Crystal structure and anti herpes simplex virus activity of 2,2'-anhydro-1-beta-D-arabinofuranosylthymine

1-beta-D-Arabinofuranosylthymine (aThy; ara-T) is a potent selective anti herpes simplex virus drug. Its anhydro analogue, 2,2'-anhydro-aThy, was shown to be 9-fold less active and at least 3-fold less toxic than aThy. This compound was relatively stable at physiological pH and in strong acid but was rapidly hydrolyzed in base with a half-life of 18.3 min. The three-dimensional crystal structure of 2,2'-anhydro-aThy revealed a rigid structure with the arabinose ring in the unusual O1' endo, pucker, conformation. The trans-gauche conformation along the C4'-C5' bond permits only intermolecular hydrogen bonding of the 5'-hydroxy and O3'.