Synthesis and Enzymatic Deprotection of Fully Protected 2′‐5′ Oligoadenylates (2‐5A): Towards a Prodrug Strategy for Short 2‐5A |
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| Authors: | Emilia Kiuru Mikko Ora Leonid Beigelman Lawrence Blatt Harri Lönnberg |
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| Affiliation: | 1. Department of Chemistry, University of Turku, FIN‐20014 Turku, (phone: +358‐2‐333 6780;2. fax: +358‐2‐333 6776);3. AliosBiopharma, 260 E. Grand Ave, 2nd Floor, South San Francisco, CA 94080, USA, (phone: +1‐650‐635 5500;4. fax: +1‐650‐872 0584) |
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| Abstract: | 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. |
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| Keywords: | Oligoadenylate Oligonucleotides Prodrugs Protecting groups Hog liver carboxyesterase |
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