A pro-chelator triggered by hydrogen peroxide inhibits iron-promoted hydroxyl radical formation.
The synthesis and structural characterization of a new pro-chelating agent, isonicotinic acid [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene]-hydrazide (BSIH), are presented. BSIH only weakly interacts with iron unless hydrogen peroxide (H2O2) is present to remove the boronic ester protecting group to reveal a phenol that is a key metal-binding group of tridentate salicylaldehyde isonicotinoyl hydrazone (SIH). BSIH prevents deoxyribose degradation caused by hydroxyl radicals that are generated from H2O2 and redox-active iron by sequestering Fe3+ and preventing iron-promoted hydroxyl radical formation. The rate-determining step for iron sequestration is conversion of BSIH to SIH, followed by rapid Fe3+ complexation. The pro-chelate approach of BSIH represents a promising strategy for chelating a specific pool of detrimental metal ions without disturbing healthy metal ion distribution.
Charkoudian
Louise K
LK
Department of Chemistry, Duke University, P.O. Box 90346, Durham, North Carolina 27708, USA.
Pham
David M
DM
Franz
Katherine J
KJ
D000447:Aldehydes / Q000737:chemistry; D001897:Boronic Acids / Q000737:chemistry; D018360:Crystallography, X-Ray; D003855:Deoxyribose / Q000737:chemistry; D005290:Ferric Compounds / Q000737:chemistry; D005296:Ferrous Compounds / Q000737:chemistry; D006835:Hydrazones / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000737:chemistry*; D017665:Hydroxyl Radical / Q000037:antagonists & inhibitors / Q000737:chemistry*; D007501:Iron / Q000037:antagonists & inhibitors / Q000737:chemistry*; D007502:Iron Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry*; D007539:Isonicotinic Acids / Q000737:chemistry; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet
D000447:Aldehydes; D001897:Boronic Acids; D005290:Ferric Compounds; D005296:Ferrous Compounds; D006835:Hydrazones; D007502:Iron Chelating Agents; D007539:Isonicotinic Acids; D011355:Prodrugs; C013243:salicylaldehyde; D017665:Hydroxyl Radical; D003855:Deoxyribose; D006861:Hydrogen Peroxide; D007501:Iron