Document 0576
 DOCN  M9480576
 TI    Synthesis and antiviral activity of 3'-azido-3'-deoxythymidine
       triphosphate distearoylglycerol: a novel phospholipid conjugate of the
       anti-HIV agent AZT.
 DT    9410
 AU    van Wijk GM; Hostetler KY; Kroneman E; Richman DD; Sridhar CN; Kumar R;
       van den Bosch H; Centre for Biomembranes and Lipid Enzymology, Utrecht
       University,; Netherlands.
 SO    Chem Phys Lipids. 1994 Apr 19;70(2):213-22. Unique Identifier : AIDSLINE
       MED/94306606
 AB    Phospholipid conjugates of 3'-azido-3'-deoxythymidine (AZT) show
       activity against the human immunodeficiency virus (HIV) in vitro. In a
       previous report (K.Y. Hostetler, L.M. Stuhmiller, B.H.M. Lenting, H. van
       den Bosch and D.D. Richman (1991), J. Biol. Chem. 265, 6112-6117) the
       syntheses and anti-HIV activities of AZT mono- and diphosphate
       diglyceride have been described. We now report on the synthesis,
       characterization and biological activity of 3'-azido-3'-deoxythymidine
       triphosphate distearoylglycerol (AZTTP-DSG). The compound was prepared
       by the condensation of AZT diphosphate with distearoylphosphatidic acid
       morpholidate in anhydrous pyridine at room temperature and purified by
       means of high-performance liquid chromatography using a silica column.
       Characterization was performed with 31P-NMR and IR analyses and
       determination of the fatty acid, phosphorus and nucleoside content of
       the product. AZTTP-DSG inhibited HIV-1 replication in both CEM and
       HT4-6C cells at a level intermediate in potency between its mono- and
       diphosphate analogs. The IC50 values of AZTTP-DSG were 0.33 and 0.79
       microM in these two cell lines, respectively. In addition, AZTTP-DSG was
       less toxic to CEM cells in vitro than the other AZT liponucleotides and
       reduced viable cell numbers in this cell type by 50% at 1000 microM.
       Initial studies on the metabolism of AZTTP-DSG revealed that both AZT
       and AZT monophosphate were liberated from the lipid pro-drug by a rat
       liver mitochondrial enzyme preparation. These phospholipid derivatives
       of AZT nucleotides represent pro-drugs for the intracellular delivery of
       phosphorylated antiviral nucleoside analogs.
 DE    Antiviral Agents/*CHEMICAL SYNTHESIS/ISOLATION & PURIF/  *PHARMACOLOGY
       Comparative Study  Hela Cells  Human  HIV/*DRUG EFFECTS  HIV
       Infections/DRUG THERAPY  Phosphatidic Acids/*CHEMICAL
       SYNTHESIS/ISOLATION & PURIF/  *PHARMACOLOGY  Support, U.S. Gov't,
       Non-P.H.S.  Support, U.S. Gov't, P.H.S.  Zidovudine/*ANALOGS &
       DERIVATIVES/CHEMICAL SYNTHESIS/ISOLATION &  PURIF/PHARMACOLOGY  JOURNAL
       ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).