Branched-chain C-cyano pyranonucleosides: Synthesis of 3′-C-cyano & 3′-C-cyano-3′-deoxy pyrimidine pyranonucleosides as novel cytotoxic agents

This report describes the total and facile synthesis of 3′-C-cyano & 3′-C-cyano-3′-deoxy pyrimidine pyranonucleosides. Reaction of 3-keto glucoside 1 with sodium cyanide gave the desired precursor 3-C-cyano-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (2). Hydrolysis followed by acetylation led to the 1,2,3,4,6-penta-O-acetyl-3-C-cyano-D-glucopyranose (4). Compound 4 was condensed with silylated 5-fluorouracil, uracil, thymine and N(4)-benzoylcytosine, respectively and deacetylated to afford the target 1-(3′-C-cyano-β-D-glucopyranosyl)nucleosides 6a–d. Routine deoxygenation at position 3′ of cyanohydrin 2, followed by hydrolysis and acetylation led to the 3-C-cyano-3-deoxy-1,2,4,6-tetra-O-acetyl-D-allopyranose (10). Coupling of sugar 10 with silylated pyrimidines and subsequent deacetylation yielded the target 1-(3′-C-cyano-3′-deoxy-β-D-allopyranosyl)nucleosides 12a–d. The new analogues were evaluated for their antiviral and cytostatic activities. It was found that 6a was endowed with a pronounced anti-proliferative activity that was only 2- to 8-fold less potent than that shown for the parental base 5-fluorouracil. None of the compounds showed activity against a broad panel of DNA and RNA viruses.