A conformation-activity relationship for all monofluoro-substituted and difluoro-substituted dideoxypentofuranosyl nucleosides with uracil and cytosine bases was established through the use of variable temperature/high field 1H NMR studies. The first synthesis ever of a dideoxydifluoro nucleoside with a beta-D-lyxo configuration was accomplished. The beta-D-lyxo stereochemistry was associated with an unprecedented reactivity of the aglycon moiety that permitted conversion of the uracil analogue to the corresponding cytosine by simple treatment with aqueous ammonia at room temperature. Normally, this conversion requires a two-step activation of the uracil moiety. A similar study with the corresponding 4'-thiodideoxypentofuranosyl nucleosides was completed to the stage that all of the X-ray structures have been secured. Variable temperature/high field 1H NMR studies continue to establish a new conformation-activity relationship for this series that appears to differ significantly from the dideoxypentofuranosyl series. Active F-ddI prodrugs have been designed and synthesized in an attempt to improve anti-HIV ddN transport properties into the CNS. Hydroxyurea was found to potentiate the activity of the dideoxypurine nucleosides ddI and F-ddA. F-ddA, an LMC anti-AIDS compound, is scheduled to start clinical trials during 1995.
