Thiol reduction of 3'-azidothymidine to 3'-aminothymidine: kinetics and biomedical implications.
The ability of thiols to reduce 3'-azidothymidine (AZT) to 3'-aminothymidine has been investigated. Incubation with glutathione, dithiothreitol (DTT), or mercaptoethanol at pH 7.2 and 37 degrees C leads to quantitative reduction of the azido moiety to an amine. The reaction is first order in AZT and first order in reducing agent (mono- or dithiol). The second-order rate constants are 2.77 x 10(-3), 6.55 x 10(-5), and 6.35 x 10(-6) M-1 sec-1 for the dithiothreitol, glutathione, and mercaptoethanol reductions, respectively. The thiol reduction of alkyl azide to amine under mild conditions is a synthetic method particularly suitable for water-soluble azido compounds that are sensitive to catalytic hydrogenation. The potential for the mono- or dithiol-mediated reduction of alkyl azides under biological conditions must be considered when conducting studies of azido drugs.
Handlon
A L
AL
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
Oppenheimer
N J
NJ
D002851:Chromatography, High Pressure Liquid; D015224:Dideoxynucleosides; D004229:Dithiothreitol; D007700:Kinetics; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000032:analysis*; D013936:Thymidine / Q000031:analogs & derivatives* / Q000032:analysis; D015215:Zidovudine / Q000032:analysis*
D015224:Dideoxynucleosides; D013438:Sulfhydryl Compounds; D015215:Zidovudine; C019252:3'-aminothymidine; D004229:Dithiothreitol; D013936:Thymidine