Redox properties of benzoquinone ansamycins in aqueous solutions

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.