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A concise synthesis of five new analogues of the second messenger cADPR (cyclic adenosine 5'-diphosphate ribose) is presented. The synthetic plan centered around the key derivative 8-Br-N1-cIDPR (cyclic 8-Br-inosine 5'-diphosphate ribose, 2), which was prepared in only three steps from IMP (inosine 5'-monophosphate) via an unusual enzymatic cyclization reaction. The enhanced stability of 2 allowed for the direct modification of this cyclic dinucleotide at the 8 position, providing the unsubstituted parent N1-cIDPR (4) as well as the 8-phenyl (5), 8-azido (6), and 8-amino (7) N1-cIDPR analogues. In Jurkat T-lymphocytes, N1-cIDPR 4 induced Ca2+ release with an almost identical profile as the natural agonist cADPR, illustrating the value of this approach.

Original publication

DOI

10.1021/jo050085s

Type

Journal article

Journal

J Org Chem

Publication Date

10/06/2005

Volume

70

Pages

4810 - 4819

Keywords

Animals, Aplysia, Combinatorial Chemistry Techniques, Cyclic ADP-Ribose, Molecular Structure