The nucleoside analog 2,4-diamino-7-(2-deoxy-2-fluoro--D-arabinofuranosyl)pyrrolo[2,3-d]pyrimidine (T70080) and several related compounds were evaluated for anti-hepatitis B virus (HBV) activity by using cultured 2.2.15 cells. T70080 reduced episomal viral replication in these cells by 50% at a concentration of 0.7 g/ml. At the same time, T70080 reduced cellular proliferation by 50% at a concentration in excess of 100 g/ml, yielding a therapeutic index of >143. In cells cultured for 12 days in the presence of 10 or 50 g of T70080 per ml and then with drug-free medium, for an additional 12 days, viral DNA replication was completely inhibited initially but resumed between 6 and 12 days post-drug removal. In view of the potent anti-HBV activity shown, T70080 is a good candidate for further evaluation as a treatment of human HBV infection.
Tumor necrosis factor alpha (TNF alpha), a polypeptide produced by activated macrophages, is a highly pleiotropic cytokine which elicits inflammatory and immunological reactions. The binding of TNF alpha to tumor necrosis factor receptor type I (TNFRI) is considered the initial step responsible for some of the multiple biological functions mediated by TNF alpha. The role of TNF alpha as an inflammatory mediator through human TNFRI makes TNFRI an attractive target for intervention in both acute and chronic inflammatory diseases. In this study, we have identified partial phosphorothioate oligodeoxyribonucleotides (ODNs) containing C-5 propynyl or hexynyl derivatives of 2'-deoxyuridine which specifically inhibited TNFRI and subsequently inhibited the functions of TNF alpha mediated through TNFRI. The most active ODNs were directed against the 3'-poly adenylation signal site on the TNFRI mRNA, and in a cellular assay, gene-specific antisense inhibition occurred in a dose-dependent fashion at submicromolar concentrations, in the presence of Cellfectin. The inhibition of gene expression correlated with the binding affinity of the ODN for the target mRNA. The ODNs lowered TNFRI protein levels and TNF alpha-mediated functions by specifically reducing levels of TNFRI mRNA. These anti-TNFRI ODNs offer a novel approach for controlling biological functions of TNF alpha and may be useful as human therapeutic agents for treating diseases in which TNF alpha has been implicated.
The preparation of 2‐penten‐1‐yl and 3‐methyl‐2‐buten‐1‐yl derivatives of adenine 2a,b, 7‐deazaadenine 2c,d, 2‐aminopurine 4a,b and 5a,b, 4‐aminopyrazolo[3,4‐d]pyrimidine 7a,b and 7‐amino‐v‐triazolo‐[4,5‐d]pyrimidine 8a–10a and 8b‐10b is described. The synthesis of compounds 2a‐d was accomplished by the functional group transformation reaction, whereas the synthesis of 4a‐8a and 4b‐8b was performed by the alkylation of the sodium salt of the heterocycles with alkenyl bromides. These alkenyl derivatives prepared as congeners of pentoxifylline (methylxanthine) were evaluated for their anti‐tumor necrosis factor a activity in human monocytic leukemia cells. Only compounds 7a and 7b exhibited significant activity and a poor toxicity profile in this assay. In peripheral blood mononuclear cells, compounds 7a and 7b, inhibited tumor necrosis factor a production in a dose dependent manner.
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