D017665:Hydroxyl Radical; D003300:Copper; D006861:Hydrogen Peroxide; D007501:Iron