2′-Fluoro-2′,3′-dideoxyarabinosyladenine: A metabolically stable analogue of the antiretroviral agent 2′,3′-dideoxyadenosine

Rizwan Masood, Gurpreet S. Ahluwalia, David A. Cooney, Arnold Fridland, Victor E. Marquez, John S. Driscoll, Zhang Hao, Hiroaki Mitsuya, Carlo Federico Perno, Samuel Broder, David G. Johns

Research output: Contribution to journalArticlepeer-review


In this report, we have compared the uptake, metabolism, and relevant enzymology of a novel anti-acquired immunodeficiency syndrome drug, 2′-fluoro-2′,3′-dideoxyarabinosyladenine(2′-F-dd-ara-A) with the corresponding properties of its parent compound 2′,3′-dideoxyadenosine (2′,3′-ddAdo) in three human T cell lines, MOLT-4, ATH8, and CEM. In previous communications, we have reported that the primary route of metabolism of 2′,3′-ddAdo in human T lymphoblasts is catabolic, i.e., deamination to 2′,3′-dideoxyinosine (2′,3′-ddIno). At this point, the metabolic pathway diverges, to result in either cleavage and inactivation of 2′,3′-ddIno by purine nucleoside phosphorylase or in 5′-phosphorylation by a phosphotransferase, a reaction that generates 2′,3′-inosine monophosphate and ultimately the putative active metabolite 2′,3′-dideoxy-ATP. Studies with kinase-deficient mutant CEM lines indicate, however, that 2′-F-dd-ara-A favors a more direct anabolic route toward formation of 2′-fluoro-dideoxynucleotides, catalyzed initially by 2′-deoxycytidine kinase. In MOLT-4 cells, amounts of 2′-fluoro-dideoxyarabinosyladenine di- and triphosphate formed were approximately 20-fold and 5-fold greater than the respective accumulation of 2′,3′-dideoxy-ADP and 2′,3′-dideoxy-ATP over the same time of exposure. This metabolic profile was supported by enzymological studies, which revealed that 2′-F-dd-ara-A is deaminated 10 times less rapidly than ddAdo and that the resulting deaminated product is resistant to hydrolysis by purine nucleoside phosphorylase. Under similar conditions, ddAdo was rapidly degraded through cleavage of its deamination product ddIno. Like ddAdo, 2′-F-dd-ara-A was found to be transported by passive diffusion and does not enter cells via the purine nucleoside transport carrier system. However, the rate of entry of 2′-F-dd-ara-A was about half that of ddAdo (9.7 pmol/106 cells/min for 2′-F-dd-ara-A versus 18.4 pmol/106 cells/min for ddAdo). This investigation, therefore, demonstrates that, under the conditions studied, 2′-F-dd-ara-A and its deamination product 2′-fluoro-2′,3′-dideoxyarabinosylhypoxanthine have metabolic properties that differ significantly from those of their parent compounds ddAdo and ddIno. These properties, combined with the previously reported resistance of the fluorinated nucleosides to acid degradation, make these compounds interesting candidates for further study as orally administered agents for the inhibition of human immunodeficiency virus replication in patients with acquired immunodeficiency syndrome.

Original languageEnglish
Pages (from-to)590-596
Number of pages7
JournalMolecular Pharmacology
Issue number4
Publication statusPublished - Apr 1990

ASJC Scopus subject areas

  • Pharmacology


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