TY - JOUR
T1 - One-electron reduction of 17-(Dimethylaminoethylamino)-17- demethoxygeldanamycin
T2 - A pulse radiolysis study
AU - Goldstein, Sara
PY - 2011/8/18
Y1 - 2011/8/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80051755711&partnerID=8YFLogxK
U2 - 10.1021/jp205161v
DO - 10.1021/jp205161v
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C2 - 21718076
AN - SCOPUS:80051755711
SN - 1089-5639
VL - 115
SP - 8928
EP - 8932
JO - Journal of Physical Chemistry A
JF - Journal of Physical Chemistry A
IS - 32
ER -