3'-Azido-3',5'-dideoxythymidine-5'-methylphosphonic acid diphosphate: synthesis and HIV-1 reverse transcriptase inhibition.
- 1 August 1992
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 35 (17) , 3192-3196
- https://doi.org/10.1021/jm00095a014
Abstract
3'-Azido-3'-deoxythymidine-5'-phosphonate was synthesized by a five-step reaction sequence. The 5'-phosphonate was inactive against HIV-1 in MT4 cells. The absence of activity against HIV-1 was at least partially explained by demonstrating that the Km value for the 5'-deoxy-5'-methylphosphonic acid diphosphate analog with HIV-1 reverse transcriptase (RT) was 320-fold greater than the Km value for 3'-azido-3'- deoxythymidine-5'-triphosphate (AZTTP), and the kcat value for the 5'-deoxy-5'-methylphosphonic acid diphosphate analog was one-seventh the value for AZTTP. These differences in kinetic constants were due to a change in the rate-determining step from dissociation of the RT chain-terminated template-primer complex to the catalytic step. Thus, substitution of a methylene group for the 5'-oxygen atom of AZTTP resulted in an 1800-fold reduction in the rate constant for RT-catalyzed phosphodiester bond formation.Keywords
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