Prochelator BHAPI protects cells against paraquat-induced damage by ROS-triggered iron chelation.
A prochelator named BHAPI (N'-(1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)phenyl)ethylidene)isonicotinohydrazide) based on the structure of experimental metal chelator HAPI (N'-[1-(2-hydroxyphenyl)ethyliden]isonicotinoylhydrazide) has been synthesized. The prochelator, which shows limited affinity for metal ions, is converted efficiently upon reaction with hydrogen peroxide into its chelator form, which binds di- and trivalent metal ions, including Zn(2+), Cu(2+) and Fe(3+). This work shows that the prochelator has a protective effect on cells under oxidative stress induced by either hydrogen peroxide or the cytotoxic herbicide paraquat. The effect of BHAPI and HAPI on cellular iron status was assessed by monitoring the mRNA level of the transferrin receptor. Whereas the chelator HAPI induces iron deficiency in cultured retinal pigment epithelial cells, the prochelator does not, providing evidence that the differential metal-binding capacity of these compounds observed in vitro is replicated in the cellular context.
Duke University, Department of Chemistry, Durham, NC 22708, USA.
Filip
F
Kielar
Marian E
ME
Helsel
Qin
Q
Wang
Katherine J
KJ
Franz
D001896:Boron Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D019610:Cytoprotection / Q000187:drug effects*; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008856:Microscopy, Fluorescence; D018384:Oxidative Stress / Q000187:drug effects; D010269:Paraquat / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology; D012664:Semicarbazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet; D013312:Stress, Physiological / Q000187:drug effects; D013997:Time Factors
D001896:Boron Compounds; D006834:Hydrazines; D007502:Iron Chelating Agents; C577566:N'-(1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)phenyl)ethylidene)isonicotinohydrazide; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D011990:Receptors, Transferrin; D012664:Semicarbazones; D006861:Hydrogen Peroxide; D007501:Iron; D010269:Paraquat