Synthesis and antiviral activity of 3'-azido-3'-deoxythymidine triphosphate distearoylglycerol: a novel phospholipid conjugate of the anti-HIV agent AZT.
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.
van Wijk
G M
GM
Centre for Biomembranes and Lipid Enzymology, Utrecht University, Netherlands.
Hostetler
K Y
KY
Kroneman
E
E
Richman
D D
DD
Sridhar
C N
CN
Kumar
R
R
van den Bosch
H
H
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000494:pharmacology*; D054306:Dideoxynucleotides; D006678:HIV / Q000187:drug effects*; D015658:HIV Infections / Q000188:drug therapy; D006367:HeLa Cells; D006801:Humans; D010712:Phosphatidic Acids / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000494:pharmacology*; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology
D000998:Antiviral Agents; D054306:Dideoxynucleotides; D010712:Phosphatidic Acids; C088420:3'-azido-3'-deoxythymidine triphosphate distearoylglycerol; D015215:Zidovudine