Synthesis, Biological Properties and Anti-HIV-1 Activity of New Pyrimidine P₁,P₂-Dinucleotides

Abstract

New homo- and hetero-P₁,P₂-dinucleotides were prepared with the use of multistep procedures starting from the monophosphates of 3′-fluoro-2-thiothymidine, 3′-fluoro-4-thiothymidine, AZT and 1-[(2-hydroxyethoxy)-methyl-5-propyl-6-phenylselenenyl]uracil. Anti-HIV properties of the synthesized P₁,P₂-dinucleotides were evaluated against laboratory syncytia inducing strain HIV-1 in CEM-T4 cells. Anti-HIV activities were in the range of 5–45 nM, and therapeutic indexes were higher than 4666–14000. Interactions of the above mentioned compounds with recombinant HIV-1 reverse transcriptase were also investigated. The obtained results point to reverse transcriptase inhibition, with somewhat lower inhibitory activity than that of their parental nucleoside-5′-triphosphates. Compound 6 may be regarded as a potent anti-HIV/AIDS drug.

KEYWORDS:

• P₁,P₂-dinucleotides
• anti-HIV agents
• reverse transcriptase inhibitors

Acknowledgments

This work was supported by KBN 3PO5F 00825 grant.