Structure-activity relationships of fluorinated nucleoside analogs and their synergistic effect in combination with phosphonoformate against human immunodeficiency virus type 1

Abstract

One hundred nucleoside analogs with fluorine substitutions at various positions on the pentose ring were evaluated for inhibitory activity against human immunodeficiency virus type 1 (HIV-1). Nine compounds emerged as inhibitors of HIV-1 replication, with various degrees of selectivity; the most active of these was 3'-fluoro-3'-deoxythymidine, followed by 5'-amino-3'-fluoro-3'-deoxyadenosine. Substitution of fluorine at the 2'-deoxy or 3'-deoxy position resulted in increased antiviral activity of the thymidine analogs, whereas the activity of adenosine or cytidine analogs was not increased by fluorination at either position. The most potent inhibitor, 3'-fluoro-3'-deoxythymidine, was shown to give synergistic inhibition of HIV-1 replication in combination with the PPi analog phosphonoformate.

Penetration of zidovudine and 3'-fluoro-3'-deoxythymidine into the brain, muscle tissue, and veins in cynomolgus monkeys: relation to antiviral action

“…Animal models of HIV infection have only recently become available, the clinically most relevant probably being infection of macaque monkeys with the simian immunodeficiency virus (SIV) (5,13) or with HIV type 2 (HIV-2) (16). The effects of zidovudine and 3'-fluoro-3'-deoxythymidine (FLT) on HIV-1 in vitro (9) and on SIV-infected monkeys in vivo (12) were recently investigated, and it was found that FLT is approximately 10 times more potent than zidovudine. The pharmacokinetic properties of FLT are similar to those of zidovudine in monkeys, the most important difference being that FLT is not protein bound (12).…”

Metabolism of 3′-Azido-3′-Deoxythymidine and 3′-Fluoro-3′-Deoxythymidine in Combination in Human Immunodeficiency Virus Infected Lymphoblastoid Cells

“…FLT was phosphorylated better than AZT in all three cell types, despite the lower concentration of FLT used, which is presumably the basis for the higher antiviral activity and higher toxicity of FLT compared to AZT (Balzarini et al, 1988;Hartmann et al, 1988;Matthes et al, 1988;Bazin et al, 1989;Koshida et al, 1989a).…”

“…* P < 0.005 compared to uninfected H9 cells ** P < 0.001 compared to uninfected H9 cells dNTP pools of GEM,H9, The dNTP pools of GEM, H9, and HIV-infected H9 cells (Koshida et al, 1989a), AZT and castanospermine (Johnson et aI., 1989), AZT and 9-(2-phosphonylmethoxyethyl)-adenine (Smith et al, 1989), and AZT and dipyridamole (Szebeni et et., 1989). We also showed the combination of AZT and FLT to be synergistic against HIV replication in cell culture (Harmenberg et al, 1990a).…”

“…Cell growth and viability, and number of cells ml-1 were the same for persistently infected and uninfected cells. Infected cell cultures were shown by immunofluorescence (Koshida et al, 1989a)to consist of >80% infected cells. HIV-infected CEM cells were not used in these experiments, since in our hands the infection in these cells is rapidly lytic, making accurate measurement of nucleotide pools difficult (data not shown).…”

“…The most studied of these, 3'-azido-3'-deoxythymidine (AZT), is used clinically to treat AIDS patients, and other dideoxynucleosides are currently undergoing clinical trials, including 3'-fluoro-3'-deoxythymidine (FLT) one of the most active dideoxynucleosides described to date (Hartmann et al, 1988;Matthes et al, 1988;Bazin et al, 1989;Koshida et a/., 1989a). These compounds are phosphorylated intracellularly (by the thymidine salvage pathway in the case of AZT and FLT) and, as the triphosphate, inhibit the HIV reverse transcriptase (RT) by chain termination, since they lack the 3'-hydroxyl necessary for further elongation (Furman et al, 1986;Matthes et al, 1988).…”