ENZYMATIC-SYNTHESIS OF 2'-O-ACYL PRODRUGS OF BETA-D-ARABINOFURANOSYL)-5(E)-(2-BROMOVINYL)URACIL AND OF 2'-O-ACYL-ARAU, 2'-O-ACYL-ARAC AND 2'-O-ACYL-ARAA

Pig liver esterase (EC 3.1.1.1) catalysed regioselective hydrolysis of -(2,3,5-tri-O-acyl-beta-D-arabinofuranosyl)uracil, -cytosine and -ade nine to give the corresponding 2'-monoesters effectively and in high y ield. This methodology enabled the preparation of a-D-arabinofuranosyl )-5-[(E)-(2-bromovinyl)]uracil prodrugs which, although slightly less active than the parent 1-(beta-D-arabinofuranosyl)-5(E)-(2 bromovinyl) uracil (sorivudine; BV-araU), were strongly active in vitro against va ricella-zoster virus (ED50 2.4-45 ng/ml). The retarded rates of enzyma tic hydrolysis of the 2'-esters imply that they might function as lipo philic prodrugs, leading to increased plasma and cellular concentratio ns. In view of the marked in vitro activity, they represent an interes ting approach to arabinofuranosyl nucleoside prodrugs with improved ph armacokinetics and enzymatic stability.