Synthesis and antiviral activity of pyranosylphosphonic acid nucleotide analogues.

Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.

Synthesis and antiviral activity of pyranosylphosphonic acid nucleotide analogues.

J Med Chem. 1996 Mar 15;39(6):1321-30. Unique Identifier : AIDSLINE MED/96251036
Alexander P; Krishnamurthy VV; Prisbe EJ; Gilead Sciences, Inc., Foster City, California 94404, USA.

Abstract: Pyranosyl nucleotide analogues have been designed so that the intramolecular base to phosphorus distance closely approximates that of natural nucleotides. This was achieved by attaching the phosphorus directly at the anomeric position and the base at the 4-position of the carbohydrate. A series of compounds incorporating natural bases and having this novel structure were made via a short synthesis starting from commercially available glycals. Addition of triisopropyl phosphite to the glycals furnished alpha- and beta-2-enopyranosylphosphonates which were then substituted with the heterocycle using Mitsunobu chemistry. Deprotection afforded the 2',3'-unsaturated isonucleotide analogue. In some cases the deprotection sequence induced double-bond migration leading to the 1',2'-unsaturated derivative. NMR spectroscopic structural analysis established an axial preference for the base and an equatorial preference for the beta-phosphorus which results in intramolecular base to phosphorus distances within 1 A of that of natural nucleotides. All of the deprotected compounds were screened for inhibition of HCMV, HSV-2, and HIV replication. Several compounds inhibited HCMV and HSV-2, the most potent of which was the unsaturated cytosine analogue 18 (HCMV IC50 = 10 microM, HSV-2 IC50 = 85 microM). None of the compounds were cytotoxic at the highest dose (1 mM) tested. None of the compounds were inhibitory to HIV.

Keywords: Antiviral Agents/CHEMISTRY/*CHEMICAL SYNTHESIS/PHARMACOLOGY Cytomegalovirus/DRUG EFFECTS Herpesvirus 2, Human/DRUG EFFECTS Nucleotides/*CHEMICAL SYNTHESIS/PHARMACOLOGY JOURNAL ARTICLE
960930
M9690901

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