New lipophilic alkyl/acyl dinucleoside phosphates as derivatives of 3′-azido-3′-deoxythymidine: Inhibition of HIV-1 replication in vitro and antiviral activity against Rauscher leukemia virus infected mice with delayed treatment regimens

Cell-cycle arrest and p53-independent induction of apoptosis in vitro by the new anticancer drugs 5-FdUrd- P -FdCydOct and dCydPam- P -FdUrd in DU-145 human prostate cancer cells

“…However, it will be important to demonstrate that, with the dimers, plasma concentrations comparable to those of the parent drug can be reached in vivo without causing untolerable toxic eects. In our previous studies, similar heterodinucleoside phosphate dimers composed of the antivirally active nucleosides azidothymidine and dideoxycytidine were found to have signi®cantly dierent pharmacokinetic properties from those of the parent hydrophilic nucleosides and excellent antiviral eects in the murine Rauscher leukaemia virus model (Peghini et al 1998;Schwendener et al 1994).…”

The novel heterodinucleoside dimer 5-FdU-NOAC is a potent cytotoxic drug and a p53-independent inducer of apoptosis in the androgen-independent human prostate cancer cell lines PC-3 and DU-145

“…Thus, due to expected changes of the pharmacokinetic properties and the prodrug character of 5-FdU-NOAC, the lipophilic dimer may have more favorable in vivo properties than the individual compounds 5-FdU and NOAC. In previous studies performed with similar heterodinucleoside phosphate dimers composed of the antivirally active nucleosides azidothymidine and dideoxycytidine, significantly different pharmacokinetic properties and superior antiviral effects in comparison to the parent hydrophilic nucleosides were obtained in the murine Rauscher leukaemia virus model [42].…”

Synthesis andin vitroAntiviral Properties of Amphiphilic Dinucleoside Phosphate Derivatives of 2′,3-dideoxycytidine (ddC)

“…The ddC derivatives 1, 3a and 3b were compared with AZT and ddC for their effects on p24 antigen production in the supernatant of HIV-1-infected cells as previously described (Schwendener et al, 1994). Briefly, H9 cells were infected with HIV-1 (1IIB) at 0.004 50% tissue culture infective dose per cell for 1-2h at 37°C, extensively washed, and distributed in 48-well plates at a density of 1.2 x 105 cells per well before addition of medium containing the drugs or empty Iiposomes (0.08-8 11M phospholipids) as control.…”

“…The signal for H8 appears at 5.86 ppm in 3a and at 7.22 ppm in 3b, whereas H9 is shifted from 8.07 to 8.35 ppm. strated that such derivatives are active in vitro against HIV-1 and in vivo in a murine Rauscher leukemia virus model (Schott et al, 1994a;Schwendener et al, 1994).…”

“…In the in vivo situation, it is conceivable that additional mechanisms for drug release, transport and activity exist which may alter the antiviral efficacy of the dimers in comparison to the parent nucleoside ddC. In previous studies, we demonstrated excellent antiviral activities of micellar and liposomal dinucleoside phosphate dimers containing AZT as the active compound in vitro and in vivo, as liposome preparations, in a murine Rauscher leukemia model (Schott et el., 1994a;Schwendener et et., 1994). The amphiphilic dinucleoside phosphate derivatives, which are composed of a non-toxic natural nucleoside and a therapeutically active nucleoside, represent a new class of nucleoside compounds.…”