Stability of the Hsp90 Inhibitor 17AAG Hydroquinone and Prevention of Metal-Catalyzed Oxidation

17-(allylamino)-17-demethoxygeldanamycin (17AAG) is a benzoquinone ansamycin Hsp90 inhibitor which has promising anticancer activity in vitro, in animal models and in clinical trials. 17AAG has poor water-solubility which is a potential problem for clinical formulation. The hydroquinone derivative of 17AAG, 17AAG hydroquinone (17AAGH(2)), is considerably more water soluble and since we previously demonstrated that 17AAGH(2) was a more potent Hsp90 inhibitor than its parent quinone, it is a good candidate for clinical use and is currently in clinical trials. However, 17AAGH(2) can be oxidized back to 17AAG under aerobic conditions so we tested the relative stability of 17AAGH(2) and the effect of different metal ions and metal chelators on the oxidation of 17AAGH(2). We found that copper could accelerate 17AAGH(2) oxidation while copper chelators such as D-penicillamine could inhibit oxidation. Human serum albumin (HA) has copper-binding ability and we found that HA diminished the rate of 17AAGH(2) oxidation. Although we found that 17AAG could associate with HA, no association was observed between 17AAGH(2) and HA. In summary, our data demonstrates that copper chelators can prevent 17AAGH(2) oxidation and suggests that HA prevents 17AAGH(2) oxidation via a copper chelation mechanism. Agents that prevent oxidation may be useful in clinical formulations of 17AAGH(2). (c) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5147-5157, 2008