Branched-chain sugar nucleosides: stereocontrolled synthesis and bioevaluation of novel 3′-C-trifluoromethyl and 3′-C-methyl pyranonucleosides

• Synthesis of 3′-C-CF3 and 3′-C-CH3 nucleosides.
• Molecular Dynamics calculations.
• 3′-Deoxy-3′-C-CH3 ribonucleoside exhibited significant cytotoxic activity (∼7 μM).

A new series of 3′-C-trifluoromethyl- and 3′-C-methyl-β-d-allopyranonucleosides of 5-fluorouracil and their deoxy derivatives has been designed and synthesized. Treatment of ketosugar 1 with trifluoromethyltrimethylsilane under catalytic fluoride activation and methyl magnesium bromide, gave 1,2:5,6-di-O-isopropylidene-3-C-trifluoromethyl (2a) and 3-C-methyl (2b)-α-d-allofuranose, respectively, in a virtually quantitative yield and with complete stereoselectivity. Hydrolysis followed by acetylation led to the 1,2,4,6-tetra-O-acetyl-3-C-trifluoromethyl (3a) and 3-C-methyl (3b)-β-d-allopyranose. Compounds 3a,b were then condensed with silylated 5-fluorouracil and deacetylated to afford the target nucleosides 5a,b. Deoxygenation of the peracylated allopyranoses 3a,b followed by condensation with silylated 5-fluorouracil and subsequent deacetylation yielded the target 3′-deoxy-3′-C-trifluoromethyl and 3′-deoxy-3′-C-methyl-β-d-glucopyranonucleosides 14a,b. The newly synthesized compounds were evaluated for their potential antiviral and cytostatic activities. The 3′-deoxy-3′-C-methyl- ribonucleoside 11b showed significant cytotoxic activity (∼7 μM) almost equally active against a variety of tumor cell lines.

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