title: Phosphatidyl-2',3'-dideoxy-3'-thiacytidine: synthesis and antiviral activity in hepatitis B-and HIV-1-infected cells.
abstract: We recently found that phosphatidyl-2',3'-dideoxycytidine (phosphatidyl-ddC) had substantial anti-hepatitis B virus (HBV) activity in vitro compared to 2',3'-dideoxycytidine (ddC) (Hostetler et al. (1994) Antiviral Res. 24, 59-67). Upon administration of liposomal phosphatidyl-ddC to mice, a 40-fold higher drug area under curve was observed in the liver. To evaluate the possibility of using liver-targeted anti-HBV nucleosides to treat woodchuck hepatitis virus, we wanted to find the most potent and selective lipid conjugates. It has been shown that 2',3'-dideoxy-3'-thiacytidine as a racemic mixture of the cis-isomer (cis-(+/-)-BCH-189) has much greater activity against HBV viruses than ddC in vitro. Recently, it was shown that the (-)-beta-L-enantiomer (3TC) is more active and less toxic than the (+)-beta-D-form ((+)-BCH-189). To determine whether phospholipid conjugates of 3TC retain antiviral activity in 2.2.15 cells as demonstrated previously with ddC, we synthesized the 1,2-dipalmitoyl-sn-glycerol-3-phosphate conjugates of (+/-)-BCH-189 and 3TC and assessed their anti-HBV and anti-HIV activities, in vitro. Phosphatidyl-3TC and phosphatidyl-BCH-189 had antiviral activity comparable to the respective free drugs in 2.2.15 cells which chronically produce HBV. In HIV-1-infected human peripheral blood mononuclear cells and HT4-6C cells, phosphatidyl-3TC and phosphatidyl-(+/-)-BCH-189 exhibited significantly lower activity than the corresponding free nucleosides. In view of the documented ability of phosphatidyl-ddC to target drug to the liver, it seems reasonable to expect that phosphatidyl-3TC or phosphatidyl-(+/-)-BCH-189 could be employed to provide greatly enhanced hepatic antiviral activity in HBV infection in vivo.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla 92093, USA.
authors.forename: H
authors.initials: H
authors.lastname: Xie
authors.forename: M
authors.initials: M
authors.lastname: Voronkov
authors.forename: D C
authors.initials: DC
authors.lastname: Liotta
authors.forename: B A
authors.initials: BA
authors.lastname: Korba
authors.forename: R F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: D D
authors.initials: DD
authors.lastname: Richman
authors.forename: K Y
authors.initials: KY
authors.lastname: Hostetler
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects*; D006515:Hepatitis B virus / Q000187:drug effects*; D006801:Humans; D019259:Lamivudine; D015394:Molecular Structure; D011355:Prodrugs / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D016047:Zalcitabine