1-(2,3-Dideoxy-.beta.-D-glycero-pent-2-enofuranosyl)thymine. A highly potent and selective anti-HIV agent

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Abstract
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 (1) on a large scale. The triphosphate of d4T (8) 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 .mu.M, 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 .mu.M, it takes only 1 .mu.M 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 values of 10 and 6.7 .mu.M, respectively.

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