Today, a year after the phase I clinical trial of LMCh's 6-amino-9-(2,3- dideoxy-2-fluoro-b-D threo-pentofuranosyl)-9H-purine (beta-F-ddA) has nearly concluded, a more ambitious protocol that includes two other antiretroviral agents will be implemented. This will increase the demand for more drug and the need to develop more efficient and expedient syntheses of beta-FddA. We have discovered a promising method that starts from commercially available arabinofuranosyl adenine (ara-A). From ara-A (suitably protected), the fluorine atom can be introduced readily onto the sugar moiety, but with the """"""""wrong"""""""" alpha stereochemistry (all attempts to introduce the fluorine with the """"""""correct"""""""" beta stereochemistry from adenosine analogues failed, as substantiated from the literature and our own research). Inversion of the alpha stereochemistry to the desired beta stereochemistry was achieved via the formation of an intermediate methanesulfonate ester that underwent ready elimination to give the corresponding 6-amino-9-(5- O-monomethoxytrityl-2 fluoro-2,3-dideoxy-b-D-glycero-pent-2- enofuranosyl)adenine (the key vinyl fluoride intermediate!). Catalytic hydrogenation of the double bond, and the simultaneous removal of the monomethoxytrityl group gave the desired beta-FddA, with the threo- configuration, in good yield. The exquisite stereoselectivity of the reduction has prompted us to look for more efficient ways to get to the critical vinyl fluoride intermediate. Additional methods of producing the desired elimination product regardless of the initial stereochemistry of the fluorine are being investigated. The availability of the alpha-FddA isomer, a compound that is completely inactive against HIV in vitro, inspired us to investigate the reasons for its inactivity. Suitable pro-drug constructs of the inactive alpha-FddA, which deliver the monophosphate by bypassing the initial phosphorylation step, showed remarkable activity against HIV in CEM/O lymphocytes with EC50s as low as 2 microM. The ultimate goal of this investigation is to try to correlate the configuration (and hence the conformation) of the nucleoside with its capacity to function effectively at each of the intervening steps from the initial phosphorylation to its final interaction with reverse transcriptase (RT). The syntheses of the triphosphate of alpha-FddA has just been completed and its activity against RT will be investigated. AIDS title: Fluorodideoxynucleosides as Reverse Transcriptase Inhibitors for the Treatment of AIDS.
