Stereochemical influence on lipase-mediated hydrolysis and biological activity of stampidine and other stavudine phosphoramidates

Stampidine and other halogen substituted stavudine phosphoramidates can be activated by lipase-mediated hydrolysis. The target site for the lipase appears to be the methyl ester group of the L-alanine side chain. Accordingly, the D isomers are resistant to lipase-mediated hydrolysis and exhibit substantially less anti-HIV activity. Molecular modeling results indicate that L-configured isomer and not D is preferred in the lipase binding pocket.