Preventing  Geldanamycin’s Toxicity

Preventing Geldanamycin’s Toxicity

Author: Melania Tesio

Heat shock protein 90 (HSP90) is an important anti-cancer target as it stabilizes proteins involved in tumor growth. While geldanamycin, a benzoquinone ansamycin antibiotic (pictured), and its synthetic analogs potently inhibit HSP90, they induce hepatotoxicity and, thus, have a limited clinical use.

This issue promoted Russell Kitson, University of Nottingham, UK, and colleagues to develop strategies to decrease geldanamycin-induced liver damage. Since this side effect has been attributed to the reaction of biological nucleophiles at the 19-position of the quinone ring, the researchers synthesized novel 19-substituted benzoquinone ansamycins. These compounds retained the potency of their parent quinones but showed less toxicity when tested in vitro as the C-19 substitutions prevented the reaction with thiol nucleophiles. The new geldanamycin derivatives are, therefore, promising anti-cancer drugs.

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