5'-O-ALKYL AND ACYL PRODRUGS OF 1-BETA-D-ARABINOFURANOSYL-E-5-(2-BROMOVINYL)URACIL

5'-O-Alkyl derivatives of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl) uracil (BV-araU) were synthesized by selective alkylation and deprotec tion of 2',3'-bis-O-tetrahydropyranyl BV-araU to enhance metabolic sta bility and evaluated for efficacy as oral prodrugs of BV-araU. For com parison, their acyl congeners, and 3'-O- and 2'-O-ethyl BV-araU, were also prepared by direct acylation of BV-araU and by selective protecti on, alkylation, and deprotection, respectively. The 5'-O-alkyl prodrug s were stable in acidic solutions, whereas the 5'-O-acyl analogues wer e unstable under the same conditions. When incubated with enterobacter ia, the 5'-O-acyl derivatives resulted in the formation of BV-uracil t hrough non-enzymatic hydrolysis of BV-araU, but the 5'-O-alkyl prodrug s did not. 5'-O-Short-chain aliphatic alkyl (not longer than butyl) an d generally acyl prodrugs gave higher blood concentrations of BV-araU than the aromatic derivatives. Plasma concentrations of BV-araU were e qual or slightly higher than those after equivalent oral doses of BV-a raU. 5'-O-Ethyl BV-araU was effective against intracerebral, intraperi toneal, and cutaneous infections with herpes simplex virus type 1 in m ice. 5'-O-Short-chain aliphatic alkyl derivatives may prove to be usef ul oral prodrugs of BV-araU because of increased metabolic stability.