Redox properties of benzoquinone ansamycins in aqueous solutions

Amram Samuni, Sara Goldstein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Geldanamycin (GM) is an inhibitor of heat shock protein 90 (Hsp90) with potent and broad anti-cancer properties, but with unacceptable levels of hepatotoxicity. These characteristics have led to the devise of a range of less toxic GM structural analogues. Redox properties and thiol reactivity are central to the therapeutic and toxicologic effects of quinones, and the question arises as to whether the toxicity of GM and its analogues relates to the reduction potential of the quinone. Using pulse radiolysis, we have previously determined the one-electron reduction potentials (vs. the normal hydrogen electrode [NHE]) at pH7.0 of GM, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), and 17-allylamino-17-demethoxygeldanamycin (17-AAG) to be -62±7mV, -194±6mV, and -273±8mV, respectively. These experimental results are now used to establish a predictive relationship for the reduction potential of GM analogues based on the Hammett para substituent constants. These values correlate well with the drugs effects in vivo. We show that cytotoxicity of the benzoquinone ansamycin increases as its respective reduction potential increases, even after blocking of the C19-position from nucleophilic addition. We conclude that the cytotoxicity is directly related to the reduction potential of the quinone/semiquinone couple.

Original languageEnglish
Pages (from-to)316-320
Number of pages5
JournalIsrael Journal of Chemistry
Volume54
Issue number3
DOIs
StatePublished - Mar 2014

Keywords

  • biological activity
  • geldanamycin
  • nucleophilic addition
  • pulse radiolysis
  • redox chemistry

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