Bioorg Med Chem 2003 May;11(9):2041-9
Munch U, Chen L, Bayly SF, Torrence PF.
Section on Biomedical Chemistry, Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, MD 20892-0805, Bethesda, USA
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2-5A trimer [5′-monophosphoryladenylyl(2′-5′)adenylyl(2′-5′)adenosine] activates RNase L. While the 5′-terminal and 2′-terminal adenosine N(6)-amino groups play a key role in binding to and activation of RNase L, the exocyclic amino function of the second adenylate (from the 5′-terminus) plays a relatively minor role in 2-5A’s biological activity.
To probe the available space proximal to the amino function of the central adenylate of 2-5A trimer during binding to RNase L, a variety of substituents were placed at that position. To accomplish this, the convertible building block 5′-O-dimethoxytrityl-3′-O-(tert-butyldimethylsilyl)-6-(2,4-dinitrophenyl)thioinosine 2′-(2-cyanoethylN,N-diisopropylphosphoramidite) was prepared as a synthon to introduce 6-(2,4-dinitrophenyl)thioinosine into the middle position of the 2-5A trimer during automated synthesis. Post-synthetic treatment with aqueous amines transformed the (2,4-dinitrophenyl)thioinosine into N(6)-substituted adenosines.
Assays of these modified trimers for their ability to bind and activate RNase L showed that activation activity could be retained, albeit with some sacrifice compared to unmodified p5’A2’p5’A2’p5’A.
Thus, the spatial domain about thisN(6)-amino function could be available for modifications to enhance the biological potency of 2-5A analogues and to ligate 2-5A to targeting vehicles such as antisense molecules.
PMID: 12670655 [PubMed – in process]