4'-Thioarabinonucleosides, which are potential antiviral agents, were synthesized from D-glucose. 1,4-Anhydro-4-thioarabitol (8), which can be derived from diacetone glucose in nine steps, was subjected to Pummerer rearrangement after protection of the hydroxyl groups to give 1-O-acetyl-4-thioarabinose (11), which was condensed with nucleobases to give 4'-thioarabinonucleosides. The 5-substituted-4'-thioaraU (6a-e) derivatives showed anti-HSV-1 activity (ED50 = 0.43-3.50 micrograms/mL). 4'-ThioaraG (6h) and 2,6-diaminopurine 4'-thioarabinonucleoside (4'-thioaraDAP, 6g) showed antiviral activity against several herpes viruses and were particularly potent against human cytomegalovirus (0.010 and 0.022 microgram/mL, respectively).

Ingenol 3,5,20-triacetate (ITA), one of the ingenol derivatives, is a selective inhibitor of human immunodeficiency virus (HIV) replication in vitro. ITA inhibited the replication of HIV strains in MT-4 cells at concentrations of 0.051 to 0.65 microM. This concentration was approximately 10(3)-fold lower than its cytotoxic threshold. The mechanism of action of ITA is primarily attributed to the inhibition of viral adsorption to the host cells, but it is distinct from the mechanism of inhibition by other adsorption inhibitors.

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We have previously reported that ingenol derivatives are highly potent inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in acutely infected cells. In this study, however, we have found that some ingenol derivatives strongly enhance the replication of HIV-1 in chronically infected cells at nanomolar concentrations. One of the derivatives could activate nuclear factor kappa B (NF-kappa B), a potent inducer of HIV-1 replication, through the activation of protein kinase C (PKC). Whereas another derivative, which affected neither PKC nor NF-kappa B, significantly enhanced HIV-1 replication, suggesting that a PKC-independent mechanism may also exist in ingenol derivative-induced HIV-1 upregulation.

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4-(2,6-Dichlorophenyl)-1,2,5-thiadiazol-3-yl N,N-dialkylcarbamate (TDA) derivatives were found to be highly potent and specific inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in a variety of cell cultures. The most potent congener of TDA derivatives, RD4-2024, inhibited HIV-1 replication by 50% at concentrations of 12.5 and 4.8 nM in MT-4 cells and peripheral blood mononuclear cells, respectively. These concentrations were more than 2,000-and 30,000-fold lower than its 50% cytotoxic concentrations, respectively. Although the TDA derivatives were active against 3-azido-3-deoxythymidine-resistant HIV-1, no antiviral activities were observed against HIV-2 and nonnucleoside reverse transcriptase inhibitor-resistant mutants of HIV-1. The TDA derivatives inhibited recombinant HIV-1 reverse transcriptase activity, depending on the template-primer used for the assay. However, they did not interact with HIV-2 reverse transcriptase. Thus, the TDA derivatives belong to the family of nonnucleoside reverse transcriptase inhibitors. Because of their potent anti-HIV-1 activities in vitro and their low levels of toxicity in mice, the TDA derivatives deserve further evaluation as candidate drugs for the treatment of patients with AIDS.

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