One-Electron Reduction of 17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin: A Pulse Radiolysis Study

Geldanamycin, a benzoquinone ansamycin antibiotic, is a natural product inhibitor of Hsp90 with potent and broad anticancer properties but with unacceptable levels of hepatotoxicity. Consequently, numerous structural analogs, which differ only in their 17-substituent, have been synthesized including the water-soluble and less toxic 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG, Alvespimycin). It has been suggested that the different hepatotoxicity reflects the redox active properties of the quinone moiety. The present pulse radiolysis study was aimed at studying the one-electron reduction of 17-DMAG. The UV -visible spectrum of the semiquinone radical, its pK(a), and the second-order rate constants for the reactions of 17-DMAG with CO2 center dot- and (CH3)(2)(COH)-O-center dot have been obtained. The reduction potential of 17-DMAG has been determined to be -194 +/- 6 mV (vs NHE) using oxygen, 1,4-naphthoquinone, and menadione as electron acceptors. This reduction potential is lower than that of O-2 demonstrating that thermodynamically the serniquinone radical can reduce O-2 to superoxide, particularly since the concentration of O-2 is expected to exceed that of the drug in cells and tissues.