Abstract
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 CO 2 •- and (CH 3) 2C •OH 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 semiquinone 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.
| Original language | English |
|---|---|
| Pages (from-to) | 8928-8932 |
| Number of pages | 5 |
| Journal | Journal of Physical Chemistry A |
| Volume | 115 |
| Issue number | 32 |
| DOIs | |
| State | Published - 18 Aug 2011 |
All Science Journal Classification (ASJC) codes
- Physical and Theoretical Chemistry
