Publications

The therapeutic efficacy of three new antiviral agents-5-iodo-3',5'-diacetyl-2'-deoxyuridine (diacetylidoxuridine, 1% Ac2IDU), E-5-(2-bromovinyl)-2'-deoxyuridine (0.25% BVDU), and 3% thymine arabinoside-is compared with available antivirals in an experimental model of herpes simplex virus type 1 (HSV-1) keratitis in New Zealand white rabbits. Compared with placebo, Ac2IDU significantly reduced ulcerative keratitis on days 4 through 8 after inoculation with virus and iritis on day 8 after inoculation. Compared with placebo, thymine arabinoside reduced ulcerative keratitis but not significantly. Thymine arabinoside caused significant iritis in all eyes. The epithelial disease in BVDU-treated eyes was significantly less than that in placebo-treated eyes on days 5 through 8 after inoculation. The results indicate that 1% Ac2IDU and 0.25% BVDU were effective in our ocular model of HSV-1 keratitis, whereas thymine arabinoside was not.

Novel 5,6-dichlorobenzimidazole nucleoside analogues structurally related to the well-known riboside DRB have been synthesized. The 1′,2′- trans nucleosides were prepared by condensation of peracylated sugars with 5,6-dichlorobenzimidazole, whereas the 1′,2′- cis β-D-arabinofuranosyl and β-D-lyxofuranosyl nucleosides were obtained by inversion of configuration on the sugar moiety. Chiral acyclic derivatives were stereospecifically prepared by ring-opening of furano- or pyrano-nucleosides by means of periodate oxidation, followed by borohydride reduction. The in vitro activities against a range of DNA and RNA viruses, as well as the cytotoxicities in human T-lymphocyte MT-4 cells, have been determined for these novel compounds and for DRB. No truly selective activity (i.e. clearly below the cytotoxic concentration) was observed against any of the viruses used. Some of the compounds, including DRB, were cytotoxic to MT-4 cells at CC 50 values of less than 10 μg ml −1 .

Starting from 2',5'-di-O-TBDMS-3'-ketouridine 1 or its thymine analogue 2, both xylo (3-10) and ribo (20) epimers of a series of 3"-substituted 3'-spironucleosides have been obtained in good yields and with a total stereoselectivity. Most new compounds were moderately cytotoxic with in some cases slightly selective antiproliferative activities. None of these compounds was active against HIV, but some other antiviral activities against HSV-2, CMV, EBV, or VZV, in the micromolar range, were noted in specific cases.

Abstract The reaction between 3-bromo-5-chloromethylpyridine hydrochloride (4) with the mono sodium salt of ethylene glycol was investigated. 3-Bromo-5-(2-hydroxyethoxymethyl)-pyridine (5) was synthesized and converted to the 3-carboxy analogue using butyllithium and CO2. Subsequent treatment with diazomethane and ammonolysis gave the corresponding acyclic nicotinamide C-nucleosides. The latter compounds were converted into the thioamide analogues by reaction with Lawesson's reagent. The pyridine N-oxide derivatives were obtained by treatment with peracetic acid or hydrogen peroxide. All compounds were identified with the aid of 1H- and 13C-NMR and mass spectrometry. The acyclic pyridine C-nucleosides were evaluated against a number of viral strains and cancer cell lines but no significant biological activity was found.

Abstract For Abstract see ChemInform Abstract in Full Text.

International audience

We have synthesized a modified 6-mer using Hotoda's 6-mer TGGGAG with 5'- and 3'-end modifications as a template. We have replaced from one to all four 2'-deoxyguanosines by 8-aza-3-deaza-2'-deoxyguanosine (c3z8dG, 1) in order to investigate the anti-HIV structure activity relationship (SAR). ODN 4 (TGGG*AG) is the only one that exhibits a moderate anti-HIV-1 activity.