Enzymatic Synthesis of 2′-O-acyl Prodrugs of 1-(β-D-arabinofuranosyl)-5(E)-(2-bromovinyl)uracil and of 2′-O-acyl-araU, -araC and -araA

Abstract

Pig liver esterase (EC 3.1.1.1) catalysed regioselective hydrolysis of 1-(2,3,5-tri-O-acyl-β-D-arabinofuranosyl)uracil, -cytosine and -adenine to give the corresponding 2′-monoesters effectively and in high yield. This methodology enabled the preparation of 1-(2-O-acyl-β-D-arabinofuranosyl)-5-[( E)-(2-bromovinyl)]uracil prodrugs which, although slightly less active than the parent 1-(β-D-arabinofuranosyl)-5(E)-(2 bromovinyl)uracil (sorivudine; BV-araU), were strongly active in vitro against varicella-zoster virus (ED50 2.4–45 ng/ml). The retarded rates of enzymatic hydrolysis of the 2′-esters imply that they might function as lipophilic prodrugs, leading to increased plasma and cellular concentrations. In view of the marked in vitro activity, they represent an interesting approach to arabinofuranosyl nucleoside prodrugs with improved pharmacokinetics and enzymatic stability.