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A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding.

Publication ,  Journal Article
Kielar, F; Wang, Q; Boyle, PD; Franz, KJ
Published in: Inorganica chimica acta
December 2012

Iron chelating agents have the potential to minimize damage associated with oxidative stress in a range of diseases; however, this potential is countered by risks of indiscriminant metal binding or iron depletion in conditions not associated with systemic iron overload. Deferasirox is a chelator used clinically for iron overload, but also is cytotoxic to cells in culture. In order to test whether a prodrug version of deferasirox could minimize its cytotoxicity but retain its protective properties against iron-induced oxidative damage, we synthesized a prochelator that contains a self-immolative boronic ester masking group that is removed upon exposure to hydrogen peroxide to release the bis-hydroxyphenyltriazole ligand deferasirox. We present here the synthesis and characterization of this triazole-based, self-immolative prochelator: TIP (4-(5-(2-((4-boronobenzyl)oxy)phenyl)-3-(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid). TIP does not coordinate to Fe(3+) and shows only weak affinity for Cu(2+) or Zn(2+), in stark contrast to deferasirox, which avidly binds all three metal ions. TIP converts efficiently in vitro upon reaction with hydrogen peroxide to deferasirox. In cell culture, TIP protects retinal pigment epithelial cells from death induced by hydrogen peroxide; however, TIP itself is more cytotoxic than deferasirox in unstressed cells. These results imply that the cytotoxicity of deferasirox may not derive exclusively from its iron withholding properties.

Duke Scholars

Published In

Inorganica chimica acta

DOI

ISSN

0020-1693

Publication Date

December 2012

Volume

393

Start / End Page

294 / 303

Related Subject Headings

  • Inorganic & Nuclear Chemistry
  • 3402 Inorganic chemistry
  • 0399 Other Chemical Sciences
  • 0306 Physical Chemistry (incl. Structural)
  • 0302 Inorganic Chemistry
 

Citation

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Kielar, F., Wang, Q., Boyle, P. D., & Franz, K. J. (2012). A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding. Inorganica Chimica Acta, 393, 294–303. https://doi.org/10.1016/j.ica.2012.06.011
Kielar, Filip, Qin Wang, Paul D. Boyle, and Katherine J. Franz. “A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding.Inorganica Chimica Acta 393 (December 2012): 294–303. https://doi.org/10.1016/j.ica.2012.06.011.
Kielar F, Wang Q, Boyle PD, Franz KJ. A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding. Inorganica chimica acta. 2012 Dec;393:294–303.
Kielar, Filip, et al. “A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding.Inorganica Chimica Acta, vol. 393, Dec. 2012, pp. 294–303. Epmc, doi:10.1016/j.ica.2012.06.011.
Kielar F, Wang Q, Boyle PD, Franz KJ. A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding. Inorganica chimica acta. 2012 Dec;393:294–303.
Journal cover image

Published In

Inorganica chimica acta

DOI

ISSN

0020-1693

Publication Date

December 2012

Volume

393

Start / End Page

294 / 303

Related Subject Headings

  • Inorganic & Nuclear Chemistry
  • 3402 Inorganic chemistry
  • 0399 Other Chemical Sciences
  • 0306 Physical Chemistry (incl. Structural)
  • 0302 Inorganic Chemistry