Synthesis and antiviral activity of a series of 1'-substituted 4-aza-7,9-dideazaadenosine C-nucleosides

Abstract

A series of 1'-substituted analogs of 4-aza-7,9-dideazaadenosine C-nucleoside were prepared and evaluated for the potential as antiviral agents. These compounds showed a broad range of inhibitory activity against various RNA viruses. In particular, the whole cell potency against HCV when R=CN was attributed to inhibition of HCV NS5B polymerase and intracellular concentration of the corresponding nucleoside triphosphate.

Graphical abstract

Scheme 1

Reagents and conditions: (a) 1,1,4,4-tetramethyl-1,4-dichlorodisilylethylene (1.2 equiv), NaH (2.2 equiv, 60% mineral oil), n-BuLi, (3.3 equiv), THF, −78 °C followed by addition of 5, 1 h, 60%; (b) TMSCN (4 equiv), BF₃·OEt₂ (3 equiv), CH₂Cl₂, −78 °C, 5 h, 58% (85:15 β/α) 7a; AlMe₃ (5 equiv), BF₃·OEt₂ (4 equiv), CH₂Cl₂, 0 °C, 12 h, 45% (1:1 β/α) 7b; vinyl magnesium bromide (6 equiv), THF, 0 °C to rt, 2 h, and then methanesulfonic acid (cat.), CH₂Cl₂, rt, 3 h, 85% (1:1 β/α) 7c; ethynyl magnesium chloride (6 equiv), THF, 0 °C to rt, 2 h, and then methanesulfonic acid (cat.), CH₂Cl₂, rt, 3 h, 65% (2:1 β/α) 7d; (c) BCl₃ or BBr₃(4–8 equiv), CH₂Cl₂, −78 °C, 1 h.