Synthesis of potent agonists of the D-myo-inositol 1,4, 5-trisphosphate receptor based on clustered disaccharide polyphosphate analogues of adenophostin A.
Clustered disaccharide analogues of adenophostin A (2), i.e. mono-, di-, and tetravalent derivatives 6-8, respectively, were synthesized and evaluated as novel ligands for the tetrameric D-myo-inositol 1,4, 5-trisphosphate receptor (IP(3)R). The synthesis was accomplished via Sonogashira coupling of propargyl 2-O-acetyl-5-O-benzyl-3-O-(3, 4-di-O-acetyl-2, 6-di-O-benzyl-alpha-D-glucopyranosyl)-beta-D-ribofuranoside (16) with iodobenzene 18, 22, or 25, followed by deacetylation, phosphorylation, and deprotection. The abilities of the target compounds 6-8, as well as ribophostin 4, propylphostin 5, and IP(3) (1), to evoke Ca(2+) release from permeabilized hepatocytes or displacement of [(3)H]IP(3) from its receptor in hepatic membranes were compared. Although the binding affinities of 4-8 were similar, there were modest though significant differences in their potencies in Ca(2+) release assays: tetraphostin 8 > IP(3) approximately diphostin 7 > phenylphostin 6 > ribophostin 4 approximately propylphostin 5.
de Kort
M
M
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
Correa
V
V
Valentijn
A R
AR
van der Marel
G A
GA
Potter
B V
BV
Taylor
C W
CW
van Boom
J H
JH
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D004187:Disaccharides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008024:Ligands; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000378:metabolism; D012617:Sea Urchins; D013329:Structure-Activity Relationship
D015220:Calcium Channels; D004187:Disaccharides; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; C085029:adenophostin A; D015544:Inositol 1,4,5-Trisphosphate; D000241:Adenosine; D002118:Calcium