Modifying aroylhydrazone prochelators for hydrolytic stability and improved cytoprotection against oxidative stress.
Journal Article (Journal Article)
BSIH ((E)-N'-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)isonicotinohydrazide) is a prodrug version of the metal chelator SIH ((E)-N'-(2-hydroxybenzylidene)isonicotinohydrazide) in which a boronate group prevents metal chelation until reaction with hydrogen peroxide releases SIH, which is then available for sequestering iron(III) and inhibiting iron-catalyzed oxidative damage. While BSIH has shown promise for conditionally targeting iron sequestration in cells under oxidative stress, the yield of SIH is limited by the fact that BSIH exists in cell culture media as an equilibrium mixture with its hydrolysis products isoniazid and 2-formylphenyl boronic acid. In the current study, several BSIH analogs were evaluated for their hydrolytic stability, reaction outcomes with H2 O2 , and prochelator-to-chelator conversion efficiency. Notably, the para-methoxy derivative (p-OMe)BSIH ((E)-N'-(5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)isonicotinohydrazide) and the meta-, para-double substituted (MD)BSIH ((E)-N'-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d][1,3]dioxol-5-yl)methylene)isonicotinohydrazide) showed 1.3- and 1.9-fold improved hydrolytic stability compared to BSIH, respectively, leading to a 22 and 50% increase in chelator released. Moreover, both prochelators were found to protect retinal pigment epithelial cells stressed with either H2 O2 or paraquat insult.
Full Text
Duke Authors
Cited Authors
- Wang, Q; Franz, KJ
Published Date
- December 2018
Published In
Volume / Issue
- 26 / 22
Start / End Page
- 5962 - 5972
PubMed ID
- 30429096
Pubmed Central ID
- PMC6314015
Electronic International Standard Serial Number (EISSN)
- 1464-3391
International Standard Serial Number (ISSN)
- 0968-0896
Digital Object Identifier (DOI)
- 10.1016/j.bmc.2018.11.004
Language
- eng