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 (−)-β- l-enantiomer (3TC) is more active and less toxic than the (+)-β- 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.