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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.
G A Freeman, and
J L Rideout, and
W H Miller, and
J E Reardon
January 2005,
Nucleosides, nucleotides & nucleic acids,
G A Freeman, and
J L Rideout, and
W H Miller, and
J E Reardon
January 1999,
Nucleosides & nucleotides,
G A Freeman, and
J L Rideout, and
W H Miller, and
J E Reardon
April 1992,
Chemical & pharmaceutical bulletin,
G A Freeman, and
J L Rideout, and
W H Miller, and
J E Reardon
November 1993,
Biochemistry,
G A Freeman, and
J L Rideout, and
W H Miller, and
J E Reardon
March 2012,
Medicinal chemistry (Shariqah (United Arab Emirates)),
G A Freeman, and
J L Rideout, and
W H Miller, and
J E Reardon
January 2012,
Nucleic acids research,
G A Freeman, and
J L Rideout, and
W H Miller, and
J E Reardon
October 1986,
Biochemical and biophysical research communications,
G A Freeman, and
J L Rideout, and
W H Miller, and
J E Reardon
August 2004,
Antiviral research,
G A Freeman, and
J L Rideout, and
W H Miller, and
J E Reardon
March 1987,
Antiviral research,
G A Freeman, and
J L Rideout, and
W H Miller, and
J E Reardon
January 1997,
Voprosy virusologii,
