2'-Fluorinated arabinonucleosides of 5-(2-haloalkyl)uracil: synthesis and antiviral activity

Abstract
The synthesis of 5-(2-fluoroethyl)-2''-deoxyuridine (FEDU, 4b), its 2''-fluoro analogs 1-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)-5-(2-fluoroethyl)-1H,3H-pyrimidime-2,4-dione (FEFAU, 4k), and the 2''-fluoro analogue of the potent antiherpes virus compound 5-(2-chloroethyl)-2''-deoxyuridine (CEDU), 5-(2-chloroethy)-1-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)-1H,3H-pyrimidine-2,4-dione (CEFAU, 4i), is described. The antiviral activities of these compounds were determined in cell culture against herpes simplex virus (HSV) types 1 and 2 and varicella zoster virus (VZV). All compounds were shown to possess significant and selective antiviral activity. FEDU proved less potent than CEDU against VZV replication; however, it was more active against HSV-2. CEFAU showed marked activity against HSV-1, HSV-2, and VZV. The compound containing fluorine at both positions, FEFAU, exhibited the strongest antiviral potency against HSV-1, HSV-2, and VZV. It inhibited HSV-1 at a concentration of 0.03-0.2 .mu.g/ml, HSV-2 at -0.1-0.3 .mu.g/mL, and VZV at 0.03 .mu.g/mL. Neither FEDU nor CEFAU or FEFAU exerted a significant inhibitory effect on cell proliferation at a comcentration of100 .mu.g/mL. Thus, the cytotoxicity of these compunds is as low as that of CEDU and compares favourably to that of previously described 2''-fluoroarabinosyl nucleoside analogues.

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