600736-36-5Relevant articles and documents
Probing the activation site of ribonuclease L with new N6-substituted 2′,5′-adenylate trimers
Muench, Ursula,Chen, Ling,Bayly, Suzanne F.,Torrence, Paul F.
, p. 2041 - 2049 (2003)
2-5A trimer [5′-monophosphoryladenylyl(2′-5′)adenylyl (2′-5′)adenosine] activates RNase L. While the 5′-terminal and 2′-terminal adenosine N6-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 N6-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 thisN6-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.
