Synthesis and Enzymatic Deprotection of Fully Protected 2′‐5′ Oligoadenylates (2‐5A): Towards a Prodrug Strategy for Short 2‐5A

Fully protected pA2′p5′A2′p5′A trimers 1a and 1b have been prepared as prodrug candidates for a short 2′‐5′ oligoadenylate, 2‐5A, and its 3′‐ O ‐Me analog, respectively. The kinetics of hog liver carboxyesterase (HLE)‐triggered deprotection in HEPES buffer (pH 7.5) at 37° has been studied. The deprotection of 1a turned out to be very slow, and 2‐5A never appeared in a fully deprotected form. By contrast, a considerable proportion of 1b was converted to the desired 2‐5A trimer, although partial removal of the 3′‐ O ‐[(acetyloxy)methyl] group prior to exposure of the adjacent phosphodiester linkage resulted in 2′,5′→3′,5′ phosphate migration and release of adenosine as side reactions.