Redox properties and thiol reactivity of geldanamycin and its analogues in aqueous solutions.

Geldanamycin (GM), a benzoquinone ansamycin antibiotic, is a natural product inhibitor of Hsp90 with potent and broad anticancer properties, but with unacceptable levels of hepatotoxicity. Less toxic C17-substituted analogues have been synthesizedincluding 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) and the water-soluble 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG). Redox properties and thiol reactivity are central to the therapeutic and toxicologic effects of quinones, and the question arises as whether the extent of toxicity of GM, 17-AAG, and 17-DMAG is related to their redox potentials. Using pulse radiolysis, the one-electron redox potentials (vs NHE) at pH 7.0 of GM and 17-AAG have been determined to be -62 ± 7 mV and -273 ± 8 mV, respectively, whereas a value of -194 ± 6 mV has been previously published for 17-DMAG. The rate constants of the reaction of GM and its analogues with glutathione, cysteine, or dithiothreitol under anoxia at pH 7.4 followed the order GM > 17-DMAG > 17-AAG, which correlates with the order of the redox potential of the quinone/semiquinone couple. Thus, GM reacts much faster with thiols compared to the less toxic 17-DMAG and 17-AAG, and is also expected to be more readily reduced by reductases to the respective semiquinone radical, which either decomposes to yield the respective hydroquinone or reduces oxygen to superoxide. Because both redox cycling and thiol reactivity have been associated with quinone toxicity, it is concluded that the toxicity of benzoquinone ansamycins is directly related to the redox potential of the quinone/semiquinone couple.