5′-O-Alkyl and Acyl Prodrugs of 1-β-D-Arabinofuranosyl-E-5-(2-Bromovinyl)Uracil

Abstract

5′- O-Alkyl derivatives of 1-β-D-arabinofuranosyl- E-5-(2-bromovinyl)uracil (BV-araU) were synthesized by selective alkylation and deprotection of 2′,3′-bis- O-tetrahydropyranyl BV-araU to enhance metabolic stability and evaluated for efficacy as oral prodrugs of BV-araU. For comparison, their acyl congeners, and 3′- O- and 2′- O-ethyl BV-araU, were also prepared by direct acylation of BV-araU and by selective protection, alkylation, and deprotection, respectively. The 5′- O-alkyl prodrugs were stable in acidic solutions, whereas the 5′- O-acyl analogues were unstable under the same conditions. When incubated with enterobacteria, the 5′- O-acyl derivatives resulted in the formation of BV-uracil through non-enzymatic hydrolysis of BV-araU, but the 5′- O-alkyl prodrugs did not. 5′- O-Short-chain aliphatic alkyl (not longer than butyl) and generally acyl prodrugs gave higher blood concentrations of BV-araU than the aromatic derivatives. Plasma concentrations of BV-araU were equal or slightly higher than those after equivalent oral doses of BV-araU. 5′- O-Ethyl BV-araU was effective against intracerebral, intraperitoneal, and cutaneous infections with herpes simplex virus type 1 in mice. 5′- O-Short-chain aliphatic alkyl derivatives may prove to be useful oral prodrugs of BV-araU because of increased metabolic stability.