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Previous structure-activity relationship studies of adenophostin A, a potent IP(3) receptor agonist, led us to design the novel adenophostin A analogues 5a-c, conjugating an aromatic group at the 5'-position to develop useful IP(3) receptor ligands. The common key intermediate, a D-ribosyl alpha-D-glucoside 10alpha, was stereoselectively synthesized by a glycosidation with the 1-sulfinylglucoside donor 11, which was conformationally restricted by a 3,4-O-cyclic diketal protecting group. After introduction of an aromatic group at the 5-position of the ribose moiety, an adenine base was stereoselectively introduced at the anomeric beta-position to form 7a-c, where the tetra-O-i-butyryl donors 9a-c were significantly more effective than the corresponding O-acetyl donor. Thus, the target compounds 5a-c were synthesized via phosphorylation of the 2', 3' ', and 4' '-hydroxyls. The potencies of compounds 5a-c for Ca(2+) release were shown to be indistinguishable from that of adenophostin A, indicating that bulky substitutions at the 5'-position of adenophostin A are well-tolerated in the receptor binding. This biological activity of 5a-c can be rationalized by molecular modeling using the ligand binding domain of the IP(3) receptor.

Original publication

DOI

10.1021/jm060310d

Type

Journal article

Journal

J Med Chem

Publication Date

21/09/2006

Volume

49

Pages

5750 - 5758

Keywords

Adenosine, Animals, Calcium, Calcium Channels, Cell Line, Chickens, Inositol 1,4,5-Trisphosphate Receptors, Ligands, Models, Molecular, Molecular Conformation, Rats, Receptors, Cytoplasmic and Nuclear, Recombinant Proteins, Stereoisomerism, Structure-Activity Relationship