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Modifying aroylhydrazone prochelators for hydrolytic stability and improved cytoprotection against oxidative stress.

Publication ,  Journal Article
Wang, Q; Franz, KJ
Published in: Bioorganic & medicinal chemistry
December 2018

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 H2O2, 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 H2O2 or paraquat insult.

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Published In

Bioorganic & medicinal chemistry

DOI

EISSN

1464-3391

ISSN

0968-0896

Publication Date

December 2018

Volume

26

Issue

22

Start / End Page

5962 / 5972

Related Subject Headings

  • Structure-Activity Relationship
  • Oxidative Stress
  • Molecular Structure
  • Medicinal & Biomolecular Chemistry
  • Hydrolysis
  • Hydrazones
  • Humans
  • Dose-Response Relationship, Drug
  • Cytoprotection
  • Chelating Agents
 

Citation

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Wang, Q., & Franz, K. J. (2018). Modifying aroylhydrazone prochelators for hydrolytic stability and improved cytoprotection against oxidative stress. Bioorganic & Medicinal Chemistry, 26(22), 5962–5972. https://doi.org/10.1016/j.bmc.2018.11.004
Wang, Qin, and Katherine J. Franz. “Modifying aroylhydrazone prochelators for hydrolytic stability and improved cytoprotection against oxidative stress.Bioorganic & Medicinal Chemistry 26, no. 22 (December 2018): 5962–72. https://doi.org/10.1016/j.bmc.2018.11.004.
Wang Q, Franz KJ. Modifying aroylhydrazone prochelators for hydrolytic stability and improved cytoprotection against oxidative stress. Bioorganic & medicinal chemistry. 2018 Dec;26(22):5962–72.
Wang, Qin, and Katherine J. Franz. “Modifying aroylhydrazone prochelators for hydrolytic stability and improved cytoprotection against oxidative stress.Bioorganic & Medicinal Chemistry, vol. 26, no. 22, Dec. 2018, pp. 5962–72. Epmc, doi:10.1016/j.bmc.2018.11.004.
Wang Q, Franz KJ. Modifying aroylhydrazone prochelators for hydrolytic stability and improved cytoprotection against oxidative stress. Bioorganic & medicinal chemistry. 2018 Dec;26(22):5962–5972.
Journal cover image

Published In

Bioorganic & medicinal chemistry

DOI

EISSN

1464-3391

ISSN

0968-0896

Publication Date

December 2018

Volume

26

Issue

22

Start / End Page

5962 / 5972

Related Subject Headings

  • Structure-Activity Relationship
  • Oxidative Stress
  • Molecular Structure
  • Medicinal & Biomolecular Chemistry
  • Hydrolysis
  • Hydrazones
  • Humans
  • Dose-Response Relationship, Drug
  • Cytoprotection
  • Chelating Agents