1-(2,3-Dideoxy-beta-D-glycero-pent-2-enofuranosyl)thymine. A highly potent and selective anti-HIV agent.
The nucleoside analogue 1-(2,3-dideoxy-beta-D-glycero-pent-2-enofuranosyl)thymine (d4T, 1) was prepared by ring opening of the 3',5'-anhydro compound 5. This method has been refined such that it can be used to prepare d4T on a large scale. The triphosphate of d4T was also synthesized from 1 in order to examine the mode of action. The in vitro inhibitory activity of d4T was found to be comparable to that of AZT in HIV-infected CEM cells. The triphosphate of d4T (8) and that of AZT inhibited the HIV reverse transcriptase with poly(rA):oligo(dT) as the template:primer with Ki values of 0.032 and 0.007 microM, respectively. The in vitro toxicity of d4T against normal human hematopoietic progenitor cells (CFU-GM) was measured in comparison to AZT. While d4T reduces colony-forming units by 50% at a concentration of 100 microM, it takes only 1 microM AZT to have a similar toxic effect. With erythrocyte burst forming units (BFU-E) the in vitro toxicities for d4T and AZT have comparable ID50 values of 10 and 6.7 microM, respectively.
Mansuri
M M
MM
Bristol-Myers Pharmaceutical Research and Development Division, Wallingford, Connecticut 06492-7660.
Starrett
J E
JE
Ghazzouli
I
I
Hitchcock
M J
MJ
Sterzycki
R Z
RZ
Brankovan
V
V
Lin
T S
TS
August
E M
EM
Prusoff
W H
WH
Sommadossi
J P
JP
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D006678:HIV / Q000187:drug effects*; D018119:Stavudine; D013936:Thymidine / Q000378:metabolism; D015215:Zidovudine / Q000494:pharmacology
D000998:Antiviral Agents; D015224:Dideoxynucleosides; D015215:Zidovudine; D018119:Stavudine; D013936:Thymidine