Synthesis of adenophostin A analogues conjugating an aromatic group at the 5'-position as potent IP3 receptor ligands.
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.
Mochizuki
Tetsuya
T
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Kondo
Yoshihiko
Y
Abe
Hiroshi
H
Tovey
Stephen C
SC
Dedos
Skarlatos G
SG
Taylor
Colin W
CW
Paul
Michael
M
Potter
Barry V L
BV
Matsuda
Akira
A
Shuto
Satoshi
S
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
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