Lodenosine, 6-Amino-9-(2,3-dideoxy-2-fluoro-beta-D-threo- pentofuranosyl)-9H-purine, an antiretroviral agent discovered and developed in this laboratory is currently in Phase I/II clinical trials (www.aegis.com/pub/beta/1998/BE981003.html) for the treatment of AIDS. The LMC is currently interested in developing new, alternative synthesis of lodenosine to improve efficiency and lower the cost of the drug. The new approach reported last year, which consisted in the reduction of the corresponding methyl xanthate of 6-methoxy-9-(2-deoxy- 2-fluoro-5-benzoyl beta-D-arabinofuranosyl)-9H-purine to beta-F-ddA, was further improved by using isopropanol as solvent and reducing agent instead of diglyme. The new radical reduction is very efficient, avoids the use of the expensive and flammable tributyltin hydride, and produces lodenosine in high yield after ammonolysis of the 6-methoxy group. At the mechanistic level, a conformational study where the triphosphate of lodenosine and its corresponding 2?-anomer (alpha-FddA) were docked at the active site of the ternary complex of HIV-1 RT-DNA- dNTP (by replacing the dNTP with either triphosphate analogue) strongly suggests that the alpha-FddATP, despite having a favorable A- conformation (North sugar pucker), is less effective than beta-FddATP due to a strong steric clash between the fluorine atom and Tyrosine 115. Tyrosine 115 is a highly conserved amino acid that functions as a gate keeper in HIV-1 RT to prevent the incorporation of ribonucleotides. Indeed the measured IC50 for inhibiting HIV-1 RT demonstrated that there is a 4-fold difference in potency favoring the beta-FddATP. Pro-drug delivery of beta-F-ddA continues to be an important avenue of research to by-pass adenosine deamination. Preliminary information indicates that the pro-drug approach is highly beneficial in improving the potency of lodenosine.AIDS title: Fluorodideoxynucleosides as Reverse Transcriptase Inhibitors for the Treatment of AIDS. - AIDS, dideoxynucleosides, fluoronucleosides, HIV, Reverse Transcriptase,
