title: Synthesis of adenophostin A analogues conjugating an aromatic group at the 5'-position as potent IP3 receptor ligands.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mochizuki
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Kondo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Abe
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Tovey
authors.forename: Skarlatos G
authors.initials: SG
authors.lastname: Dedos
authors.forename: Colin W
authors.initials: CW
authors.lastname: Taylor
authors.forename: Michael
authors.initials: M
authors.lastname: Paul
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D002460:Cell Line; D002645:Chickens; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; C085029:adenophostin A; D000241:Adenosine; D002118:Calcium